Good morning, everyone, and thank you for joining us on the 3rd day of the Needham Healthcare Conference. My name is Gil Blum, and I am a senior biotech analyst with a focus on immune oncology. I have with me today, Samarth Kulkarni, CEO of CRISPR Therapeutics, and as a reminder. Any viewers who are watching through our conference portal are able to submit questions via the ask a question box below the video feed window. And with that, Sam, I think we can, you know, have a bit of an introduction, although I feel most people should be familiar with CRISPR. So from a 50,000-foot view and given, you know, recent historic approval for Casgevy, how should investors view the upcoming year, 2024, regarding CRISPR's strategy and drivers?
Yeah, thank you, Gil, for having us at this conference. I think from a 50,000-foot level, we feel pleased with how we've grown and developed the company over the last nine years, and we feel we're well positioned for the next nine years of growth. The, you know, the approval of Casgevy was a historic approval, and it proves that, you know, these new modalities can move much faster with the convergence of new technologies. You know, the fact that delivery technologies, editing technologies, and our knowledge of genetics are all coming together, you know, show that this can be a secular wave in cell and gene therapies that's going to make this a big part of the market.
CRISPR itself, what we've done is stage one was to focus on sickle cell and thalassemia, get that drug to approval, and now we're pleased to have Vertex as the lead on the commercial front, and they're best positioned to commercialize this drug from a rare disease perspective. To now, you know, focus on the diversified portfolio we have across oncology, autoimmune, in vivo indications, and cardiovascular diabetes. You know, we have seven different trials ongoing right now. We turn over the cards on these in the near term, which will dictate the future trajectory and direction of the company. You know, we're now looking forward to growing from a, you know, a company that has one asset to many assets that we'd be prosecuting in parallel.
Okay. So in our view, CRISPR has some of the most important ingredients for success in cell and gene therapy, and those include controlling your own manufacturing, a strong commercial partner, and a commanding cash position. So kind of on that last one, how is CRISPR, with all your projects ongoing, husbanding, you know, this war chest to continue your leadership here?
Yeah, I think, and it's, you know, there are a few things we've learned about cell and gene therapies over the last few years. You know, there's, you know, always tremendous excitement in the space, and then there was, you know, some sort of air let out of the space. But you need to have some scale to succeed in cell and gene therapies. You know, it's very hard to have a small company with a single asset develop manufacturing and capabilities to bring this to the clinic and develop it all the way. It's different in small molecules and antibodies because, you know, it's much easier to prosecute almost in an outsourced fashion. You could have the, you know, the drug manufactured somewhere else at a CDMO. You could have an outsourced clinical, you know, operations model. See how the data tell you.
It's almost like a program management type of effort in many cases, but it doesn't work in cell and gene therapies. I think you need to have synergies across the different assets you're developing. Competencies that are, you know, that you're co-opting from one asset to another. And so we have that scale. In fact, you know, you can see that in our efficiencies. You know, we spend about $400 million-$500 million a year. But we do everything that, you know, a company that's doing allogeneic cell therapy is doing across two to three different assets. We're doing everything that a company that's doing in vivo cardiovascular is doing, everything that another company that's doing diabetes is doing. So all that, which if you add up those operating costs would be $1 billion, we're doing that for less than half of that operating spend.
So I think that, you know, in many ways tells you the synergies, the efficiencies. But most importantly, the competencies that matter come into play that create the moat for other companies coming into this market. And I can say that on sickle cell and thalassemia. There are other competitors developing drugs with a similar approach. I just don't think they're going to be commercially viable or economically viable to make that kind of investment when you're that far behind. So that's an example where scale, first-mover advantage. And specific competencies can give you a big advantage in the long run.
Okay, we'll start with Casgevy because that's, you know, the biggest news to date. How, maybe starting with kind of, you know, from the government perspective, how has recent guidelines on making SCD a priority indication influenced potential uptake in your negotiation with CMS?
Well, I think, you know, generally, what we've been positively surprised by is the fact that the system has really supported Casgevy. You know, there were a lot of questions two to three years ago about how are you going to get Medicaid to cover Casgevy or how are you going to get, you know, European payers to pay for this? And what we've seen is tremendous support from the ecosystem, whether it's payers, the government, and all regulators, and that's not just in the U.S., but globally. And so I think, you know, the fact that the White House put a press release out. The fact that there is CMS support to create mechanisms for payment reflect the great unmet need for this population.
The fact that the ecosystem wants to provide these patients with sickle cell disease something finally, after years of waiting, and they're willing to support it.
Maybe speaking to specific, you know, patient journey. What can you tell us about the typical characteristic of a sickle cell disease patient going on Casgevy? What does their disease burden look like? How common are these patients?
Yeah, you know, there's nearly 100,000 sickle cell patients in the U.S. alone, and nearly a quarter of them are pretty severe, have severe disease. In other words, you know, a telltale marker is the number of hospitalizations they have, you know, or emergency room visits. But, you know, there's all sorts of other symptoms they deal with, all sorts of other comorbidities they deal with, whether it's, you know, risk of strokes. Some people are on transfusion requirements. Others have chronic pain. And so each patient is an N of one in a way. They all have a slightly different manifestation of the disease. But what's true across the board for these severe sickle cell patients is it's a very low quality of life. You know, many of them can't even go to work.
Many of them are not productive citizens of society, but they also are living a terrible life where they have a specter hanging on their head of mortality at any given time. So that's what you're dealing with from a patient population standpoint. It's unfortunate that we haven't come up with the drug for these patients. In the last 70 years, we've known the disease, but we finally have an option for them. I think it'll be a test of the ecosystem and us as companies to make sure that these patients do get the therapy they deserve.
Okay. We know there would be some level of delay in revenue recognition for Casgevy. Can you provide any guidance on how much of a delay or is this still TBD?
Well, I mean, you know, it's a new phenomenon in the pharma market because, you know, it's not how people have learned to model it. But if you look at the medical device landscape, it's not a very new phenomenon. People have been used to sort of a lag between, you know, getting a patient on treatment to when the revenues come, right? And here, what you're going to have is a patient who starts treatment in a way which is essentially you get prior authorization to get their cells collected and have their cells manufactured. And that begins the journey, but it may be five to six months by the time they're treated with the edited cells. And so there is a lag in revenue recognition. So the most important metric is not revenues, but the number of patients starts essentially for a launch like this.
What I think ultimately will benefit this launch and similar launches is the fact that there's an opportunity for exponential growth. You know, on one hand, you're going to add more centers that can provide this therapy to patients. On the other hand, as centers get more used to administering a therapy like this, they'll start doing more per month. So you get this compounded growth effect. And which you again, you've seen in medical devices. And I expect the same for Casgevy. And so the next three to four quarters are very important in terms of dictating the launch trajectory. But at this point, I think we're making good progress in adding centers and making sure they're all prepared to not only treat patients, but treat more patients over time and add capacity.
Speaking to your partner, Vertex, they did mention on their earnings call about 50 U.S. and 25 European centers are currently active and 12 U.S. and three European and one Saudi center getting onboarded. How should we view the cadence of center additions?
Yeah, you know, this is something where Vertex will provide an update, you know, during their typical earnings calls and we'll provide guidance around this. But, you know, I think there is a with these centers, you know, you start with a lot of the most important centers and you get them on board. As you saw with some of the auto CAR-T center activation. There is a little bit of it takes a little bit of time to get the center fully up and running in terms of the contracting, in terms of them understanding how to deal with supply chain, how to deal with the samples, how to deal with shipping, etc. But, you know, it's better to take that time to get the center fully prepared than have any room for error anywhere.
I think what Vertex is doing is, and as with everything they do, is a very robust process and a very solid way of dealing with, you know, bringing centers on board and getting them fully prepared for eventually dosing patients.
More on regulatory interactions. Casgevy did not receive a recommendation by NICE. Is there any read-through to potential other European agencies or this is a case by case?
No, I think it's a case by case. And I think, you know, you've had NICE say this, you know, have an initial opinion, then change their opinions. You know, on thalassemia, they had a different opinion. And I think this is just a matter of routine course discussing with them, educating NICE and the regulatory bodies, but also the payer bodies around the benefits you're getting for this therapy. Especially as we, you know, keep accruing more and more data on these patients and that we've treated in our clinical trials. So I see that as normal course in terms of launch in Europe.
Okay. A related question, I mean, some of these gene therapy drug launches have been, yeah, not the most successful, especially in Europe. What have we learned specifically as it relates to pricing or maybe some other items as to, you know, how to optimize drug launch in this space?
Yeah, I think, you know, what I see is, you know, you have to look at the different regions differently. The U.S. is a different paradigm completely. You know, Europe is in a different paradigm and then the rest of the world, you know, we have significant opportunity in the Middle East, for instance, with Casgevy. And in Europe, they will come around to it because, you know, the way they've treated something like a hemophilia drug may not be applicable to how they look at Casgevy, you know, and I think, you know, some of the resistance they've had to other cell and gene therapies is on the basis of other available therapies, you know, in sickle cell and thalassemia, you really don't have other available therapies.
So it changes the equation, but there's a lot to work through because there is a process of educating the payer bodies, the HTA authorities in each of these countries. And again, it's very hard for a small biotech to do. But it's something that Vertex is best positioned to do. So I do feel like even Europe will be an attractive market for Casgevy.
Another strategy to expand the market would be to, you know, find ways to reduce the toxicity of the myeloablative conditioning. I know that it's actually not that simple to just reduce intensity. What is the company thinking in this regard?
Well, both Vertex and us have had significant efforts in developing a targeted conditioning agent and a targeted conditioning agent for this purpose, right? I think we've had fits and starts in this space because a lot of the companies developing targeted conditioning agents were doing it for other indications. They weren't doing it for they weren't doing it for sickle cell where you need something to be a quick hit. An agent that doesn't linger because you don't want it to in any way impact the drug product. Yet at the same time, have efficacy in the stem cells in making room in the marrow, but not have no toxicity. So I think that profile, you know, we're working with the c-Kit ADC that we've disclosed before. We're making progress there. Vertex have their own agents with different targets and different toxins.
So, you know, we're going to put it all in the hopper and see what works best and, you know, whatever agent is developed, I think can have a significant boost to Casgevy prospects because in my mind, it's going to triple the rate of adoption. If you have a gentle conditioning agent and also significantly expand the addressable pool of patients.
Maybe it's a blue skies question. If you had an in vivo strategy to target bone marrow, that would kind of circumvent some of this transplant. What are you guys thinking of now?
We are working on an in vivo strategy as well. You know, we have a Gates grant that is, you know, that we were beneficiaries of that helps fund some of that work, but also we're putting a lot into it. There are ways to detarget the liver with an LNP that gets into HSCs. I think it's going to take a lot more work for the in vivo approach than what you may hear from a new startup doing this work, for instance, because, you know, what you have to show is that you, you know, you detarget other organs, you get it only into the hematopoietic system. You have to do that with great fidelity. You have to, you know, the preclinical work needed to show that something like that is safe. The bar will be higher from the regulators.
So we, you know, while we're doing a lot of work in the space and we're encouraged by what we're seeing, the timeline may take some time to get there. The other thing is, you know, it's one thing there are people, companies that have shown data with reporter genes like GFP or a Cre-Lox system. That is not reflective of gene editing. You know, I think you may not, you may be able to get a few mRNA expressing GFP in these cells, but you may not get enough to get gene editing that's durable. So more to work out on in vivo, but I feel very good about targeted conditioning as something that may not be as far as people may anticipate or investors may anticipate.
I think you touched on something very important there. You need a pretty significant efficiency. You need to reach a pretty significant portion of that bone marrow in order to achieve a therapeutic effect. That's why it's always been the transplant setting. It's not that surprising.
Exactly. You need to get a high efficiency and you need to get no other off-target editing, right? I mean, that becomes the second challenge then. As you increase efficiency for hematopoietic cell editing, you oftentimes will get editing in spleen or adrenal glands or other tissues. And then you get into a regulatory hurdle of proving that that's not deleterious or harmful to the patients.
I do want to shift gears to talk about the cell therapy portfolio. It's very large and expanding. By the way, I want to thank you for attending our panel yesterday and sending Alex to walk us through some of the developments there. Starting with CTX 112 versus the older generation CTX 110, just to remind everyone and orient them what the new additions are.
Yeah, so I think, you know, with CTX 112, we've made two edits, additional edits to CTX 110 chassis. One is Regnase-1 and the other is TGF-beta R2. And, you know, interestingly, these were not Regnase-1 was not a known target that everybody had said, "Aha, it makes sense." This came out of a large empirical screen and we did that screen and a partner of ours also did that screen. And it came out to the same sort of conclusion. This is the best edit. It is an edit that's an intracellular transcription binding domain that somehow affects cytokine expression and retains a more memory-like phenotype for these CAR-Ts. And, you know, two years later, I think Carl June published something in this area which shows that Regnase-1 is an important edit for CAR-Ts to make them more robust and persistent.
And I think the fact that we're starting out with this edit and it seems to have great synergy with TGF-beta R2 or basically to prevent TGF-beta mediated sort of mitigation of the CAR-T cytotoxicity. And I think this pair of edits is going to make these CAR-Ts much more potent. You know, interestingly, as a byproduct of the edits has also been that they expand more in manufacturing and our manufacturing efficiency has gone up dramatically and reduced our COGS almost fourfold. Bringing us into antibody or small molecule territory for these CAR-Ts. And so with CD19 CAR-T with CTX112 with these new edits, we're quite excited about both the LBCL as well as autoimmune, which we spoke about yesterday.
Yep. Yeah, Alex mentioned the increase in production capacity as well. A bit of an, you know, an interesting nuance here. Both of these edits are targeted towards fitness of the T cell, but you know, you haven't added any new immune evasions once this is in contrast to some of your competitors. Why is that?
Well, I think, you know, what we're seeing, you know, from the autologous experience and we've now dosed over 100 patients and we have a lot of data on autologous as well. You know, most of the tumor killing happens in the first 14-15 days, even with autologous therapies. And, you know, our cells with the beta-2M edit do last about a month. What we did see was that about day 15, the cells were pretty exhausted. So the big need was not to have the cells go beyond a month because if they're exhausted, it doesn't matter if they go beyond a month. It was more to increase the potency in that window that we have. And that may be sufficient to kill the tumor entirely.
We're seeing long-term durable responses, you know, I think we haven't published these data with CTX110 yet, our first generation program. There are patients out 3+ years with a durable complete remission. If you wouldn't see that if it weren't for the fact that these CAR-Ts are completely killing all the tumor cells during that window that they have, whether it's 14 days or 30 days. That was the logic behind focusing on potency edits versus persistence edits.
That also came up in the debate yesterday with Alex. It looks like depth of activity may matter more than persistence. It just makes me wonder why some of your competitors are still doing a lot of work making their T cells more evasive.
Yeah. No, I mean, it is important work to pursue. You know, it doesn't mean that we've stopped work on persistence. I just don't think, you know, it's going to be that easy to get six-month persistence on these CAR-Ts or a year-long persistence. And, you know, persistent, what's important is functional persistence. You know, persistence without activity may not amount to much at all. And so that's why we had to focus and make a call on what's more important, what are the edits that matter more at this point? And I think we made that sort of choice. We're monitoring the space carefully.
You know, in autoimmune, certainly it's playing to our advantage that we don't have very long persistence because I don't think you want these CAR-Ts hanging around, you know, six months to a year and cause long-term B-cell aplasia or even have a risk of secondary malignancies if they last too long. So I, you know, it is an interesting feature almost now that our cells are very potent. They do their job and then they go away.
Maybe a last point for compare and contrast. You know, you guys use donor-derived T cells. There are companies out there that use iPSC-derived program. How would you compare and contrast with those conceptually?
Well, you know, one of the reported advantages of iPS-derived CAR-Ts was that, you know, from a regulatory standpoint, it's going to be easier because all the cells are the same. Second was that you actually have a cost-of-goods advantage. And, you know, those two factors, but if you look at where we are now with our healthy donor-derived CAR-Ts, you know, our COGS are probably the same, if not lower than iPS-derived CAR-Ts. Because, you know, we've had these edits now biologically that make them expand more. We also have perfected the process, made a lot of improvements, right? So the cost-of-goods equation doesn't come into play anymore. And from a regulatory standpoint, again, we don't seem to have an issue getting these through with regulators because, again, the amount of characterization we've done and the amount of experience we have. So now comes the efficacy part.
We almost think that the heterogeneity of the phenotypes of the CAR-Ts from a healthy donor-derived source actually will have greater potency than an iPS-derived CAR-T. And it does matter that there are different degrees of differentiation in the T cells. They all do a slightly different job. And they're shown to be potent CAR-Ts, right? I mean, versus having to prove the whole iPS-derived equation again. So we've done a lot of work on iPS-derived CAR-Ts with iPS-derived NK cells. We've done that head-to-head versus healthy donor-derived CAR-Ts. And in our hands right now, healthy donor-derived CAR-Ts seem to be the most potent relative to iPS-derived CAR-Ts or healthy donor-derived NK cells.
So given your experiences with CTX110, where do you think the bar for success for CTX112 sits in lymphoma?
Yeah, yeah, we have this conundrum in the lymphoma space, you know, especially in the U.S. You know, you have only 25%, a quarter of the patients that could benefit from an autologous CAR-T are getting it because, you know, most of the availability is niche to these academic medical centers, right? Still, it's not in community settings. Yet it's relatively tricky to develop because you have auto CAR-T approved in second line as a second line therapy, right? So where does that put us in terms of the bar? I think, you know, long-term data now for Yescarta, for instance, tell us that about one in three get a durable response from an ITT standpoint.
You know, there was at some point a notion that bispecifics are at about 30% durable response, but I don't think that's holding water because if you look at the long-term publications on glofitamab or epcoritamab, for instance, now, what you're seeing is they continue to fall off, patients continue to fall off. So if you look at the two-year durability or two-year CR rate, it's now in the 17% range. Whereas the one-year durability CR rate looks much higher. And it's not the case with allo CAR-T. With allo CAR-T, if you have one-month, whatever the one-month CR rate is, that holds for a very long time because I think the patients are either, in fact, even the six-month CR rate is kind of reflective of what the two-year CR rate might be. It's the difference in the number of regimens you have and all that kind of stuff, right?
So, you know, getting to a close to a 25 to between 25% and 30% durable CR rate for an allogeneic CAR-T that can get into community settings, I think is a winning target. I mean, that could be worth a multi-billion-dollar product. And so that's where we're focused on, although we, you know, we recognize the challenge of the development, clinical development now, given the fact that auto CAR-Ts approved in the big, you know, academic medical centers, we feel confident. We haven't had any enrollment challenges. That always is a good indicator of whether there's interest in the product. You know, I know you saw recently there was some news about an approved product potentially getting pulled or getting pulled because they didn't finish the confirmatory trial. You know, it reflects investigator interest and enrollment is a key indicator of how people see the product.
So I do want to add a little bit more nuance there because I think it's fascinating. We recently had a couple of ODACs on use of CAR-Ts in early lines of multiple myeloma. And one big feature that came out of this is treatment-free intervals. Especially when compared to, you know, standard of care bispecifics. Do you think we're going to see a similar dynamic in B-cell lymphoma?
Yeah, I mean, I think it was interesting, you know. By the way, it was also interesting in the ODACs is, you know, the number of patients that die before they get the CAR-T.
Interesting, yeah.
Right?
Yeah.
So there are things we're learning. And, you know, with bispecifics, people have taken different routes. For instance, you know, with glofitamab, there's a fixed dose, fixed nine-cycle regimen where it's not the same for epcoritamab. And people are learning about these therapies as they get more experience. But I do think ultimately, you know, well, maybe when the route in a frontline setting is a single dose of allo CAR-T followed by maintenance with a biologic, maybe a winning combo. Because then it's easily available. You don't have the burden of an auto CAR-T. It's less expensive for the system. And you can have the same effect, durable effect that you see with auto CAR-T.
Switching gears to autoimmune disease. There was a bit of a sense based on, you know, the company deck from J.P. Morgan that maybe the company is now moving away from oncology more to focus on autoimmune disease. Is this a fair observation?
No, no, we're fully committed to oncology, but we're putting a lot of effort into autoimmune. You know, what we have, you know, for a variety of reasons, you know, what we have is a situation where we're in pole position autoimmune because, you know, for one, auto CAR-T, I think, is going to be difficult in autoimmune for various reasons. You know, you're going to have larger trials. They're not just not able to move at the speed of allo CAR-T. And I don't know if it's a, you know, TPP of an auto CAR-T doesn't quite fit what rheumatologists are looking for in autoimmune. And you have this risk of secondary malignancies with Lenti-based auto CAR-Ts. Within the allo space, I think we're sitting right at that, you know, the sweet spot of efficacy and safety. You know, we have, you know, relatively safe profile.
We're more efficacious than, as I said earlier, I think I think we're going to be more efficacious than iPS-derived CAR-Ts or NK cells. But it's sufficient efficacy to completely deplete the B cells and provide that reset, yet have a safe profile with the standard for depletion that we use. So, you know, given the confluence of factors and the, you know, what's going into, you know, all this in terms of characteristics of what would be ideal in space, we feel like we're best positioned. So we don't want to, you know, lose out on the opportunity to be the leaders in space. So we're putting a lot of resources behind it. We're putting a lot of, we're trying to capture, you know, talk to all the centers, whether it's U.S. or ex-U.S., and make sure we're moving parallel across many different indications.
Over time, would you consider kind of attenuating the lymph depletion? I mean, right now you're going in with standard as a first go, but what are your thoughts?
Over time we would. You know, but priority for us right now is, you know, getting the durability of remissions is the key. You know, obviously the data from Georgetown and others are remarkable, but we do need to make sure that every patient gets durable remission. And we'd rather see that versus, you know, trying to reduce the lymph depletion in the first go. And we already are at a lower lymph depletion than a lot of the other alloplayers at this point. So we'll stay.
That's the allo-evasive profile. You don't get as much rejection. Yeah.
Exactly. Exactly.
I do want to ask kind of another question related exactly to that. That's been the profile in lymphoma patients who may have, you know, a pretty messed up immune system. Do you think this is likely to hold in patients with autoimmune disease?
What the.
The allo-evasiveness of your CTX112.
Yeah, I mean, I think, you know, enough to give us the window of opportunity, right? So the beta-2M added does do something to give you a window of opportunity to kill the B cells. And I think we do see, you know, we took samples from our oncology trials to look at patients who had B cells to see how much depletion you're getting. And you're getting the same type of depletion of B cells from these oncology patients that you saw with autologous CAR-T. So, you know, that points to the fact that we could get effective depletion in autoimmune patients and get that reset without having to have these CAR-Ts stick around too long.
Just given how many companies are in the space, do you expect challenges to enrollment?
Yeah, I think it will be competitive. You know, I don't think it's going to be that straightforward. One, because, you know, rheumatologists are not used to CAR-Ts, so they'll have to rely on their oncology colleagues at centers. There are a number of companies now getting into this space. But that's where I think our balance sheet, our executional effectiveness, and our established competencies in enrollment, etc., will come into play. You know, it's going to be very hard for a smaller company to compete with us when we're all in. And especially for an auto company that's doing auto CAR-T, it's going to be very, very hard when they are compounded by the fact that they have to wait to manufacture.
Okay. Before we move on, so into, you know, regarding your solid tumor programs, any updates that we can expect on CTX131?
Yeah, so we're continuing dose escalation on solid tumors. You know, the timeline of solid tumors is a bit longer than CD19 or B-malignancies because, you know, typically the scans are wider apart after you dose patients and then you have to serial process these patients to a certain extent at each dose level. And you start with a smaller dose so you don't, you know, see any safety events in these patients. So we're continuing to move this solid tumor trial along.
Okay. I want to spend our last few minutes here discussing some of the in vivo programs. Starting with something a little bit negative. I mean, I'm sure you saw the Verve news. It seems like LNPs and LNP technology still matters a lot here. What gives you confidence that you are not likely to run into the same issues of ALT elevations and tox?
Yeah, we've done a lot of work. You know, I think while we were behind Intellia, for instance, in the whole in vivo space, you know, we've done a lot to catch up. And we evaluated the advantage of being behind in a way is you get to evaluate everything. You know, we looked at all sorts of families of LNPs. Did, you know, significant testing of each of those in LNP models, sorry, in NHP models to compare and contrast what's going to work the best and what's going to give you the best therapeutic window. You know, LNPs do have tox, but these the tox that you observe are, it's pretty temporal. You know, it kind of goes away. Unlike siRNA or other modalities, we have to keep dosing patients and you can't, you know, tolerate a certain level of tox.
Here, you're talking about a one-time event, which then disappears two weeks later. So, you know, it's hard for us to comment on Verve's data and what they saw. You know, they haven't disclosed everything fully in terms of the side effects, but it's a bit puzzling to us, but there may be other reasons to move to a different LNP. But we feel like our formulation, our LNP that we've picked and the way we formulated the drug product, and this goes into all the details of what the size of the nanoparticles are and what do you see in terms of, you know, the endosomal escape, etc. All that's really important and we feel very good about our programs.
And, you know, typically in a different industry, you know, when you have a competitor have a setback, if Boeing has a setback, Airbus stock goes up, you know. But in our industry, you know, like everybody assumes the worst for the entire class. So I think, but I do think we feel good about our approach and we continue to make progress in those trials.
If you had to think about what would you say is the core differentiator for your programs in vivo?
You know, ultimately, I think the LNP delivery to the liver is going to get commoditized to a certain extent. The core differentiator is going to be, you know, one, picking the right indications, getting the cleanest approach to gene disruption with no off-target to ensure that you have an easier regulatory path. And then, you know, excellence in clinical development. You know, I think that's how it's going to come down to it. And we feel like we're ahead right now with the targets we've picked like LPA and in a way it's ours to lose. So we're focused on execution and we're also working on a number of other targets that we haven't named yet, what we hope to name this year.
Again, with the notion that once you have a scalable platform that you've shown that works, then, you know, you want to just maximize that platform with several assets that you can take into development efficiently.
So looking into the future here and kind of the space more broadly, and once you exit the, you know, ultra-rare and rare indications that some of these targets have, do you anticipate challenges in conducting and enrolling larger studies for systemic gene editing? How would such a study be designed? A crossover would have to be, you know, required or what do you guys think?
Well, this is what I'm saying, which is, you know, each target, you know, it's going to be very tricky how you think about development, right? I think in an Lp(a), for instance, you know, there's no other therapies available. So we're able to do, you know, development in a standard fashion. You know, and that's the issue that in TTR right now, which is amyloidosis, which is there's just other available drugs. And so it makes it very challenging in terms of how you design your trial. But ANGPTL3 and Lp(a), you know, for that reason, I think we'll be in a better place. So PCSK9, I think we'll probably end up doing with a partner because again, it's going to be a long trial because of this crossover phenomenon or more so than crossover, it's getting somebody off a different drug potentially, right?
As you show efficacy with yours. You know, with the siRNA, they've shown that. They've shown that they can actually get someone off of a small molecule drug once you show durable effect with the siRNA. There are ways to address that, but that just increases the complexity of a trial.
All right, Sam. We are a little bit over. As always, a pleasure speaking with you and thank you for taking the time today.
Thank you, Gil. Bye, man.