It's with great pleasure that I'd like to welcome the CEO of CRISPR Therapeutics, Sam Kulkarni. Thanks so much for joining us today, Sam. We're gonna do fireside chat format. So maybe to start off, for those who are new to the story, if you can give a one-minute intro to the platform and programs.
Well, thank you for having us here today, Maury. It's been a great 10 years at CRISPR. You know, in the decade that's passed, we formed the company after elucidation of the technology by Emmanuelle Charpentier and Jennifer Doudna, and we've rapidly translated this technology into what's today a commercially available product in the form of Casgevy for treating severe sickle cell disease and severe beta thalassemia. And the data are quite remarkable and speaks to the power of the platform, of the platform and the technology.
But what's also been... What we're very proud of, is that we parlayed this platform into a number of other disease areas. Where we stand today, we have five programs in the clinic across seven clinical trials, and we have 10 preclinical programs that we've also announced, and many more beyond that, as we build a sustainable R&D engine that hopefully becomes a sustainable biotech company over the long run.
Got it. Yeah, it's a great intro, and we'll definitely dive into the platform and how CRISPR-Cas9 is being leveraged at the company. Maybe to start off, you do have the commercial product with Vertex, where there's a lot of interest in that. Maybe talk about just how launch metrics are looking there, with 25 of 75 worldwide centers activated. Then, it was also mentioned that there were five patients where you've had cell collection there. Can you talk about what you're hearing from the sites as well, from the treating physicians?
Yeah. For those who are not familiar with Casgevy, this is a product where it's an ex vivo cell therapy product. We take patients' cells, edit them using CRISPR-Cas9 to produce fetal hemoglobin, and the elevated fetal hemoglobin makes up for the deficiency or defectiveness of the adult beta globin. And this was an approach that you know was pioneered over years of research. But ultimately, I think we, we've shown remarkable data with our CRISPR-Cas9 editing with these ex vivo cells. We've done this together with our partner, Vertex. The relationship we have with Vertex is a 60/40 relationship. We have 40% of the asset. We own 40% of the asset and effectively get 40% of all the profits globally.
And Vertex is responsible right now for the global commercialization of the, of the product, and we're very proud to have Vertex as a partner to lead the charge with their tremendous expertise and experience they have with rare diseases. So what, what are we seeing? You know, I think, Vertex has been providing updates around center activation, and patient cell, number of patients whose cells have been collected. Those are the two most important metrics for those who are looking to either model the launch or see where, what the trajectory looks like. Because I think what you have is a compounding effect. You know, as you get more centers online, and they all learn to have more patients go through the therapy, you're gonna see greater productivity in each ATC as well.
So you will see greater number of patient cells collected as we go through the next few quarters here. And then it takes. There's a bit of time lag between patient cells collected, where we manufacture it, and ultimately dose the patients. But that's just more of a delay in revenue recognition because, you know, almost all patients whose cells get collected eventually, in our clinical trials, went on to get treated with the drug. So, you know, what am I hearing?
Again, these are, you know, comments that Vertex have made as well, which is from all the centers that are activated and the physicians, we're hearing that, you know, an overwhelming majority of the patients wanna get a CRISPR-based approach versus a different approach if both options are available. Ex-U.S., CRISPR approach is the only option available. For these severe patients who have, you know, chronic pain, acute crises, they end up in the hospital all the time. A lot of them don't wanna wait, you know? There's... They wanna get on therapy as soon as they can. So we're seeing a groundswell of interest across the U.S. and outside the U.S. for this transformative therapy.
Got it. That's helpful. Do you have a sense of what these patients look like, these early adopters? Are they similar to your Phase III, or is it potentially a broader patient population, maybe even from less severe patients?
Yeah, it's actually... You know, this is a question we get a lot, which is, what subsegment of patients are more likely to get Casgevy before others? And it's actually very hard to, you know, put it in a bucket. You know, there are patients, you know. It's an N of one when it comes to different patients. Each of them have a different comorbidity they're dealing with in sickle cell. You know, some have lung complications, others have stroke risk, et cetera. So I think, you know, it's a function of which patients are very severe with different comorbidities and who's gonna raise their hands to say, "I wanna get.
You know, I wanna take a chance on a one-and-done therapy to be cured for life." And, some who are more educated than others, will come forth earlier because they understand the therapy, they understand it's safe, it's FDA-approved, and, and it's gone through all the rigorous testing. So I think, I think you, you know, it's hard to say if a certain type of patient is gonna be the predominant patient that's gonna be treated first. But, but again, we're seeing a lot of interest across the board.
Got it. Okay, and in the patient journey brochure, it says it could take five to six months to get the treatment. Is there room? What are the rate-limiting steps there, and is there room to optimize and make the process more efficient?
Absolutely, there's always room to optimize the, you know, how quickly we release the product, how quickly we get it back to the center. But typically, the time lag is not always based on our operations. It's based on, you know, this is an elective procedure, so the patient typically decides that they wanna get dosed during a certain window of time, where they may have a break from their job, or they may have family to support them, whatever else. So it's similar to, you know, some of the medical procedures people go through.
They wanna pick a window of time where you may be, you know, away from your work, for instance, for three or four weeks, or, you know, you may be in the hospital. So, yes, there's opportunity to improve, but it won't matter in a way. You know, it only matters in the early going. Once you start getting more patients into the funnel, that timeline won't matter in terms of what we see as more patients getting treated and how often they get treated, how quickly you get more patients treated.
Got it. Makes sense. We've talked about the different regions where Casgevy is approved, and it's approved in a couple of countries in the Middle East, which could be underappreciated. Just wondering if you could talk about the market opportunity there, and provide insights into pricing, and clarify how medical tourism could work with this therapy.
Yeah, I mean, this has been something we were keenly aware of, the opportunity. You know, as CRISPR, we did trips to Saudi Arabia back in 2018, for instance, because there were the number of patients that suffer from severe sickle cell disease is. You know, it's not well documented and well, it's not a good data source for it, but it felt to us like there was probably even more patients than the U.S. And recall that, you know, a lot of the, the reason why sickle cell is so prevalent is because it had a protective effect against malaria.
So there were, there are regions, both in the on the west coast of Saudi Arabia, the south, where there was, you know, malaria is still prevalent, and malaria is still a big killer. And so you end up with very high prevalence of sickle cell trait, which leads to high prevalence of sickle cell disease. And so you have markets where there are a number of patients. These systems have the ability to pay for these types of therapies, and it's not just Saudi or Bahrain, there's other markets there as well. And I would point to Asia as well, you know.
Now, it's different in Asia, where it's not like there's gonna be insurance coverage for every person in the population or every patient in the population, but you're gonna have a subset of patients where they're gonna have that ability to pay for it. So we're looking at every way to get the medicine to these patients. But, you know, right now, the U.S. is a primary focus for us as well. We wanna make sure the launch goes well in the U.S.
Got it. Okay, makes sense. And, I think let's, shift gears to your in vivo programs, where, you're moving pretty quickly with those, with the two in vivo gene editing programs that you're now in the clinic with. And so you've got CTX310 for ANGPTL3 and then CTX320 for Lp(a). Is there potential to see initial clinical data this year from either of these programs, and what could that entail in respect to number of patients and amount of follow-up?
Yeah, I think, you know, for those who are not familiar with these programs, chronologically, they fall later in our pipeline, but, you know, from a time to data perspective, could go very quickly. These are validated cardiovascular risk factors. You know, there is 11 million people with very high Lp(a) in the U.S. alone. 11 million, so it's a huge market. And all of them have greater susceptibility to cardiac events at pretty young ages. You know, there's people in their thirties who get heart attacks if you have very high Lp(a). And what we're talking about is a one-shot approach using an LNP to deliver the CRISPR-Cas9 with one injection in the vein that could knock down your Lp(a) by 80% for the rest of your life.
And could that-- You know, the outcomes, correlation has to be established yet, but it could be that, if the siRNA trials work out, or the ASO trials have established the outcomes, you know, what you could have is something that could be transformative for this population. ANGPTL3 is more of a rare disease. You know, while the target's well-validated, and it could be applicable to a broader population for LDL reduction.
W e're developing it in a way in these smaller segments of population, where we don't think we need outcomes trials, and we can actually get it to approval, quite rapidly, just based on how the development has gone for drugs like Evkeeza, which also target ANGPTL3 with an antibody. So, you know, we're quite excited about moving these LNP based programs forward. We haven't guided to data. We surely will have data this year, but we just wanna get to a certain threshold of data before we disclose it.
Got it. Yeah, it's, it's interesting, and, I cover Alnylam. They've got a big readout coming soon, and there's a lot of discussion around the derivative read-through from that HELIOS-B readout to other companies in the space. When we see the first outcomes data from the Lp(a) program next year, how is that gonna impact other companies in the space? As far as CRISPR, I'm guessing that investors will probably looking for other players. Will you potentially have data by that point, you think?
Yeah, it'll be a less complex equation. I think if the data are good, it'll help everybody because... You know, the HELIOS data readout is very complicated because you have the silencer versus stabilizer and the, the question of what's better and how to combine. So it's a very complex, you know, scenario analysis, if you will. But for Lp(a), I think just if you see positive correlation shown by Intellia, I think it'll read through positively to everyone's doing Lp(a) knockdown.
Yeah, makes sense. For the types of patients that are being enrolled into that, the Amgen, Arrowhead study and the Novartis Ionis, Lp(a) studies, are there specific questions you're aiming to answer strategically in your initial readout besides Lp(a)?
Yeah, absolutely. I think that one of the big questions we're, you know, one of the things we wanna look at is the levels of Lp(a) and how the subsegments read out in terms of outcomes. Because, you know, the cutoff, you know, the Novartis studies are around 150- 175. I think the Arrowhead cutoff is somewhere similar with Amgen and Arrowhead. But the subpopulation analysis for people with Lp(a) above 200 or 225, I think those levels are gonna be really important because we'd wanna start in a more severe population eventually to try to get approved, and I bet you'll see a stronger correlation in the higher the Lp(a) is.
Got it. Makes sense. And, for Intellia as a gene editing company in this space with in vivo gene editing, what have you learned from their approach when it comes to optimizing the mix or ratios of gene editing materials you want to deliver to a liver cell?
Yeah, I think there have been a few learnings in the last three years for gene editing based on what Intellia have done and some other data readouts. Firstly, you know, I think typically with all other modalities, when you went from non-human primates to humans, you saw some benefit in terms of dosing based on allometric scaling. That was typically in the 2x-3x regime, not a 5x-10x regime. But with Intellia's initial data readout on TTR, what it showed is that for gene editing, because you're using a human-targeted guide against human genetics, you get an even greater benefit going from you know, monkey dosing levels to humans. So we've shown very good preclinical data with our non-human primate studies, and we have to see how it translates to humans.
But we expect, if things play out the way it did for Intellia, that we'll have the same benefit, right? The second is, I think everybody assumed that because LNP delivery to the liver worked out for CRISPR-Cas9, it would work out for base editing, and it would work out for any other form of advanced editing. It's not always the case because the payload is different, so you have a different charge balance, you have a larger mRNA, you may have a different ratio of guides.
So, you know, it may not work for every editing approach if it's not standard CRISPR-Cas9. So, we're trying to do everything as similar as we can to Intellia. It's a different LNP, of course, and we may have a more potent LNP. Let's see where the data come out, but we don't expect the therapeutic window to be different from what Intellia have seen.
Got it. Okay, and let's talk about competition as it relates to these two assets, and also the appeal of having a one-time treatment and ultimately, how you view positioning in the commercial landscape.
Yeah, I think, I think, you know, it's hard to have a crystal ball to see how the world's gonna evolve, but the paradigm of medicine's gonna change. You know, we're gonna have this mix between small molecules, antibodies, RNA therapies, whether it's ASOs or siRNA, and gene editing. And, you know, we get questions all the time: "Why would anyone do gene editing if there is a once every three or every six month siRNA?" And, you know, you could do a survey right now, but that survey is today. You know, if you did a survey on sickle cell disease and said, "Do you want gene editing for sickle cell?" six years ago, you got a very small percentage response. But today, you'll get, you know, a third of the patients you survey saying, "You know, I'll try it," right?
So the world changes as you have more data, and so it makes a lot of sense to think that the world's gonna evolve to a place, if the data are safe, where it's one and done. Now, what may happen is, you may get this polarizing effect where you have people who like taking the once-a-day pill and people who like the one and done, at the cost of some of the biweekly antibodies or every three-month siRNA. So, you know, open question, I don't think it's gonna be winner take all. It's gonna be based on preferences, but I'm pretty excited about the role that gene editing can play across a host of common diseases and rare diseases.
Got it. And you also have a couple other gene editing programs and capabilities as well. And you've recently shown preclinical data targeting the eye and additional programs, including your 340 program targeting AGT in refractory hypertension and 450 targeting ALAS1 for acute porphyria. Both targets are validated by Alnylam's RNAi. Maybe talk about the timelines for entering the clinic and then more broadly on your next-gen editing capabilities.
Yeah, I mean, we're trying to move beyond liver with LNP delivery and demonstrating that in the eye, the front of the eye with myocilin editing for glaucoma was a nice milestone, and that could move very quickly. You know, because you don't have to deal with systemic tox studies for LNP, it's very localized, it's very accessible for an injection, it's one time, and I think these patients really don't have much options. You know, you can do surgery for glaucoma, but, you know, just taking eye drops doesn't work for these genetically defined glaucoma patients, where you see deterioration over the course of years, and many of them turn blind. The other two targets, angiotensinogen for refractory hypertension, and ALAS1 for, what we—it's acute—it's a type of acute hepatic porphyria.
They're very different profiles, you know, so one may question what the logic is in going after one that's a more common indication versus rare. But, you know, what we're trying to do is to say: Where is there very strong biological validation? Because we don't want to stack biological risk on top of technical risk and a very, you know, where we're first movers from a gene editing standpoint, from a competitive standpoint, you know, share perspective, and both of these fit really well. You know, angiotensinogen has been validated by siRNA, and, you know, we could do the same with gene editing. And, you know, at first glance, you'd say: Why would you do gene editing for hy- for hypertension? What if you overshoot?
But you know, these patients that have refractory hypertension or treatment-resistant hypertension, they're on, like, five pills a day trying to control their blood pressure. So if you can give them baseline support with editing, then they may not have to take five pills. They may take one pill or two pills or maybe no pills, right? So there's a lot of titration you can do beyond the gene editing, but this is the only way you can actually control their blood pressure. And the second is with ALAS1, this is a condition that typically affects a lot of middle-aged women, early to middle-aged women who have severe GI pain, you know, often underdiagnosed, or other pain associated with a defectiveness in the heme biosynthesis pathway.
And this edit, ALAS1, has been demonstrated by an approved siRNA product to be effective, yet the approved siRNA product is a once a month injection, which comes with ALT/AST elevation, which, you know, younger people may not want for the rest of their lives. So, I think, again, it provides a more elegant solution. So what-- that's why I said, you know, we have.
This is just a start. You know, once you unlock these scalable modules of, you know, delivery with LNP to the liver, we have five or six programs behind it. Once we unlock correction of genes in the liver, we have five or six programs behind it. And so these modules are gonna open up. Once we get LNP delivery to the eye, we can have multiple programs behind it. You know, I wouldn't be surprised if we have 15 programs in the clinic by 2027 or 2028.
Got it. Interesting, and maybe let's shift gears in the last couple of minutes to your CAR T IO program. For your CD19 program, 112, you've guided to interim data this year, and for the program, you have the RAG1 and the TGF- beta knockouts in it. So how are you setting expectations when it comes to clinical efficacy, such as responses and six-month CR rate?
Yeah. We're developing CTX112, which is a CD19-directed allo CAR T, and both in oncology and autoimmune indications. And I am very confident at this point that we probably have the most potent allogeneic CAR T or CAR NK cell, you know, the class of effector immune cells in the entire industry. And so we're now developing it in oncology, in large B-cell lymphomas. We expect to have data by the end of this year, which you know, we may not have all the durability data, but you'll at least have a comparison to the first-generation program, CTX110. And then we also are starting trials in autoimmune, where we wanna dose patients with SLE and you know, the more severe lupus nephritis patients in particular.
We may not have a lot of data this year, but we'll may accrue some data, but we're probably gonna disclose the data next year. So, very exciting on the CAR T front. You know, we're also manufacturing it ourselves with very low cost of goods, make it antibody-like cost of goods, which is a major breakthrough for us, going from where we started, to reduce our cost of capital and reduce the, you know, capital outlay that we need against these programs. So we can do large trials, and we have all the inventory needed to do 300-400 patient trials.
For autoimmune, is your strategy any different from some of the other autoimmune CAR T players?
Yeah, we're gonna start with the standard lymphodepletion as opposed to tinkering with that up front. We wanna, we may eventually change that, but we wanna start with what's shown to be working in the CAR T space, and we wanna show a few durable responses, and then from there, we can go and optimize that conditioning.
Got it. You mentioned your CAR T is the most potent versus the others. Is it one factor that makes it that way, or is it kind of the multivariable?
It's these edits. The RAG1 edit is a very interesting edit. It makes the cells more naive and central memory phenotype, at the same time, making it more cytotoxic with the cytokine profile that it releases. So it's a, it's a very interesting edit that we're gonna learn more about as we put this into the, into the clinic, as we complete our clinical trials, but others, others put it into the clinic as well, and the TGF- beta R2 edit matters as well. So a lot of the fundamental innovation outside of process changes and manufacturing comes from the biology itself.
Got it. We're pretty much almost out of time, but maybe if you wanna comment on your Regen Med platform and just highlight key catalysts ahead that investors should be focused on over the next six to 12 months.
Yeah, I'll comment on both the Regen Med platform and also our CRISPR X platform. You know, Regen Med, we're doing pretty amazing things with our iPS cells, where we can do ten edits now on iPS cells, so we're doing, you know. We're making that a big platform for ourselves on Regen Med. And on CRISPR X, we're doing all forms of next-gen editing, including gene writing. We'll disclose more about that either towards the end of this year or early next year in terms of timelines to the clinic. But the science, this—we have a wonderful balance of execution and innovation right now, which is hard to maintain, and I'm very pleased with the early stage progress as well as the late stage.
Got it. Thanks so much for joining us today, Sam.