Good morning, everyone. Welcome to day two of Jefferies Global Healthcare Conference. My name is [Fiona Jia]. I cover mid-cap biotech companies at Jefferies. It is my great pleasure to welcome to the stage Artiva Biotherapeutics CEO, Dr. Fred Aslan, to this fireside chat with me. Welcome, Fred. Thank you, [Fiona]. Thanks for having us. Yeah, Fred, you've been busy. You just gave us impressive RA data just last month, and you also got the FDA alignment on the single pivotal trial, and you're having some data presenting as we speak at EULAR. Give us some highlights on what's the setup from here. Yeah. We're really excited about this space. I would argue that the data that has been presented by auto CAR-T in autoimmunity is probably the most potent mechanism that we are seeing today in terms of the possibility of taking refractory patients and giving them durable responses. Right? This is an area that has drawn a lot of strategic interest. I think if we look, almost every single pharmaceutical company not only has one program in the deep B-cell depletion space, but many of them have actually three, which just shows the degree of interest in the space, because at the end of the day, it's going to be about the target product profile and are you first to market? Are you second to market? Those ultimately are the things that matter when you have a really crowded space that is evolving rapidly. In our mind, when we pivoted into the autoimmune space and we were coming off of really good data from oncology, it was a challenging time because you had so many companies coming into the space, and each one is trying to, in a way, convey what the potential advantages would be from their specific modalities. It was all speculation at that time because there was no available data. Companies chose different paths. Some of them started to share data on one or two patients, whereas others decided to just wait until they had a more substantive update. We chose to do the latter because we felt that that would be the most impactful way to have more substantive conversations once we're able to show that. A lot has happened, and to your point, everything sort of came together in the last month. Number one, we shared our first efficacy data set. These were around 37 patients that we treated with autoimmune disease. To date, we have treated over 70, which we think is one of the largest data sets that have been generated to date in the deep B-cell depletion space. We shared data on 37 patients, and together with our oncology data, that conveyed a very consistent picture of auto CAR T-like efficacy. We demonstrated that in non-Hodgkin's lymphoma, we demonstrated that in Hodgkin's lymphoma, and then we shared data on RA, Sjögren's, and scleroderma showing this consistent benefit. The second thing we shared, and we had done this a few months prior, was to show that our therapy really has a very compatible ease of use with the community setting, right? The vast majority of our patients were treated in a community setting, so these were rheumatologists who were treating their patients in his or her infusion chair. The patient would get the IV infusion, and they would go home. This is as close as we get to a cell therapy being like a biologic from an ease of use. Then finally, there's been a lot of competition in terms of which indications to go after. I think the auto CAR-Ts gave us a good roadmap of the different indications where one could pursue, and that validated the deep B-cell hypothesis. Whereas there was a lot of competition around lupus, and everybody started in lupus because that was Dr. Schett's initial data set, we chose indications where we could be first. We think that that is really important because if you are first to bring something as potentially clinically compelling as what we're doing, that will make a difference, particularly if the efficacy is indeed similar to what we've seen with auto CAR-T, if you really are tolerable enough to use in a community setting, and if indeed, the benefits from the therapy can be durable. We wanted to share all this data after having a conversation with FDA about a potential registrational trial in rheumatoid arthritis. That's our first indication. We are pursuing patients that have rheumatoid arthritis where they have already failed two or more biological-targeted synthetic DMARDs, and we're coming in as an alternative approach to just cycling through your third, fourth, fifth. Based on the results we shared, we're pretty encouraged that with efficacy like that, if we have the possibility of being first to market, which we are slated to become if everything goes according to plan, that this could make a really big difference. Yeah, absolutely. Yeah, definitely a lot to unpack there. Let's dive in some deeper questions. Whenever we talk to people about RA, I think a common misconception is that this market is so saturated, too many players, too crowded. First of all, you are not in RA, you're in two-plus refractory RA. Just give us some idea of how big this market actually is and what's the unmet need there. There are around 14 different approved drugs in rheumatoid arthritis covering six different mechanisms. There's been very heavy competition to actually get an approval in RA so you can be the first agent that people use in RA or even so you can be the second agent that people use in RA because it is the largest autoimmune indication. Nobody has ever developed a product or actually spent a lot of time reviewing what happens to patients after they have failed their first drug. Then they go on to the second drug, and they fail that, and now they have to go into their third drug. The reality is that 25% of patients that ever go on a biologic or a JAK become refractory to two mechanisms. If you actually go through the real world registries and the different trials that have been run, it's pretty clear that the opportunity for an ACR50 response, and I use that as my lens to discuss the market since that's the regulatory endpoint, the opportunity for getting an ACR50 response is in the 10%-20%. Out of the $20 billion that's spent today on biologics and JAKs, around $5 billion of that is spent on patients that are refractory to two mechanisms already, and their opportunity for an ACR50 is only in the 10%-20%. There is a massive opportunity, but these patients are actually really difficult to treat. Some physicians, I would say many physicians, in the absence of actually having any other alternative, what you do is you just keep cycling them through it. If you spend the time, and I know you guys have, asking some physicians about how optimistic they are that they're going to get a good response in patients that have failed, they're not that optimistic. Today they have no option. That's the only thing that you do. Given the potency of the deep B-cell depletion mechanism, and given some of the preliminary data that we've seen with auto CAR-T, we had the hypothesis, we weren't alone, many people had that hypothesis, but that you could really make a difference in this patient population. It's a very large population. It's one where the patients are spread out in the community. We felt that this would play to our strength. Our therapy is a non-genetically modified, NK cell with a monoclonal that has the efficacy that can be auto CAR-T like, but with an ease of use that's more like a biologic, so it can be easily used in the community setting. That makes a lot of sense. Just getting back to this benchmark, as you mentioned, 10%-20% seems very low, ACR50. How did you get that? I know there's not a lot of large trials on refractory RA. Just talk to us about the CorEvitas registry. Yeah. There are two ways to get at that. Number one, the Europeans have actually defined patients like this as difficult-to-treat RA. It's not just failing two medications. There's other criteria. That is at the core of that definition. We have seen academic studies run in difficult-to-treat RAs. That's one data set that you can use. The other data set that we found to be pretty robust is the CorEvitas database. Many people are not familiar with that. That is the largest U.S. registry of physicians that input data on their RA patients, and it has 25 years of existence. They have treated thousands of patients, and this database was actually purchased by Thermo Fisher, who now offers the mining of that database as a service to pharmaceutical companies and biotech companies. It's a very valuable tool because you can ask questions. For example, show me every patient that has been treated with two or more mechanisms that have failed these two mechanisms and then go on to a third or fourth. Show me what their ACR50 is. Don't just show me every patient, because many of the current drugs were not available more than 10 years ago. Limit that to the patients that have only been treated since 2015. Give me a breakdown of what do JAKs do in these patients? What does rituximab do in these patients? Rituximab, of course, being really important since that is going to be the active comparator in our registrational trial. That database is actually quite valuable. We find that because not too many people have talked about this, because no drug has really ever been developed for this population, that we know this happens in industry. If you don't have a drug targeting a particular population, physicians are not really educated on the specific lack of efficacy of existing drugs. They actually have a feeling that, you know, once patients fail two, they don't have that many options. Because so many drugs are approved- it's easy to say, "Well, I still think there's more drugs available," compared to, for example, scleroderma, where there are no drugs approved. Just because there are drugs approved doesn't mean that necessarily these patients can have a lot of relief. That's where we and others that are also pursuing this indication will be doing a lot of education and making sure people understand this before we get to the point where we are potentially launching the product. That makes a lot of sense. Now getting back to your data, which I think actually surprised a lot of people, pleasantly surprised a lot of people. Back when we were talking about the target, the benchmarks, and you were saying, "Oh, we're going to hit 50% ACR50," and I remember thinking, "Wow, that's ambitious." You actually hit that. You actually surpassed that. It's very impressive, and I think one of the least controversial data out there. It has a lot of interesting components. If you can give us just three highlights from this data set, what would it be? Yeah. I think the first one I would say is we actually enrolled patients that were very refractory. Like we're using the cutoff of having failed two or more mechanisms as our cutoff. We had patients that have had RA for dozens of years that have been on three, four, five different mechanisms. We really started with the patients that were the worst. This is not surprising. This was an experimental therapy. We were specifically trying to understand what would happen with patients that were refractory. Not surprisingly, the PIs in our trials were putting the patients that had been challenging for them for many years. The second thing I would highlight was the high rate of response. I would say that across the vast majority of the patients, they were responding really well. We shared the IIT data where we didn't quite collect every single component in the ACR50, but I would argue every single patient there demonstrated a benefit. If we look at the patients in our basket study, and there were seven of them that got to six months, every one of them had an ACR response with five out of the seven having an ACR50 response. It was a very high response rate. You mentioned people were surprised, and it's one of those things, like you have to generate the data for people to finally believe you. It was one of those things. For us, we were coming out of oncology, where the data was showing auto CAR-T like effects. You say, well, if it worked in B-cell cancers, why wouldn't it work in the context of autoimmune disease? It's one of those things. There's a lot of noise, a lot of companies, people are not paying attention. This is part of the reason why we waited, because if we had come out with two, three patients, people may have said, "Well, that's just your first two, three patients. With the data set of 21 RA patients and patients in other indications, I think that paints a really clear picture of the efficacy. The third thing that I would highlight is the degree of durability. Because part of what makes this different than other therapies that are going to be developed in RA in this population is that this has a profile of a one-time treatment that then allows you to be treatment-free for potentially 12, 18, 24 months, and then you get to redose those patients. We haven't had an opportunity to redose patients after they have lost a response because we haven't had a patient that has actually relapsed, so that's a good thing. They'll come. We've seen that across the board, relapses do happen even with auto CAR-T. This is a therapy that at the tail end of that, you can actually re-treat and then hope to achieve a deep response that can also be durable. This is potentially a therapy that can keep a refractory patient in control over a long period of time, and they're coming in for infrequent infusions, and during the in-between periods, they're not on a chronic drug. Ultimately, I'm sure we'll talk about the competition. That is one of the biggest differences between our value proposition and everybody else, is that we are offering a drug that you take once, and then you're off of your immunocompromising drugs over a long period of time, as opposed to being on other modalities where you constantly have to dampen either your B-cells or your IgG. You basically increase the probability that these patients will have an infection. That can be quite attractive for many rheumatologists. Yeah, definitely. Very impactful data set. I'm glad you finally got the recognition, both sentimentally and financially. Congrats on that. Well, I feel like we have the recognition in having been able to raise the money but we are still trading c lose to cash. So y ou should note that. Yeah, people should know there's still opportunity. I want to talk about the competition, like you just mentioned. We know there's some recent data that came out on the durability from T-cell engagers. Just comparing that to this durability profile that AlloNK has showed, I remember some of the patients that went on to almost 18 months and still hasn't relapsed. Talk to us about this comparison. Yeah, look, one of the disadvantages I'm going to have in trying to compare my data with everybody else's is that we are ahead of everybody else. I have to caveat that it won't be that satisfying for me to make comparisons with early data sets. The data sets that are most advanced are the ones coming from Erlangen, where we have seen their work, particularly with blinatumomab, where the responses were not durable. The majority of patients relapsed by three months, with the vast majority relapsing by six months. Now, that was a weaker TCE. It's not as potent. We have to see what other data sets look like. Again, what I would argue is, as our data evolves, and so instead of having 21 patients, you'll have data on 30 patients, 40 patients, 50 patients, because that is all happening in parallel to the RCT. As our data set evolves, we will see what other people's data sets are. Again, I would keep coming back to what is the response rate that people are having compared to others, and it may be comparable with other modalities. You have to look at the side effect profile, because many of the T-cell approaches do cause CRS, and we can talk about what CRS is and it isn't, and what lymphodepletion is and what it isn't. We have to understand whether is this a target product profile like ours, where you treat once and then you're in a long-lasting clinical response, or is this a chronic drug, i.e., a better rituximab? I think a lot of other therapies out there are playing to become a better rituximab. Another chronic drug that you can actually take every month or every two months, whatever that is, but you remain potentially immunocompromised during that period. Whereas we're offering a one-time treatment that will have a lasting result. Yep, makes sense. Let's talk about the next step. You got the green light from FDA on the pivotal trial. Tell us more about the design and the rationale behind it. Yeah. We approached FDA and we're working with CBER, right? This is the same agency that has actually discussed registrational trials for the auto CAR-Ts. We wanted to come in with a more robust design because w e just felt that enrollment was going really well for us. At the end of the day, because we are going after a population where there aren't great benchmarks, people would always be asking the question, "Okay, so this is your ACR50 response, but I wonder what the ACR50 response would be for my standard of care today." Because we use rituximab to do the targeting, again, as a reminder on our mechanism, we are a non-genetically modified NK cell that utilizes rituximab as the targeting agent. rituximab binds to the B-cell, that activates our NK cell, which then kills the B-cell. Right? Because rituximab is part of the mechanism and because rituximab is used in late-line RA, people would always wonder, "I wonder what rituximab would do in the same population." By proposing a randomized control trial, we would have an opportunity to show, "Listen, this is what rituximab, an agent that works as well as anything else in the same population, this is what it does compared to what our therapy does." We would be able to have the side effect profile side by side so people would see that our therapy actually has a very similar side effect profile as rituximab does. 150 patients randomized 2: 1 between our therapy and rituximab alone with ACR50 at six months as the primary endpoint. Patients on rituximab that do not achieve an ACR50 response, which should be the majority of them, are going to roll over into our AlloNK arm. That'll give us a really nice opportunity, not only to show or replicate the high rates of responses that we're seeing today, but to demonstrate that it could potentially be two times or three times as high as what one of the best agents today in that same population could do. Yeah. Makes sense. Any timing or updates on when the trial's going to start? When are we going to see the data? Yeah. We're planning to start the trial in the second half of this year, and the readout of that trial will be in the second half of 2028. Roughly two years from now. During those two years, we continue to enroll in our basket study where, again, as I mentioned, people will have an opportunity over time to see data in dozens of patients. We will understand, do you get a high ACR50 when you're not talking about fewer patients, but dozens of patients? You will understand what is the actual durability of the product. Most of our patients did not get to 12 months on this last update. Over the next 12, 18, 24 months, we will start to see what that looks like, and we hope to have an opportunity to re-treat patients as they lose their response so we can understand, can we actually drive a good response rate in those patients, and can it be as durable as the first time around? Yeah. That's going to be very helpful. Any gating factors before you can start a trial or any outstanding items you need to check off? Nothing that I would highlight here. Once you have alignment from FDA, it's a matter of submitting the protocol, getting through IRB, setting up the sites. We were by design planning for success during the basket study. We added a lot more sites than one would need for the limited number of patients that we were going to enroll in the basket study. Today, we already have north of 40 sites. All of the data that we shared was generated in U.S. sites, but earlier this year we opened sites in Europe and in Latin America, not because we needed those patients for the basket study, but we wanted to grease the skids for the RCT. We think that with 80 sites enrolling 150 patients, we have not had a hard time enrolling patients, w e should do that in an efficient fashion, which is why we feel confident to guide that by the second half of 2028 we would have the readout of that trial. Awesome. Definitely looking forward to the data. How much durability or follow-up data would you need to collect from this pivotal and also the basket study to support the BLA? Yeah. The BLA itself is based on the six months primary endpoint. Right? That is the primary endpoint. There is no durability requirement for the analysis of the BLA itself. What I would argue is FDA will be looking at the data from the basket study so t hey can build a complete picture of what the data set looks like. The basket study patients are the ones that will give us a really good opportunity to understand how durable the treatment really is and what that safety looks like longitudinally. I would say that the combination of the RCT plus the patients that we are generating in the basket study in RA, as well as the patients with autoimmune disease and other indications, that will all build the complete picture of the benefit of the drug as well as the tolerability profile. Yeah. Sounds like it's going to be a very holistic data package. Let's say everything goes well and you get approved, how do you think about the pricing? Because as you mentioned, there is potential optionality to re-dose. How do you balance that? It's not necessarily one and done, but there's optional for certain patients. How do you balance the pricing strategy? Yeah. I think of it as a range, right? It'll be probably somewhere between where biologics are priced in autoimmune disease to where CAR-T is priced. It'll be somewhere in between. I know that's a very wide range, at the end of the day, it's going to be based on, I think, two main things. Number one is the response rate. If you take RINVOQ, RINVOQ today I think costs somewhere between $80,000 to $100,000 a year. Right? The response rate in that population is relatively low, as I mentioned. If you come in with a therapy that has a much higher response rate, that's going to be a factor as you think about the annual expense that can go into pricing calculations. The second element is going to be the durability. Something that lasts two years is probably twice the price of something that lasts one year. One needs to take that into consideration also in the overall pricing. It's too early for us to start making those determinations, but it'll be somewhere in that range. Yeah. This also, though, this influences our strategy because, for example, if you're Cabaletta and you're starting to work on myositis, which I think is a very attractive indication for them to go after, they can actually command pretty high pricing there. One has to take into consideration pricing in the other indications. We are specifically trying to go after indications that have higher epidemiology, like rheumatoid arthritis and Sjögren's. That way, whatever pricing we arrive at is one that is compatible across the different indications that we are prioritizing, and because our COGS are so low because of the scalability of our product, we can pretty much price this anywhere and still achieve pretty high gross margins. That makes sense. Another thing that I want to touch on is when we talk to some people, for some reason, there's still a lingering concern over the Cy/Flu or just the concept of the Cy/Flu regimen. Tell us more about the regimen that you're going to use in the pivotal trial. Yeah, just how can you address those concerns? Yeah. I think it's going to be data-driven, right? Cyclophosphamide and fludarabine, we use the same doses as people have used in cell therapy. I would start off by saying that I am still waiting to see a data set that convinces me that when cell therapy is used without lymphodepletion, that you achieve the same level of B-cell depletion as you do when you're using it. There are a few data sets out there. When I look at the kinetics of the B-cell depletion, when I look at the levels of BAFF, I am not seeing the same level of B-cell depletion as one has seen with Cy/Flu. My angle with Cy/Flu is this. Why is it that there is headwinds against Cy/Flu? First of all, outside of autoimmunity, it's because when autologous CAR-T is given, it's given with Cy/Flu. One lumps the side effect profile of the entire treatment together, as one should. Just like with our treatment. AlloNK has very few side effects. The side effects come from the rituximab and the Cy/Flu, right? Auto CAR-T is the same thing. When one thinks of the side effects of auto CAR-T, one thinks of everything, including the Cy/Flu. The Cy/Flu gets a bad rep from that. It's not just there. In autoimmunity, people have moved away from using cyclophosphamide. If you're a rheumatologist and you trained in the '90s, you would have used cyclophosphamide a lot more, and then over time, people have found alternatives to cyclophosphamide. When you come in offering cyclophosphamide, they're like, "Oh, we're taking a step back?" We have to remember the following. Number one, the way you use cyclophosphamide in autoimmune disease is you're either using much higher doses than what we use in order to use that as a salvage treatment, or you're using it chronically every two weeks, every four weeks, as part of a regimen. What invariably happens in either of these two scenarios is that you are increasing the chances that patients will have infections. We're using a very low dose of cyclophosphamide and fludarabine once. If you follow our neutropenia curves, the average patient is not really neutropenic until day 12, 11, 12, 13. By day 20, they're already back at normal levels. There is a week or two when patients are cytopenic, which is exactly the two-week period we want them to be cytopenic so that the host does not attack AlloNK cells. During those two weeks, patients are on prophylactic antibacterial, antifungal, antiviral. That is why we are not seeing grade three, high rates of grade three infections or infections at all in our patients. The cyclophosphamide and fludarabine are pretty much asymptomatic for most of these patients, and so I think it's a data-driven approach. Today, if you ask somebody cold, "Hey, I have this cell therapy," and they use lymphodepletion, they're like, "I don't know if this is for me. The data set that we have so far is actually pretty surprisingly clean. Today, we only have 55 patients that we presented on. If I have 100, 200, 300 patients worth of data, I think at some point people realize, "You know, this is not as bad as we imagined." I think that instead of fighting this battle of we need to get rid of cyclophosphamide and fludarabine because everybody hates it, I almost take the other approach, which is it seems to be quite tolerable. We haven't seen any great evidence that cell therapy works without it. We also chose rheumatoid arthritis and Sjögren's disease because the target population is an older population because there is the lingering concern of fertility in younger females, if you're addressing lupus, it's hard to ignore the concerns around Cy/Flu, but if you're dealing with elderly patients or older patients, then again, our safety data speaks for itself. Yeah. We should just let the data fight for itself. I want to touch on the EULAR data that you're going to presenting or presenting as we speak. I know there's some data on the RA data that you just presented and also some on Sjögren's. Tell us, give us some highlight, without actually giving us the data. Yeah. What we shared as part of the financing, so we raised $300 million just three weeks ago, and as part of that, we shared the data, a lot of the data that was going to be coming out at EULAR. The EULAR data provides even more detail on that data set in RA so that people can understand even more around the specific components and the benefits that the patients receive. We're going to be sharing more color on the Sjögren's data. We haven't yet decided what our second indication is. We like Sjögren's for many of the reasons we like RA. It's a really big indication. It's the same physician that's treating them, and they're mostly in the community setting. That would be a very good call point for the type of drug that we are developing. What has been impressive about our Sjögren's data is that when you look at efficacy around Sjögren's patient, it's a combination of the clinical endpoints, the PROs, as well as some of the objective measures like salivary flow. The EULAR data actually provides more color on the individual components and how specific patients are doing, and then we just share some more information on the translational and more information on the safety. Yeah. We'll definitely be looking forward to the data. Lastly, with the financing, where does this put you in terms of finance? Yeah. We have a runway now extended into 2029, and as I mentioned before, we are going to be reading out on our RCT in the second half of 2028. This is enough financing to get us through the RCT and RA, and if we're successful, we would be the first one out of any deep B-cell depleting product to get into RA. It also funds continuing to enroll patients across all the indications we're interested in in an open label fashion, so that data becomes available out there, and it also gives us an opportunity to actually initiate a second RCT or pivotal study if we choose to. Yeah. I would say exciting time for Artiva. Thank you everybody for listening and watching. Thank you, Fred. Thank you, [Fiona].