All right, morning everyone. Welcome to Jefferies Healthcare London Conference 2025. My name is Roger Song, one of the senior analysts covering Smith Biotech at Jefferies in the U.S. It's my pleasure to have the next fireside chat with Ativa Therapeutics CEO Fred. How are you, Fred? Great. Thank you for having us. Accent excellent. Yeah, I think Artiva is in the inflection point to create a real value for cell therapy in the autoimmune disease. Maybe. Fred, why don't you give us some very high level view how you think Artiva is differentiated cell therapy for autoimmune disease. And then we can go right into it. Right? I think that there's a lot of excitement around the potential of the deep B cell depleting space. I personally have no doubts that this is gonna be an area that's gonna wash over all the autoimmune indications given the data, very encouraging data that we have seen from the AutoCAR T modalities. Now, the issue with AutoCAR T is even though it's demonstrated great efficacy, that efficacy comes at a cost in terms of scalability and perhaps the requirement for hospitalization and the cost. What AlloNK offers is an opportunity for an off the shelf product with the potential to actually have what one wants from cell therapy activity, as we have demonstrated in cancer, but with a tolerability profile that looks a lot more like a biologic, as I'm sure we're going to get into. We dose our patients primarily in a community setting. It's primarily community rheumatologists giving our drug. They give our drug to patients in the infusion chair, the patients go home. This combination of cell therapy activity with biologics-like tolerability gives us an opportunity to actually access a number of indications that are more challenging to do if you have a more complicated and expensive therapy. Absolutely. Okay, great. I think this is a great promise to deliver for the cell therapy non-immune disease, B cell depletion. You're not just in the concept stage now anymore, right? You are in clinical. Maybe give us what's the current ongoing clinical trial. I believe you just gave us some safety update from the trial and then maybe give us some highlights. What's the data you have shown pretty recent. Then we can ask a couple detailed questions. Yeah, so we have treated over 100 patients overall. It's important to note that a number of these patients were in the oncology setting. We ran a trial in non-Hodgkin's lymphoma where we saw very high rates of complete responses with strong durability. We provided an update on that durability just a few months ago and we had not reached the median duration of response and we were at 19.4 months. There are some conversations about people assuming that NK cells don't have durability, but in my mind, every product is different and one has to look at the individual product and understand that in order to drive durability in cancer, as well as perhaps responses in autoimmune disease, one needs to have a really deep B cell depletion in order to achieve the MOA. We had the NHL trial which completed enrollment and we're following those patients. We also ran a trial in Hodgkin's lymphoma with a CD30NK cell engager. That trial also demonstrated high rates of complete responses with some nice durability. A couple years ago we transitioned into autoimmunity. Right now we're in the process of running three trials. One is an investigator-initiated trial and two are company-sponsored studies. There are five indications that we're primarily focused on in terms of, you know, treating patients with those indications. That includes RA, which we have already announced is our lead indication. We're also treating patients with myositis, scleroderma, lupus and lupus nephritis, and Sjogren's. From those patients, as we have guided, we have already treated 32 patients and we continue to enroll. The safety data that we provided, we provided two things. First of all, we have realized that whenever one looks at the results of AutoCAR T, the results are clearly directionally compelling. There is quite a bit of variability when one looks at the academic studies. It generally works in every patient all the time. When we look at the totality of AutoCAR T, including all the companies that are working on it, for the most part it works pretty well. There is a degree where some patients respond more than others. That makes a lot of sense because across all the autoimmune diseases, depending on the degree of fibrosis, the history of your condition, sometimes there is only so much that immunomodulation will do. What is left is fibrosis and pain that is left over. We believe that it's important to actually have a sizable data set within a follow up in order for that data to be interpretable. What we discuss is we would wait until the first half of next year to share data on at least 15 patients with RA, which is our lead indication. At that point, several of those patients should have six months or more of follow up. What we thought would be valuable is to actually pull all our data in order to discuss safety, since safety should be the same regardless of indication, as well as taking a translational look at B cell depletion. Again, across all these indications, the objective is to drive a really deep B cell depletion. We provided an update on 32 patients that had been treated as of the cutoff date. It had a really clean safety profile, unlike what one sees with other products and other modalities in this space. We saw no CRS at all, no ICANS, no GVHD. Even though we provide cyclophosphamide and fludarabine to our patients, there was only one patient out of 32 that was actually hospitalized for an infection. The patient received IV antibiotics for three days and went home. It was pretty much as clean of a safety profile as we could have hoped for, despite the use of cyclophosphamide and fludarabine. We think that there is a lot that is misunderstood about the risks of cyclophosphamide and fludarabine that is generally used at these doses in the context of AutoCAR T. It is very hard to tease apart what is the toxicity that comes from the AutoCAR T, which is the reason why patients are hospitalized, versus the CY flu itself, which can be very easily given in an outpatient setting. It typically is. Even in the context of AutoCAR T, the CY flu is generally given in the outpatient setting. On the safety side, we were able to demonstrate that using NK cells, using cyclophosphamide at the doses we are using actually leads to a fairly tolerable safety profile, which we believe is very compatible to community administration. The way we like to think about it is whenever one thinks of cell therapy, there are a number of things that come to your mind, given the toxicities that we have seen in the past. Here I think the point, the most important point that I want to come across is the fact that treating with our full regimen is a lot closer to a community physician treating with rituximab alone than it is to what usually comes to mind with cell therapy. Now on the. Can I just pause for a moment for the safety. I think that's very critical. No CRS, no ICANS, no GVHD. And then for the site flu-related AE or infection, one case hospitalization just like you said, it's very hard to tease out between the site flu versus the CAR T or AutoCAR T kind of which cause what. And then how are you gonna make sure this is not caught in by the, okay, is that the kinetics of the site flu or the severity of the infection? You think it's not related to that? Okay, let's separate a couple of things. When I say it's complicated to tease out, nobody thinks that the reason why one is hospitalized when they utilize AutoCAR T is because of the side flu. You generally get hospitalized for two reasons. It's the CRS and the ICANS, period. Right. We know that AutoCAR T can cause CRS and it can cause ICANS. We've had, you know, close to 200 patients now treated with AutoCAR T in the context of autoimmune disease. Whereas the CRS and the ICANS can be managed in a hospital setting quite effectively using tocilizumab. The point is, NK cells, they do not cause that same runaway CRS and ICANS as T cells or T cell engagers can actually do. That has been shown not just by us, based on our experience in oncology, but also just in the literature. There have been a lot of trials utilizing NK cells, and it is just not a feature. The reason why it is not a feature of NK cells is that when T cells kill B cells, they typically expand. The way in which they kill the B cells causes this release in cytokines, which causes the CRS and the ICANS. NK cells do not do that. They do not do that for two reasons. Number one, because it is a different effector cell, so the release of cytokines is actually very different. Number two, they do not expand the way that CAR T and AutoCAR T does. That expansion in and of itself also releases a lot of cytokines. We give billions of NK cells, which for the most part do not expand, and so they are able to kill the B cells without actually causing those side effects. That is the piece of separating the safety from the Cy Flu from the safety of AutoCAR T. When it comes time to what is the safety profile, what should one expect from Cy Flu? First thing I will note is the doses of Cy that we are using are actually very low doses. If you look at the Euro-Lupus protocol, which is the lowest dose Cy recommended, which is a relatively low dose and very well tolerable, our dose of Cy is half of the exposure of what one gets in that protocol. Very low doses. When you look at the dose of Flu that we use, on the one hand, rheumatologists are not used to using Flu, fludarabine. On the other hand, there's been a lot of studies actually exploring the effects of fludarabine in patients with rheumatological diseases. In those studies they generally give the same dose that we give, but they give it every month for six months, so six times our doses. Even on those studies it was determined that it was fairly well tolerated. The main issue is that it didn't work very well. Right. We feel really confident going in that the SIFU does not create a significant tolerability issue. When you look at the entire package of the entire tolerability of the whole regimen, again, it looks a lot more like a biologic, like using rituximab than utilizing cell therapy. Maybe the last thing I'll say is we need to take a step back and ask what is the SIFLU doing. Right. Like what should a treating physician be thinking about? What the SIFLU does is it literally reduces your lymphocytes and your neutrophils during a period of one to a few weeks. That's all it's doing. It's basically a lab value that you have to follow because if the patient is symptomatic, if they develop a fever, or if you're concerned that there may be an infection, then you have to actually address it. As we have demonstrated in 32 patients, there was only one patient that had an infection that actually required the physician to say you may have an infection. Let's send you to the ER to actually find out if you need something. We are really confident that this combination of components in our treatment regimen can actually deliver this cell therapy-like activity, but with a very tolerable tolerability profile. Yeah, that's very clear. Thank you for that. Just one follow up and then we can move on to the translational data as well. For the safety, I understand it's completely different from the AutoCAR T and then the side fluid is on the low end and then nothing really concerning. Any specific NK related AE you really watching for? Because it seems CRS and the ICANS is more related to the CAR T. Let's just separate them, right? Not related to the NK. What you will be in all the field already start to see NK, if any specific AE we should be watching for? Look, I'm going to be honest and I'm going to tell you nothing because the side effects of the S flu and the side effects of the rituximab are the side effects that you see when you're treating with a drug. Now we've treated over 100 patients. I can tell you that there isn't a single AE that we have seen that we're like, ah, that's the NK cell. That's like a classic NK cell AE. Everything that you see you could attribute to either the cyclophosphamide, fludarabine, or to the monoclonal itself. NK cells have been deemed to be actually quite safe. Yeah, that's in line with what I'm thinking. I just want to hear from you as well because you are also differentiated from maybe some of the other NK programs is you are all NK. You're not really doing any specific engineering or additional engineering to the current NK. So that's maybe adding an additional layer of the safety. Correct? Yeah. Just to remind people that may be listening, our NK cell therapy is a non-genetically modified NK cell because we do not engineer in a CAR. We utilize monoclonals to do the targeting. The monoclonal binds to the antigen on the B cell. Then the Fc portion of the monoclonal binds to CD16 on NK cells, including our NK cell. That is what activates the NK cell and that kills the B cell. There are many engineered programs out there. Engineering introduces more complexity both into the manufacturing. There is the convenience that it is a single product. I will say that NK cells in general have been pretty safe. Even if they are engineered, they are still pretty safe. Now the one disadvantage of engineering is that you do have to follow these patients for a long period of time because it's an engineered product, which is not a requirement with a non-engineered cell. There is that nuance that makes it convenient. In general, NK cells have actually been quite safe. In general. Yeah. Yeah. I like this more endogenous approach, like not adding too much on top of what's in the nature already. Give us, give people a boost on NK cell, which do a better job for the normal kind of NK cell in the body, right? Yeah. And the scalability. Right. From one umbilical cord unit we make trillions of NK cells. Right. And the COGS, the projected COGS for a dose, our lowest dose in the trial is a total of 3 billion cells per patient, which we estimate to have a COGS of $3,000. The highest dose we're using in the trials is 12 billion cells per patient, which is a COGS of $12,000 or less. So regardless of where we price it, you know this is the type of cell therapy that can give you biologics like margins. Yeah. You say you want to achieve biologic-like profile and the safety profile and maybe efficacy gets you the cell therapy and the COGS is also in the biologics level. That's very critical because everyone asks about the cell therapy, how viable the business is, what's the business model for that? Right. I got that. On the efficacy side, maybe on the earlier side of the efficacy translational data. You have shown us how the B cell depletion and all the depths and the durability and then how have you started to see the reconstitution? What's the B cell look like? Maybe I will have a follow-up question related to how you're going to differentiate. This is caused by your NK versus the other part of the—because you're also using a toxin. Let's see the data first. Yeah. So what we did is if we take a step back and we think about what is the objective here, what is the MOA? What we're doing is we're trying to achieve a deep B cell depletion in the tissue. Right. Because that's the place where it's believed, according to all the academic work, that that will drive an important clinical response. What makes us confident that we can deploy the B cells in the tissue itself is our experience in aggressive B cell cancers. I mean, if you cannot eliminate all the B cells in tissue in an aggressive NHL, then you can't have patients that are walking around two years after treatment in a complete response. Right. I think we have proven in oncology that we can drive a pretty deep B cell depletion. The question was, well, what are you doing in autoimmunity? We do not have tissue samples in every patient and it is actually hard to get tissue samples. The proxy that everybody uses is looking at B cell depletion in the periphery. Right. Most of the assays that are used and that we have seen, published and presented by companies, utilize an assay called the TBNK assay to look for the presence of B cells in the periphery. The challenge with that assay is that the sensitivity is not very good. Usually the lower limit of detection is around 5-10 cells per microliter. What we have seen from the literature is that when you treat with a B cell depleter like rituximab, that is able to reduce B cells in the periphery at levels below 5-10 cells per microliter. When you use a high sensitivity assay, which has been used by Genentech and a couple of others, one actually sees that rituximab still shows the presence of one to two B cells per microliter, which you can catch with a high sensitivity assay that has a 0.1 limit of detection. We felt it was important for us to investigate the level of B cell depletion in our product, with our product using a high sensitivity assay, because there are a lot of folks that demonstrate that they drop B cells down to quote unquote zero using the regular assays. We see a bounce back up that happens very quickly that does not look like the curve that has been presented by the AutoCAR Ts. In this case, utilizing the high sensitivity B cell assay, we were able to demonstrate that in every patient that we treated at one point following the treatment, they had no detectable B cells at all. Every single patient. This is really important because this is as close as we can ascertain to what is happening at the tissue level. Of course, ultimately the only way to know whether it's working or not is looking at clinical responses in the actual patients. Yeah, sure. Okay, that's very critical. Right, so you can actually attribute the B cell depletion to the NK because it's more than the toxin historical can achieve. Right, okay, got it. In terms of the time course and, you know, when you start to see the reconstitution and then how the reconstituted B cell receptor look like at this point, and then what's the durability you have shown? Yeah, so what we are showing is that by around six months, the B cells start to reconstitute. That has only happened to a handful of patients. We shared in the presentation the results of all the patients that were treated with rituximab and AlloNK that also had B cell reconstitution. We see that when the B cells reconstitute, you see a predominant, present 95%+ presence of naive or transitional B cells, which is exactly what Dr. Shett demonstrated and what one sees in all the papers and all presentations that come out with AutoCAR T treatment. The good news is we are seeing exactly the same MOA and that is our approach. We are pursuing exactly the same MOA as AutoCAR T but with a product that can deliver a very compelling level of efficacy, but biologics-like tolerability. Excellent. Okay. We get through the hard part in terms of clinical and then. Okay, next year you're going to give us some clinical response data update from that program. Tell us what's your expectation and will be the next step you can moving to the pivotal because that's a speed to the market also very critical here. Yeah, I think that our entire field. So again, just taking a step back, I think the deep B cell depletion space is going to be. I do not think it is fully appreciated that it is going to be a very attractive mechanism across the board and a lot of products are going to be successful. I think some of the challenges is that it is very competitive. Right now everybody talks about what they do from the point of view of the mechanism of action and what is biologically different about their product from someone else. Soon we have to get back to what we normally talk about in biotech. What indication are you going after? What is the unmet need there? What is the standard of care? How much better are you and are you going to be the first to get there? By choosing RA, we chose an opportunity to be the first company in this entire field to have the opportunity to start a pivotal trial in RA. That would clearly allow us to break away from the rest of the pack in terms of our efficacy choices and we're setting a high bar for ourselves. In RA, when you have not yet had a biologic and you generally have your first JAK inhibitor or you have your first TNF, you have an opportunity for a 35%-50% ACR50 response. Said differently, 35%-50% of the patients has an opportunity to get to that 35%-50% range. By the time you start failing targeted mechanisms, then that probability lowers significantly to somewhere around the 10%-20%. The bar we are setting to ourselves is we want to give those patients that have already failed multiple targeted mechanisms to have an opportunity for 50% of them to have an opportunity to actually have that ACR50 response, which would clearly be superior than anything else that has been approved. When you look at the late stage pharma pipeline or biotech pipeline, still there are no agents that are promising to show such a high degree of response in a late line population. We are excited about the potential. In the first half of next year, we will both share our clinical data in RA as well as we plan to share some feedback that we hope to receive from FDA with regards to our thoughts on a pivotal trial. Okay, so we're going to get both updates and then do you think you will be able to move into the pivotal pretty quickly in this refractory RA population? We hope so. A lot depends on what we agree with FDA, but we are increasing fairly rapidly the number of sites that we have. All of the patients that we treated so far that we have shown have been treated in the U.S. and we're in the process of actually activating international sites. By the time we start that pivotal trial, if we have an opportunity to do that, we should have a pretty strong clinical piping in place with dozens of sites that are actually open with RA patients that we can then leverage in order to enroll into the pivotal trial. Got it. How big is this post 2 line of therapy for RA? Because that's not a typical study population we have been seeing. Correct. It's the largest market in autoimmune disease of refractory patients. There are over a million patients in the U.S. alone that have RA. The specific population that have failed at least two targeted therapies is in the 150,000-200,000 patients in the U.S. alone. It's a really large market. If we have the opportunity to be the first to bring this mechanism into that market, that could be really exciting. I totally agree. Yeah. Okay, so last minute, you know, what's your cash balance sheet look like and then how you think your financing is supporting this program going forward? Forward, yeah. As of the end of September, we had $123 million of cash. As we've guided, we have enough runway into Q2 of 2027. A decent amount of runway to actually get through many of the milestones that we talked about. Excellent. You have the money, you have the data. Now just we're looking for next year, this update from the clinical response and then also the FDA feedback. Correct. Awesome. Great. Thank you for the time this morning. Thank you everyone for listening. Thanks, Roger. Thank you.