For attending Jefferies' London Healthcare Conference. My name is Kelly Shi, one of the senior biotech analysts here. In this first chat session, we are very pleased to have Mr. Fred Aslan, Chief Executive Officer, and also Ms. Neha Krishnamohan, I hope I pronounced your last name correctly, Chief Financial Officer join us today. Welcome both. I know you actually flew from ACR, and we keep you very busy. Maybe start at a high level, given that Artiva is actually a new company flipped to the public side this year. What have you been working on? Maybe following that, also, what are the key learnings from ACR for the space Artiva is actually focusing on?
Great. Thank you, Kelly, for having us. So Artiva is a five-year-old company. A few things I'll mention. First, we're a spinoff of a Korean company called GC Cell. And that's important because the work that has gone into our platform to scale and NK cells has been going on for over a decade. And so today, from one single umbilical cord unit, we can make thousands of vials that have a billion cells each, which means that we can have low COGS and consistent product and very high scalability. The second element is our mechanism of action. So our lead asset is called AlloNK, and it's a non-genetically modified NK cell. So unlike our peers who are engineering their cells, most of them, we use non-genetically modified NK cells. Therefore, when we dose our cells, we dose them together with a monoclonal. So the monoclonal does the targeting.
The monoclonal binds to the B cell. The Fc portion of the monoclonal binds to our NK cell, activates the NK cell, and that drives the cell killing. A few years ago, before we had data in oncology, people questioned this notion that a non-genetically modified NK cell with a monoclonal could drive as much efficacy of engineered products, and this is where oncology has been very valuable for the field, and I think very relevant in autoimmunity. We have at least seen on oncology that out of all the off-the-shelf approaches, we have been able to generate data that is as good as anyone else. Said differently, nobody with an engineered product off-the-shelf or a T-cell engager has generated stronger data in aggressive NHL patients as we have.
And of course, this becomes very relevant as we go into autoimmune diseases since we hope to have this deep and durable deep B cell depletion response. And then the final thing is the reason to pay attention to NK cells, and really the most important one, is the fact that, again, from oncology, we have learned that whenever you utilize an auto CAR- T or an allo CAR-T or a T-cell engager, whenever it's the T-cell that's killing the B cell, we see rapid expansion, and we see cytotoxicity that leads to CRS. So there has been a very strong correlation in oncology of efficacy with CRS. And the one special thing about NK cells is that we decouple that notion of activity with the CRS.
We have been able to see as deep and as potent of an effect in NHL, but without driving that runaway CRS, which is the reason why the approved auto CAR- Ts and the approved TCEs have on their label that patients have to be hospitalized.
Great. And as you have a strong focus in autoimmune, and even it's in very early days, but there are a lot of debates or discussions around classic CAR T-cell therapies and also T-cell engagers and which one would be in the winning position. And you have actually differentiated the approach from either. And also, when we think about autoimmune and oncology, we think regarding both efficacy requirement, safety requirement, and the cost and the logistics could be actually differentiated. So how do you think your platform actually fits in autoimmune relative to other actual approaches?
Yeah. So maybe let's start at the highest level, right? So the first thing I would say is the data that we first saw with Schett is really exciting, and it points to a very large market opportunity. I do think that in a lot of my conversations with investors, people are trying to figure out who is going to win. But I wanted to start by saying that I don't think that it's going to end up being a winner-takes-all market. We have a very large opportunity. All the data that we have seen so far is better than the standard of care across the board, right? So that means that we are going to be getting therapies that are better than the standard of care. We've also learned that this works across a number of different indications, right?
And then each modality is going to have a different target product profile. It'd be nice to think that one modality is going to have the best efficacy and the best safety, but the world just doesn't happen like that, right? And so first of all, very big opportunity. The place where I think we can really differentiate ourselves is I think we're going to see different degrees of efficacy across different products and different modalities. But the one advantage we have is that we can drive up the efficacy without being worried that we're going to get that runaway CRS. Why do I mention that? Because at the end of the day, I believe, and we have already seen this in oncology, I don't see why it would be different in autoimmunity, and we can talk about that.
I think that you're going to have treatments that are going to be provided at centers that are well prepared to manage CRS if they happen. Patient develops a fever, you're concerned that it could escalate, and you're ready to give tocilizumab right away, and then you're going to have outside of these centers, centers that are trying to use these therapies as outpatient. And I believe that because of this correlation that we saw in oncology, and we can talk about the hints that we have started to see in autoimmunity that point to a similar correlation, I believe that in order to go out into the community, if you're using one of the T-cell leveraging approaches, you're going to run the risk that there's only so much efficacy you can derive before the safety issues start to emerge.
So we would like to think of ourselves as potentially the therapy that can drive one of the highest activities that one sees, but that can be used in an outpatient setting. So as you know, we're running two trials today. One of them is an IIT that we are running in a community rheumatology practice. This is a standalone community rheumatology practice. There is no oncology involved. This is a rheumatologist dosing cyclophosphamide, dosing fludarabine in his infusion chair. Patients go home after that. They come back to receive their weekly doses of AlloNK and monoclonal, and they go back home. And then if they develop a fever and infection, then he sends them across the street to the community hospital. To us, that's what you need in order to have a therapy that can truly be used in the community setting.
So far, with my bias and my lens, I still see a lot of CRS that is requiring a lot of tocilizumab usage in the context of some of these other T-cell approaches. We need more time, more data across the board to see whether these patterns are really real or not.
Fantastic. Super insightful, and you mentioned this IIT trial. You also have another trial ongoing. Maybe you can help us to actually understand the enrollment pace and when could we expect first the data from each?
Yeah. So we recognized around 18 months ago that a lot of the allogeneic cell therapy approaches were going to have a very difficult time in oncology, right? Because the reason for them to exist in the first place was to provide an alternative to auto CAR- T. But that happened 5years- 10 years after auto CAR- T was already ahead. And so by the time we were running our trials, even though we were pleased with the data, at that point, we were competing with auto CAR-T that had already been approved in the market for 5 years and already had 10-year follow-up data. So that made it really challenging. So we very quickly pivoted towards autoimmunity once we saw the data from Dr. Schett. We had an IND allowed last year, and we already announced that we treated our first patient in our company-sponsored trial.
This is a lupus with or without lupus nephritis. And we announced the second trial, which is the investigator-initiated trial that we discussed. In that trial, we have a basket of RA, lupus, pemphigus, and vasculitis. And we announced in August that we had initiated treatment on the first patient in that trial. And we are not providing any updates on the individual patient-by-patient enrollment, but we have guided that in the first half of next year, we will be sharing initial data from either one of these two trials as we generate data.
So we could expect a meaningful readout, safety, and efficacy?
Well, we have to define what meaningful is, right? Because I would argue that as we look across the different modalities, I see a few different waves of meaningful, right? The first thing that people want to see is, can your modality achieve results that look at all like what Schett did, right? And we have been learning, I would argue, for example, Faith was able to show us that an allo CAR-T can yield a very good result. It was a patient. You call that meaningful. The follow-up was very limited, but I would argue it's now convincing and compelling to know that an allo CAR-T product can actually do that. The second wave comes into the notion of, well, how many patients are receiving this benefit, right? Can we start to define what a response rate actually is?
Over time, we want to know how durable are these responses? And then eventually, what I think really matters is when is a company starting their registrational trial and in what indication? Because ultimately, that's when the clock really starts, is having a sense of, are you going to be one of the first ones to market, and what does your target product look like in that indication?
Great. And does this readout also go along with biopsy? I mean, biomarker studies through biopsy, given that I think across, I mean, pioneered by Dr. Schett and across different programs, I think everyone trying to show B-cell depletion and the B-cell reset and autoantibody reduction, or maybe even actually the tissue B-cell depletion. Curious, do you have a plan to actually give a full picture?
Yeah. We are trying to build as full of a picture as possible. I think one of the things that's challenging, and I think this is one of the reasons why there's been so much headwind for a lot of the modalities, particularly the auto CAR-Ts, is that when Dr. Schett first came out with his data, what he called a reset was something very holistic and purist. It included not only B-cell depletion, but everything moved in the right direction. So there were clinical improvements. Patients were off of their meds. The autoantibodies were gone. Urine protein creatinine ratios were completely resolved, and what we have learned from EULAR and ACR, from the more company-driven auto CAR-Ts, is that we're not replicating those results. You know, SLEDAIs are not always going to zero. Autoantibodies are not always going down to below the limit of normal.
Urine protein creatinine is not getting resolved within 90 days. And so the question is, how do we define a reset in this new world where what we are seeing that's really encouraging is we are seeing across the board improvements in terms of the clinical symptoms and in terms of patients being reduced on their medications. But what we're not seeing is this across-the-board biomarkers all getting resolved. And then the question becomes, are these results going to be as durable as the Schett results were, given that these biomarkers are still around? So the advantage to us not being in the auto CAR-T space is that we get to see a lot of that data mature in a lot of patients, and it starts to create, let's say, a benchmark, you know, a framework for us to think about our results. So we are early in our trials.
We're going to be collecting a lot of this information, and we hope to be sort of framing our data in that context. In terms of tissue, I think one of the issues with this notion of understanding B-cell depletion in tissue is that the biopsies are going to be anecdotal, and there's a lot of noise out there, right? People say, well, monoclonals may not get into the tissue. Do we know that for a fact? Because I would argue we don't know. We know that the monoclonals don't completely deplete the B-cells in the periphery. So I don't see why we would expect them, without adding anything to it, that they would be able to deplete them completely in tissue. We do have data. There's a lot of rituximab data that has been shared. Rituximab is not as good of a B-cell depleter as obinutuzumab is.
There are papers from obinutuzumab showing nice tissue lymphodepletion. There was a study in kidney transplant patients where they showed very nice B-cell depletion in the lymph nodes of patients in the kidney. And so time is going to be needed for us to truly understand this notion. Because I would argue, if our therapy works, then I think we will be challenging this notion that the monoclonals don't get into the tissue. And then the final thing I'll say, there's two ways in which we could be having the monoclonal have more impact than what's known historically. One is that the monoclonal gets into the tissue, and having this high concentration of NK cells in the tissue drives this deeper depletion. The other possibility is our NK cells have a high affinity CD16, so we bind to these monoclonals while we're circulating in the blood.
Could we be taking some of these monoclonals into the tissue and improving the tissue penetration? It's very hard to prove any of these items. So ultimately, efficacy is going to tell us whether we're actually achieving what we want to achieve or not.
Yeah. It's still very early days, I think, to draw any definitive conclusion. Also curious, what do you think about the factors that actually can explain the difference from Dr. Schett's trial and also other company-sponsored trials? Is there a patient baseline difference, or maybe how stringent the efficacy endpoint is or metrics are? And I think a more important question here is, if you talk to physicians, what would be the realistic, I mean, the clinical profile for a cell therapy should achieve and show actual significant benefit when compared to the current therapies?
Yeah. So a lot of people believe that they just, I hear that they believe. I've never seen any evidence, but that Dr. Schett is selecting his patients that he's including into the trial, as opposed to the more real-world patients that may have comorbidities. They may have other things that complicate them. I think what's happening today, and we see this, enrollment has been slow across the board, particularly when companies get started. And so when enrollment is slow, you don't have the luxury of saying, I am going to wait until I see a patient that has no other comorbidities, whereas Dr. Schett could wait, you know, just given how long he took to run the trial and the results that he has generated. So I think that that may partly explain what happens.
I don't know, though, that it's going to be this black and white, because the reality is there are some companies that work closely with Dr. Schett. We don't, but there are some auto CAR-T companies that do work closely with Dr. Schett. And I haven't heard a cogent argument of, you know, these are the patients that we are including, which are different than Dr. Schett's for this reason, and therefore we're not seeing the autoantibodies go down as low or the kidney function resolving as quickly. So the answer is that's a little bit of unknown. I'm still as curious as you to find out why Dr. Schett's results are so much better than everybody else's. But ultimately, to your question, I think what will matter to physicians is that the patients are doing better, and then they're off of their medications.
Ultimately, that is the two things that we care about. And we're worried about all of these other biomarkers because we're trying to predict whether they give us hints as to whether it's going to be very durable or whether it's likely to not be as efficacious with certain manifestations of the disease, so I think a lot of that we're going to be learning over time.
Okay. Great. So drug-free and no relapse over a certain time period could be the goal.
Drug-free and durability is what makes this entire space, which is a really big space, so much better than the standard of care.
Right. Maybe switch the topic a bit regarding the targeting strategy. Again, very limited data on CD19, CD20, BCMA, CD38, BCMA too, CD20, BCMA too. You have the flexibility actually to quickly shift to a different targeting strategy. What is your current plan, and what do you think about this overall? If actually data drop into the space, how quickly you can actually turn around?
Yeah. So you pointed out the big advantage of having a non-genetically modified NK cell is that you could work with different monoclonals. We are starting with CD20, right? And there's a lot of debate on CD19 versus CD20. So first of all, in our strategy, I think that there's a lot less friction for us to start developing a program where the monoclonal has already worked in the indication we're going after, so that then if there's ever questions of what is the monoclonal doing versus what is the rest of your therapy doing, it's very easy to answer. As we think about innovating further and taking more of that clinical risk, then as we start playing with different monoclonals, we would have to answer that question.
Now, around the 19 versus 20, what I think is unfair is when people make the argument, this is what rituximab was able to accomplish by going after CD20. That wasn't enough. And therefore now we're going after 19 with autologous CAR-T. Therefore, 19 is a better target. But that's exactly how things are being presented. And I don't think that's fair because autologous CAR-T is obviously a more potent modality than a naked monoclonal is. What I would do instead, and we have done this, we have looked at the situations where a CD19 monoclonal was used against a CD20 monoclonal, and the data with the CD19 monoclonal has not been as close as to the activity that we have seen with autologous CAR-T in terms of that depth of depletion and that potency.
The final thing I'll tell you is, you know, we see a lot of these charts that show, you know, 19 is expressed on this population, and that's a broader population than the other population. The question I would have is, we have data from, for example, BCMA-only T-cell engagers, and when we look at the B-cell depletion pattern, they depleted all the B cells. How can that be? Because that diagram said that they only exist in the plasma cells. So how are we getting rid of the other ones? The truth is that those diagrams are pointing to the relative expression of those targets. So if you are a high-expressing cell, you have that included in the diagram. If you're a low-expressing cell, you're not included there, but clearly it must mean that there must be some BCMA expression across a whole gamut of these B cells.
Otherwise, we wouldn't see that depletion. So I would argue that until we have a head-to-head of an auto CAR-T going after 20 with an auto CAR-T going after 19, we don't know which target is better. And we are starting with 20 because that's where we generated most of our clinical data. We wanted to take as little technical risk as possible going from a regimen in oncology to autoimmunity. And until proven otherwise, we're not sure that 19 is better than 20. We do think that BCMA or CD38 could provide differentiated activity. It is intriguing that out of all the auto CAR-Ts that are out there, the one that uses the dual targeting of BCMA and CD19, that data does look cleaner and closer to Schett than the data from the other auto CAR-Ts in the real world that are CD19. Early days, one company, different regions.
But the question is, you know, do you start with one, and then if you fail that, you go to another? Is dual targeting the better way to go? There are disadvantages of using BCMA or CD38 in the sense that we are seeing that when you do that, there is a higher need for IVIG injections being given. You have to be revaccinated. So the question is, do you need to go that hard, right? We just don't know yet as a field and an industry how hard and how broad you have to go in order to get that desired effect.
Great. Great insights. And when you engage study sites, curious what kind of physician feedback you have heard when a center actually has multiple choices. And when you're thinking about participating, what are the actual features that matter to physicians at the moment, even though early days, what are the most attractive features for both cell therapies and also your approach and also engagers?
Right. So look, I think one of the big advantages that the companies that have been doing this for longer than the others have, such as Cabaletta and Kyverna, is that they had already started developing relationships with these sites. And so they were basically first in line. And there's only so many trials that a lot of these CAR T centers can do. And there aren't that many CAR T centers out there, right? So I think for those of us that are coming in behind them, we are having to sort of get in line in these institutions to do it. But the one big advantage that we have is that because of our safety profile, we're not relegated to the CAR T centers.
You see, most of the modalities, as they get FDA approval to go forward, you have to be hospitalized as a patient in order to receive the product. In our protocol, we don't have to hospitalize our patients because of our safety profile. So we can talk a little bit about what is the long pole in the tent. Is it the CRS that's causing these patients to be hospitalized, which it is the CRS, or is it the lymphodepletion, right? But one advantage we have is that because we don't require our patients to be hospitalized, and just for full disclosure, it's the very first patient in each cohort that needs to be in the hospital for 24 hours. All the other patients don't have to be hospitalized.
That creates a big advantage when you think about centers out there that have been involved in autoimmunity trials that are not auto CAR-T, right? Like the vast majority of the centers are not auto CAR-T centers. So that's one advantage we have. The second advantage we have is in these auto CAR-T centers, it's been politically mostly dominated by oncology because they're the ones who have the most experience with cell therapy, and they're the ones that know how to treat CRS and watch these patients closely. The advantage of going outside of these academic centers is when you can talk to rheumatology and they can make the decisions for themselves. Because this is what's making getting these sites up and running so slowly, is that you have to talk to rheumatology. They need the buy-in from oncology. They discuss the budgets.
They each want a different proportion of the money that's coming in. They have to coordinate. That just makes it more complicated. So once people are able to move away from the auto CAR-T centers, that should make enrollment something that becomes easier for most people for those therapies that can move away from the close watch of bone marrow transplant.
Great. And lastly, maybe you can lay out the company's plan for 2025.
Yeah. So we talked a little bit about those waves, right? In an ideal world, we would like our investors, and that's going to be dependent on enrollment. We would like to show that the therapy works. We would like to show people that the therapy works across more than just one indication. We would like to start, you know, giving hints about how often it's working. But a lot of this, as I mentioned, it's you won't be able to answer all of those questions so quickly because some of them require some more time. So what we are trying to do is to, as quickly as possible, make it clear to investors and industry that our therapy is moving in the right direction in terms of checking off all those boxes.
Looking forward to it. And thank you so much for this very insightful discussion. And thanks everyone for attending.