All right, I think we're ready to get started. Welcome everyone. I'm Josh Shimmer from the Kanter Biotech Equity Research Team. Very pleased to introduce from Artiva Biotherapeutics, Fred Aslan, Chief Executive Officer, to give us a snapshot of the program. I have a feeling we're going to be talking a lot about FluCy during the course of this session. Why don't you tee it up for us first with the work Artiva is doing and the stage of involvement you're at? That's great. Just to give some background, we were founded in 2019. We are working exclusively in NK cell therapies. Our story really has three elements. The first is our NK cell therapy is a non-genetically modified NK cell. Because it's non-genetically modified, what we do is we combine it with monoclonal s. That way, the monoclonal does the targeting, the NK cells have an opportunity to enhance to ADCC, and you get a much more potent B cell killing than otherwise you would with the monoclonal alone. Because we don't genetically modify our cells, we have a significant advantage from a manufacturing CMC perspective. We source our NK cells from umbilical cord units. From one umbilical cord unit, we can generate thousands of vials with a billion cryopreserved NK cells each. Our vials have a shelf life of 3 years-4+ years. We vial our NK cells in an infusion-ready media. It's a 5 minute-10 minute IV push. Really, Josh, it's the closest a cell therapy gets to a biologic. The third element of the story, and this is the reason why NK cells in many ways are really differentiated from other therapies going into the space, is the fact that NK cells are much safer than all of the other modalities that leverage T cells. Whether you're working with auto -CAR-T or whether you're working with allo -CAR-T or T cell engagers, there have been reports of CRS happening with those. One of the things about NK cells is that you can get very potent killing without the side effects that are typically seen in these other T cell modalities. We did a lot of clinical work in the oncology space, which we can talk about. Today, we're in the autoimmunity space running a few different trials, exploring a number of different indications. I'm sure we'll be talking about that. In that answer, you kind of alluded to the things that the allo-NK platform can do that others can't. There's obviously a lot of innovation in the B cell depleting space, ranging from CAR-Ts to bispecifics. You might even consider FcRn. As we kind of think about this evolving landscape, in terms of the practicality of it to a physician or a patient, depending on where they're practicing, which is an important variable, what can the allo-NK product profile do or achieve that the others may not be able to? We're trying to get to this idea of where do you fit? Right. We like to think about that in terms of the dimension of efficacy, right? As everybody starts to share and generate their data, we're going to see that there's going to be a range of efficacy that different products will have. At the same time, we're going to see a range of the safety profile, right? Which means that you can imagine a world where you're going to have some therapies that are going to be more potent than others, and some therapies that are going to be more amenable to the community setting than others. When I think about playing to allo-NK's strengths, it's actually going after a high degree of efficacy, because that's what we have seen from our oncology experience, is that the B cell killing can actually be pretty profound, as well as trying to go after a safety profile, which would allow our therapy to be compatible with community administration. We think that's really interesting because, you know, again, the autoimmune space is very large with a lot of different indications. In some indications, it'll be very appropriate for patients with moderate severe disease to be hospitalized for some time. In other indications, that's not what patients typically do. We believe that we could play best by going after indications where we can play to the safety strengths that we have already demonstrated, as well as the potent B cell depleting effects, which we have seen so far. Okay, so maybe starting on the efficacy profile, because there is an evolution happening in the competitive space as well. We'll be talking with [Cataletta] later about their lymphodepletion-free approach and how that may have appeal to practitioners. Coming back then to the profile of the allo-NK, which does include fludarabine, cyclophosphamide, Rituxan, help us understand that safety profile, where there may be comfort or discomfort with the regimen in total. Okay, great. I do think that there's a lot of misinformation on FluCy, and I think that we will understand it better after we have more data so that people try to understand. I think concerns around FluCy first came about when people were looking at the fact that auto- CAR-T, which was really the first modality to utilize FluCy, they came to the realization that auto- CAR-T is best used in a hospital setting, right? When someone thinks about, okay, well, auto- CAR-T, which utilizes FluCy, is being done in a hospital setting, the question is, why has auto- CAR-T been used in a hospital setting? Is it because of the FluCy, or is it because of the inherent nature of auto- CAR-T and how it kills B cells? We have had an opportunity because NK cells have a very benign safety profile, and this has been shown in all NK cell trials out there. We have an opportunity to isolate the effects of Cyflu from everything else that is happening with the patient. That gives us some pretty unique insights in terms of understanding what Cyflu does and what it doesn't do. Let's first talk about why we use Cyflu. First of all, I would argue that we haven't really seen any trials of cell therapy that have not utilized Cyflu, and they have been successful. There have been reports here or there, or maybe there's some data sets that can be generated with a small N, but thus far, I would argue Cyflu has been important for any cell therapy because, number one, it prevents the immune system from actually rejecting or attacking the allogeneic cell therapy. We have demonstrated that in our hands, our NK cell therapy usually lasts for around a week. That explains our weekly dosing. The Cyflu enables the NK cells to actually survive for a week after each dose, hence giving us the opportunity to have the effect. The second thing Cyflu does is it reduces the B cell burden significantly. We can see this very clear in some of the initial [Shred] papers where he demonstrates that at the time of the treatment, he gives the Cyflu, the B cells are basically depleted in the periphery before any auto- CAR-T is even detectable in the peripheral blood, suggesting that there's an initial carpet bombing effect that the Cyflu provides. We know that Cyflu can cause a temporary depletion of both B cells as well as lymphocytes and neutrophils, but that is very transient, right? You do need that agent that's going to be the deep depletor to actually do that. Now, with Cyflu itself, then comes the question, great, we understand why it is beneficial. We understand that people that are trying to eliminate Cyflu are running the risk that their efficacy is not going to be so good. What are the things that make us comfortable that the safety profile of Cyflu is not going to be a clinical impediment or commercial impediment? First of all, the doses of Cyflu that we all use are actually really low, right? Let's take CY, first of all. Cyclophosphamide, you know, people, rheumatologists have used in varying doses. The lowest recommended dose for CY is what's called the EuroLupus regimen, where one is using roughly 3 g of CY. The amount of CY that we use, and we use it once at the beginning of the regimen, is actually half of that dose, right? We're starting with the dose of CY that has already been deemed very safe. When it comes to flu, rheumatologists are not used to using fludarabine, but if one goes back in the literature, one will find some papers and actually a chapter where dozens of patients were treated with the same dose of flu that we use once, that we all use once, but they used it monthly over 6 months. The conclusion of that chapter, for example, is that it was fairly well tolerated. The problem is that it wasn't very efficacious. We're talking about using once Cyflu, and that Cyflu, when you look at the effects on the immune system, it's actually very transient. It lasts roughly 2, 3, 4 weeks. During that period, most patients in our trial are in prophylactic antibiotics, antivirals, antifungals. When you think about the actual risk to a patient from the utilization of Cyflu, that has actually been overblown because people have not been able to see what the impact of Cyflu on its own is. Just to close it, I would say that our goal, right, we often talk about Cyflu in a vacuum. We say, do you like Cyflu or do you not like Cyflu? I don't think that that's the right question. The right question is this: we are utilizing our NK cells to enhance the activity of a monoclonal. When you add Cyflu to that, will a physician that's treating a patient manage the patient any differently, whether they're using Cyflu or not using Cyflu? I would argue if the way a physician would manage a patient on Cyflu as opposed to not on Cyflu but receiving the rituximab in our therapy, if those are very similar, then who cares if the patient's actually utilizing Cyflu? Time will tell. We have to generate more safety data. Importantly, we have to generate efficacy data. Also importantly, others have to try utilizing their cell therapy without Cyflu for us to be able to have a conversation on whether they are getting equivalent efficacy or are they taking a hit on efficacy because of the fear around Cyflu. You've got essentially four therapeutic components, if not more, to consider, right? There's the cyclophosphamide, include it. If so, what's the right dose? Fludarabine, include it. What's the right dose? Rituxan, and then, of course, the allo-NK cells. As you're looking to kind of thread this needle on pristine safety and strong efficacy, how do you think about every single lever and making sure you're up to? Do you need the fludarabine because you've got Rituxan on board and answering questions like that? Yeah, so let's think about the components. First of all, let's start with Rituxan, right? The goal of our allo-NK is to enhance the efficacy of the monoclonal. The monoclonal has been optimized over the last 20 years, regardless of the antibody you're looking at, whether it's CD19 or CD20, and regardless of the CD20, what the community has landed on is that you give a gram of the monoclonal 14 days apart, right? How does the monoclonal work? One of the most important components of how it does its work is by leveraging endogenous NK cells to drive that efficacy. What we have learned is when we give exogenous NK cells at very high doses, we really enhance the efficacy of the monoclonal. That's one component. The goal there, in terms of this combination, is you have the monoclonal, we use it exactly how the label suggests we should use it, and we add high doses of the NK cell so we can enhance the activity of the monoclonal. The Cyflu is given so that we allow the NK cell to actually do its work. We're using the same Cyflu dose that has been used traditionally in cell therapy. We don't really think about multiple different drugs being used in a way that you don't know how to compare them because we know what the monoclonal does on its own. We are going into indications where the monoclonal has been used a lot. If one wants to know, here is what the monoclonal does on its own, this is what your regimen does, we're looking for a significant difference between what the monoclonal does on its own and what we're doing. When you look at what Cyflu does, it's been shown in many clinical trials that Cyflu can give you a transient benefit in terms of B cell depletion and in terms of benefit, but that goes away. The goal of that Cyflu, as I mentioned before, was to carpet bomb the system initially in terms of B cell reduction and to give the allo-NK an opportunity to last longer. Ultimately, we do understand that people are going to ask the question, first of all, on the efficacy. Are you better than the monoclonal alone? There we have to demonstrate, first of all, the monoclonal is used chronic dosing, and we're trying to show that with one treatment, we can actually get a big benefit. You're looking for efficacy that lasts longer than what the monoclonal would do on its own. The second thing we know is that the response rates to the monoclonal are relatively low, and we're trying to go for higher response rates. On that basis, it should be pretty clear what efficacy we're generating above and beyond the monoclonal alone. You noted two to four weeks of prophylactic antibiotics, antifungals, and antivirals. That is a bit of a kick to it, that in the community setting, how do you think about receptivity either from the treating physician or the patient, which may be a good segue into the enrollment update that you recently provided via an insight into the receptivity of that profile? Yeah, so look, in the early days of a clinical trial, if you were to ask me, what are the things that a lot of our PIs ask, right, that haven't had experience with lymphodepletion, they ask the question, what is the exposure that these patients are going to get to infections? That is one of the concerns with lymphodepletion. What we do is we make it optional for them, you know, we have been making it optional for them to use prophylaxis if it makes them more comfortable. If you have a severe case of a particular autoimmune disease and the physician is treating you with something that could give you a significant improvement, I think it's reasonable to also add on top of that prophylaxis if it's going to make the physician feel comfortable. Over time, I think what we're looking for, and this is why some of the data we're going to be sharing at the end of the year is going to be pretty meaningful, we're trying to answer the question, okay, let's say you take a bunch of patients and you treat them with Cyflu and the monoclonal and the NK cell. You're saying that it's pretty safe, but how many of these patients actually have to be hospitalized because they develop a fever and now you have to hospitalize them? We know from the rituximab experience alone that there is an incidence of like 5%, 10% of serious infections, right, that have been documented. The question is, are you in line with what these biologics demonstrate or are you significantly higher? If you are significantly higher, then there is a cost to using Cyflu. If there isn't, and I think you're looking for two things. One is the overall rate of hospitalization as well as the acuity of it. One of the concerns that I have around cytokine release syndrome in general for the field is if you have a fever, a grade 1 CRS is just a fever. The question is, what do you do with that fever? Do you give tocilizumab right away? Studies have shown that if you have a fever in the context of auto- CAR-T and you give tocilizumab right away, that CRS will not escalate and it'll be pretty safe. If you don't give the tocilizumab and you just let the patient sit with that cytokine release syndrome, the question is, does it escalate and how quickly does it escalate? We know from the [erlogan] studies that they are fairly aggressive with the use of tocilizumab. Whenever a patient develops a fever, for the most part, they actually give tocilizumab because they don't want to see that patient escalate. Now, in the context of trying to use any of these modalities in the community setting, now you're a community practitioner, you're not treating your patient in the hospital setting. You're treating them in your infusion chair and you're sending them home and then they call you in the middle of the night with a fever. What do you do at that point? Do you now have to bring them in because it's a fever and you want to be safe so you have to give them tocilizumab, or can you treat them the way you can with Cyflu and with rituximab where you say, let me give you a Tylenol first, let's see how you do, and only if it gets concerning do I actually have to bring you back? Because that's ultimately the target product profile that you need in order to give this in a community setting. There is the outpatient setting, which if you go to a tertiary care center, there is a building that's called the outpatient building. One thing is to treat somebody there, send them home and call them every six hours and see how they're doing. The other thing is for you to truly be in a community setting where there's a standalone community practice, you treat the patient in an infusion chair, you send them home and the people on call are either that physician or the nurses that are there. We are trying to see whether we can generate safety data that would make our therapy compatible with that real community setting application. Give us the update on enrollment and then let's start to talk about the type of data we'll see towards the end of this year and how to interpret it. Presumably, we'll be very focused on safety, we'll be looking for signs of immune reset, but you also have Rituxan on board to adjust for us. Maybe kind of. Yeah, on the enrollment side, in our last press release, we shared that we have over a dozen sites, we have enrolled over a dozen patients. I'm happy to share that securing sites in the early part of this was actually really hard because we were approaching auto- CAR-T centers. As we've talked a lot about this, it's actually complicated to get a tertiary center to embrace an auto- CAR-T trial in the rheumatology space because you need immunology, you need rheumatology to speak with oncology, you have to organize all those contracts. We found that by knocking on the door after they were already pretty busy with a number of the leading players that have made a lot of inroads there, it was taking us a long time to secure sites. Because of the safety profile of our product, we've learned that we could be quite productive by going beyond these auto- CAR-T centers. That explains why our enrollment and our site activations have actually picked up. We've been doing pretty well there, and we're confident that in time we will generate a robust data set. Got it. Okay. Twelve patients enrolled. Any early projections in terms of, again, towards the end of this year, how many patients' worth of data? Is it going to be based on duration of follow-up where you're only going to share data with patients who've reached a certain time frame? Just kind of want to start to lay out some of the next updates and then rolling into 2026 and what we'd expect there. Right. We have over a dozen patients treated, right? You see, the difference between us and auto- CAR-T is that a lot of times you enroll a patient, but then there's a waiting period from the time you enroll them to the time when drug product is available and they're treated. With us, the minute you're enrolled, next week you're coming in to receive your drug because it's off the shelf, right? Whenever we talk about patients being enrolled, we basically are talking about them being treated because there is no delay. We haven't settled on exactly how many patients' worth of data we're going to be sharing, but the way we've laid out our guidance is, you know, as we shared before, this over a dozen patients treated were treated across a number of different indications. The reality is it's very hard to make efficacy judgments from one, two, or three patients in any one indication. The way we thought of sharing our data is we will pool the data that we have generated before year-end in the areas where you can pool data and it's meaningful. The two places I would argue where that's meaningful is in B cell depletion, trying to give a sense of how well we are depleting the B cells. The second place is on the safety side because safety should be similar regardless of the indication you're pursuing. We plan to share that data so that as part of our story build, which entails MOA is working as we plan, the safety profile is consistent with the community setting, as we have been saying. The other thing we will do before year-end is to actually announce what the lead indication is that we're pursuing. You see, right now, one of the problems that our field has is that there's a number of us that are all pursuing deep B cell depletion. We're working on a variety of different indications. That doesn't give each one of us an opportunity to break out. I think some of our auto- CAR-T colleagues have done a nice job breaking out. Kyverna now has a set of indications they're going after. [Aleta] does the same. We also want to, you know, announce an indication that we're going after and be able to have an opportunity to break out from the rest of the field because ultimately all of us need to be pursuing an indication that we're excited about with efficacy and safety compared to the standard of care that would make it really compelling. After we announce what that indication is by year-end, the idea is that in the first half of next year, we would share efficacy data on a subset of the patients that we have enrolled in that indication so that we can make the comparisons between what the standard of care does in this population as opposed to what our efficacy is. That way, people will have a complete picture of the efficacy and the safety profile of the therapy within that indication. Really, the way to break out is for an investor to be able to look at the company and say, I understand the efficacy, I understand the safety, I understand what it's going to take for them to get to a BLA, and I understand where they are relative to others in that race. We think the combination of these things, if we can do a good job demonstrating progress, generating the right data, we have an opportunity to break out. As we look at B cell depletion, are we looking for depletion with immune reset? How do we define immune reset? Or how do you define it? Right. I think that we would say that an immune reset, biologically, is this idea that you are depleting the B cells really deeply. When they are reconstituting, they're reconstituting with a more naive phenotype. The way Sheth described it is if you do that, you do see a reduction in the autoantibodies. Some autoantibodies may still be there because the plasma cells are not being knocked out if you're using CD19 or you're using CD20. You're seeing a certain degree of clinical symptoms that are meaningful, and the patients are off most of their drugs, right? What I would argue is as the field is maturing, part of the reason why we made a big deal about the B cell depletion and the immune reset is that we were looking for clues, early clues that the therapy was actually working. The reality is if I come to you with B cell depletion and I show you that cells are coming back with a more naive phenotype, you're going to say that's great, but are these patients actually doing well? What medications are they on? I don't know that we are going to be a year from now, two years from now, talking so much about B cell depletion and immune reset as much as we're going to be looking at actual response rates and actual endpoints that the FDA could use. We're going to be comparing those to the actual standard of care. The biology of it will be very interesting, but it won't be the defining factor as to whether we actually have something that's very compelling or not. When you say compared to the standard of care, what standard of care are you referring to? Does the fact that you're including Rituxan as part of the initial regimen imply that it'll just take longer for that differentiation to emerge? Do you think you can generate a data set that is both superior to standard of care if you define it as, what, don't define it as Rituxan? Is it also superior to the Rituxan monotherapy that's the component of the allo-NK regimen? Right. First of all, I would say everybody will always ask the question, what are you doing above and beyond what rituximab does, right? Clearly, we have to show what we're doing, that what we're doing is a lot better than the monoclonal alone because the monoclonal is not the standard of care in many of those indications. There are better therapies out there than rituximab, right? I would argue that whereas from a mechanistic standpoint, it's important to show that delta vis-à-vis the monoclonal, what is more important is trying to show that you're better than whatever is the best standard of care within each of these indications. You ask, what is the standard of care? It'll depend on the indication, right? Whatever is the best standard of care, whatever is the best response rates that patients are able to achieve in the absence of this new wave of deep B cell depleting therapies is what you're comparing yourself against. The hope is that this deep B cell depletion space, I think about it as a wave, is going to wash over every single indication, right? There is a very large market. There is an opportunity for most of the modalities that are out there. The question is, what is your target product profile in that lead indication that you're pursuing? It has to be much better than whatever is the standard of care in that indication. Maybe we can borrow some of the literature from the oncology setting and give us a sense of why you may be confident that the regimen, as it applies in autoimmunity, will be able to deliver the deep B cell depletion that will really benefit patients durably. Great. I think one of the things that we need to do is, it's been many years since people have been excited about NK cells. We sort of lost track of what has happened in the field. I think that if you go back for the last five years, one of the things that we have successfully been able to demonstrate is every trial that we ran was actually a very successful trial. We ran a trial utilizing our NK cell with rituximab in aggressive NHL patients, and we showed a complete response rate that was in line with auto- CAR-T. We recently presented the durability of the therapy, and we hadn't yet reached the median duration of response, but we were already at 19.4 months, 19.4 months. We have to realize that people have been saying, oh, NK cells don't have durability. What people have been saying is, in most NK cell trials, because you don't deplete the B cells deeply enough, you don't get a very good response, and the disease progresses. In our case, in our experience, we achieved high rates of complete responses with nice durability. That's with a CD20 biologic. We ran a trial with Affimed, which was a CD30 biologic in Hodgkin's lymphoma. Again, B cells, Hodgkin's lymphoma. There we were also able to show very high rates of complete response with very nice durability. I think we have been able to demonstrate that from a mechanistic approach, when you just take the monoclonal, so rituximab in the context of an aggressive NHL patient, you would never get the levels of complete responses and durability that we got with the full regimen. Same thing with the Affimed drug. When they tried their drug as monotherapy, very low response rates, but then you combined it with our NK cell with our regimen, very high response rates that were actually really durable. If the mechanism is deep B cell depletion, what a great petri dish to test this in the context of B cell cancers, where you will definitely progress if you haven't killed all the B cells that have already transformed. We're trying to take that experience into the autoimmunity space, where we're starting with a regimen that has already been shown to be quite potent from a B cell depletion perspective, and with this opportunity to have a safer profile than others have shown. Do you feel that you need to match the CAR-T on durability, or do the advantages that the allo-NK approach bring allow for a little bit more flexibility if patients start to, say, relapse after one year or two years to come back for another easy go of an easier tolerated regimen? Right. No, we don't. We don't think that we need to have the same level of efficacy as auto- CAR-T. You know, auto- CAR-T will require a more involved, you know, treatment paradigm around it compared to what we are doing. We think that the bar is going to be less for the utilization of our regimen in a community setting. Because we are off the shelf and we can give the NK cells, and because we have embraced lymphodepletion, you could do it more than once, right? Even in our current regimen, we treat patients upfront, and then the physician and the patient have an opportunity for a second cycle at six months if they haven't quite reached the level of efficacy that they would like. We would like to see that most patients benefit from a single cycle, but the protocol, because of the flexibility of how the drug is used, already allows a patient to receive a second cycle at six months. Over time, as we optimize the notion of multiple dosing, you know, will this be something that you receive every 12, 18, 24 months? Is it something that you receive as a second dose if the first dose hasn't quite achieved what you're looking for? Bottom line is, no, it's the overall target product profile that matters. It's the right degree of efficacy given the safety profile and the flexibility that you can give it multiple times. As you hone in on a target indication, lead indication, how close do you think you'll be at that point from having a robust enough data set to start thinking about a pivotal trial? What we're seeing from the field is very quick, past pivotal trials and actually very small pivotal trials. Right. Yeah, look, that's one of the advantages that we think we have in that we started in autoimmunity with a dose and a regimen that was already quite active in oncology. Our trial starts with a starting dose of 1 billion cells per dose, and the highest dose is 4 billion cells per dose, two dose levels. We tested these two dose levels in oncology. They worked very similarly. We will see what the results are in the autoimmune context. The great thing about it is because of the safety profile, there isn't a lot of optimization that needs to be done. To answer your question, yes, we are hoping that as we are defining what the indication is and generating the data we need, we will be generating that data already within the therapeutic index that we hope we can take all the way. All right. We are looking forward to these big updates towards the end of this year and into next year. Fred, thanks so much for sharing the Artiva story with us. Thanks for having us, Josh. Thanks everyone.