Good afternoon, everyone, thank you for joining the H.C. Wainwright Fourth Annual Virtual Cell Therapy Conference. My name is Emily Bodnar and I'm an equity research analyst at H.C. Wainwright. I'm pleased to introduce Fred Aslan, Chief Executive Officer of Artiva Biotherapeutics. Maybe to start, for those who are newer to the Artiva story, can you give us an intro on your allogeneic NK cell therapy, AlloNK, and your ongoing pipeline programs?
Yeah. Thanks, Emily, for having us. We have demonstrated across a variety of trials in both oncology and autoimmune disease that AlloNK is a very potent deep B-cell depleting product. Specifically, where we have generated the most data to date in autoimmune disease has been in refractory RA, and we have guided that refractory RA is our lead indication. We had a very constructive meeting with FDA a few months ago, and we're initiating a phase III trial of approximately 150 patients in refractory RA. We hope, if we're successful, that we will be the very first deep B-cell depleting agent across all the different modalities to get an approval in refractory RA, which is a very large commercial opportunity.
Great. Obviously, there's been a lot of interest and recent development for cell therapies in the autoimmune disease space. What makes Artiva's approach different from competitor programs as an allogeneic NK cell therapy?
Yeah. Let's talk about efficacy and then we'll talk about safety and scalability. On the efficacy side, what we have been able to demonstrate is that when we use our NK cells, which are not genetically engineered, together with a monoclonal for targeting, that we can drive a really deep level of B-cell depletion. I think when we look across the deep B-cell depletion data across the field, there's variable results, right? We have demonstrated, even when we use a high sensitivity assay, that we can deplete the B cells quite deeply in the periphery, and that has translated into really compelling clinical results across, as I mentioned, oncology as well as autoimmune disease.
One of the big advantages of NK cells compared to T-cells is that when T-cells expand and they kill B cells, they generate CRS and ICANS, which creates a little bit of a liability in the target product profile. The story is very similar with T-cell engagers because T-cell engagers leverage T-cells which expand and kill the B cells. NK cells, and with us, in combination with monoclonal, is able to actually drive this deep B-cell depletion but without causing these side effects. That is one thing that is different. The second thing that's different is the fact that we are not genetically engineering our cells, right? There's been concerns over genetic engineering with auto CAR T, risks around insertional mutagenesis. Patients have to be followed for their lifetime.
Because we do not genetically engineer our cells, then that's something that's not relevant for us. On safety also, we were uniquely given the opportunity from FDA to actually treat our patients in community settings right away. We presented data on approximately 37 patients at last EULAR, but we have treated over 70 as of the end of April, and the vast majority of these patients were treated in a community practice. We're talking about a private community rheumatology practice where the rheumatologist was actually treating his or her patients in an infusion chair and patients were going home. That safety profile could actually make a big difference for us as we tackle large indications like RA, where the vast majority of patients are actually located in the community setting.
The final piece is that we have a very scalable process for actually making our NK cells. From one umbilical cord unit, we isolate NK cells. We could treat over 500 patients at the current dosing regimen that we're going into our phase III trial. We have a small 9,000 sq ft facility where, again, from there, if it was running at capacity, we could treat 500 patients a year. Just think about the scalability difference when we compare this with auto CAR T. Because we don't engineer our NK cells, our COGS are actually quite low. We project that a therapy to treat a patient would cost in the order of $8,000 for the cell therapy itself, which really means that we could price this wherever we want and still achieve pretty high margins.
The final thing I'll mention is just the speed with which we have remained very focused on utilizing cyclophosphamide and fludarabine as we have before. We believe that it's quite tolerable, and our safety data has actually demonstrated that. Thanks to being very focused, we were able to move fairly quickly to the point where, as I mentioned, we had a conversation with FDA about starting a phase III trial, which we're preparing to do.
Yep. Given you're combining with rituximab, maybe just walk through the B-cell depletion you've observed with the combo relative to what's out there in the literature for rituximab on its own.
Right. It's well known that rituximab is not a very complete and consistent B-cell depleter. Particularly when you look at studies in the literature that utilized a high sensitivity assay, it's pretty clear that you still see that a large number of patients continue to demonstrate the presence of B cells even after they were treated with rituximab. In contrast, when we use our regimen, we see complete B-cell depletion in the periphery using these high sensitivity assays. It's important to realize that we use rituximab as a targeting agent. It's not that we're using rituximab and that does some B-cell depletion, and then we give AlloNK, which adds to that B-cell depletion. Because we don't engineer in a CAR, we need the monoclonal to actually do the targeting.
This combination of monoclonal binding to the B-cell and these high doses of very active NK cells that come in as an effector cell is what drives this very differentiated deep B-cell depletion.
Yep. Makes sense. You mentioned that your main program in RA, you've been kind of dosing in community settings from the get-go. How is that kind of differentiated from autologous CAR T therapies, which obviously are not able to do that?
It's because of the concern around CRS and ICANS, right? CRS needs to be monitored very closely. If you only have grade 1 CRS, people call that, "Well, that's only a fever." Is it really only a fever? Because if you have grade 1 CRS, action is required to make sure that it doesn't escalate. You may have to be brought back. You may have to be given tocilizumab. Because tocilizumab is very easy to administer in a hospitalized setting, many patients, and I think most of the allogeneic cell therapy trials and the autologous cell therapy trials, they have been conducted in hospital settings because then if patients do get CRS, then it becomes fairly straightforward to monitor them and to treat them.
Because we do not cause CRS and we do not cause ICANS, the side effects from our therapy are really the side effects from rituximab and from the cyclophosphamide and fludarabine, which are agents that are typically given in a community setting. You have to remember that cyclophosphamide and fludarabine are taken at home by patients that have cancer, and rituximab has been given to hundreds of thousands of patients in a community setting. Because the safety aspects of our therapy are the known safety aspects of known drugs that have been around for 30- 40 years, that makes our therapy a lot more compatible with community administration than other therapies that try to achieve the same level of B-cell depletion.
Maybe to talk more about the data that you recently presented at EULAR, maybe walk us through the efficacy and safety data that you presented and how that kind of compares to what you would expect with maybe standard of care or available therapies in refractory RA.
We shared data in a total of 37 patients. 21 of them were RA patients, and then we also shared data on 11 Sjögren's patients and then five scleroderma patients. All in, 37 patients that we presented data on. Starting with the RA patients, we have been specifically focused on refractory RA, and what we are calling refractory RA are patients that have failed two targeted mechanisms and continue to demonstrate moderate to high disease activity. For example, this is a patient that first started taking a TNF, then that didn't work for them. Then they were put on perhaps a JAK or perhaps Orencia. That didn't work for them. Then they have an opportunity to enroll in our trial.
As it turns out, because this was a first-in-human demonstration of the therapy, we actually had many patients that had failed three or more therapies, and I think we exclusively only had patients that had high disease severity. Those are the first patients that one would test out an experimental therapy. What we do know from real-world registries and from the literature is that the ACR50 opportunity of approved drugs, once they're being used after patients have failed two targeted mechanisms, is in the 10%-20%. Meaning only 10%-20% of patients that use existing approved drugs in the 3rd line setting, the 3rd targeted line setting, have an opportunity for an ACR50. What we were able to demonstrate is that we achieved that in 71% of the patients.
It's small N, we have guided that if we could drive a greater than 50% ACR50 in this population, you have to keep in mind that no other approved product has ever achieved an ACR50 so high in any of their labels, even though they have been approved in earlier line setting. This would be taking patients that are refractory and giving them an opportunity for an ACR50 that they probably didn't have even when they had their 1st TNF. Those results were very encouraging. Of course, we want to replicate those in a larger number of patients, ACR50 will also be the primary efficacy endpoint in our randomized control trial. In addition to measuring efficacy in terms of the ACR50s, we were also able to demonstrate that the effects were actually quite durable given the limited follow-up that we have.
Historically, a number of groups have shared data at three months, and the tricky thing of looking at efficacy at three months is that when you're treating patients, because of the steroid predosing or the Cy/Flu, you may have effects at three months that could go away by six months. By actually sharing data with patients at six months, we're able to not only show that a response at the six -month mark, but we're able to show a deepening of the response going from three months out to six months. One of the other things we shared is that none of our 21 patients that we had treated actually had lost their response since achieving it, which means they were still demonstrating the clinical benefits as of the last follow-up.
Not 1 of the 21 patients as of that April data cut was demonstrating a loss of response. That was pretty impressive on the efficacy side. On the safety side, we shared safety data on a broader number of patients, it was a total of 55 patients that had been on AlloNK and rituximab. We demonstrated that the hospitalization rates were really low. We actually, in fact, only had two patients out of 55 hospitalized in the 1st 28 days. One was a patient for dehydration. It was a Sjögren's patient that experienced dehydration, and a 2nd was an RA patient that had prior diabetes that had DKA, were hospitalized to deal with the DKA. We saw no hospitalization due to infections. We saw a very low rate of infections, almost in line with the other agents that are used in autoimmune disease.
The other thing that we demonstrated is even though the cyclophosphamide and the fludarabine drives cytopenia in these patients, these are mostly asymptomatic. It's a lab value that you follow, but they're not translating into fevers and other symptoms that would make one concerned that the patients are immunocompromised. What a lot of our translational data showed is that the cytopenia is very short-lasting and it's pretty shallow. There's a two-week period where the median patient is cytopenic, and during that whole time, they're using prophylactic anti-infectives, so antibacterials, antivirals, antifungals. That helps explain why the Cy/Flu was so tolerable and why the infection rates were low.
In addition to this data, the RA efficacy data, and the safety data across indications, we also shared efficacy data in Sjögren's, as well as efficacy data in scleroderma, where again, we were able to demonstrate that in Sjögren's, our results were as good as any of the other products that you're probably following that are in late-stage development. If anything, our KOLs were impressed with the consistency of how we achieved positive results on the clinical endpoints as well as the PROs, as well as the more objective measures like salivary flow. With scleroderma, we were able to demonstrate that our results again were in line with what the auto CAR T companies have demonstrated in scleroderma.
The goal being that we wanted to make sure that people appreciated that this is a very active agent that has worked in oncology, and therefore we're not surprised that it's working so well across autoimmune indications with a safety profile that would allow this to do well in a community setting.
Yeah. I think given the data that you presented was at six months, obviously it looks like it's been durable so far, maybe some kind of deepening of responses. Do you see that continuing and how do you think about beyond the six-month time point, maybe 12 months out? Do you still expect?
Yeah
to see these levels of responses?
Yeah, look, the beauty about a product like this, which is allogeneic and it's pretty safe to actually utilize, is the fact that you can re-treat.
Our expectation is that the target product profile would talk about, number one, the ability to drive high response rates, and then number two, that the patients could receive a re-treatment out 12 months later, 18 months later, 24 months later. Time will tell what that median duration of response is. The overall target product profile is a drug that you can take PRN infrequently and that may have an opportunity to keep patients in response for a truly long period of time. You see, Emily, there's a lot of pressure that's being put on auto CAR T to demonstrate many years of durability before the disease recurs. That pressure is there for auto CAR T because auto CAR T is not a type of product that you're going to keep redosing, given the costs and the toxicity concerns.
A drug like AlloNK is one that you can redose. When we think about durability, we don't think about it only in terms of how long do you have to wait until you re-treat, we think about the total time, the multiple years that a patient can be controlled with only our regimen. In between these infrequent treatment periods, they are off other immunomodulatory drugs. They're not as immunocompromised as they are on some of the approved agents like JAKs and TNFs, et cetera.
Yep. Are you planning to have any additional data updates from the basket trial this year? Or how should we be thinking about potential follow-up data from here?
We are. In parallel to the phase III trial, which we're going to be initiating in the second half of the year, we continue to enroll patients into our basket study. That basket study will be a very valuable source of data on two basic fronts. One, in RA, we will be able to share more patients that have been treated so we can have a better assessment of what that ACR50 looks like in larger number of patients, as well as what durability and timing to re-treatment looks like. It'll be too early to see the effects of re-treatment on patients because, as you can imagine, we need patients to lose their response, then we need to re-treat them, and then we need to follow them to see whether they achieve a good response and for how long.
It'll take a little while for that data to emerge, but we are in the process of generating that data, and we see this as a really valuable readout that we will focus on over the next two to three years. Outside of RA, our basket study includes Sjögren's, scleroderma, and myositis. There we're going to be making data-driven decisions on what a second indication could look like. We are waiting to actually generate more in with more follow-up across these indications to make a determination on what the TPP could look like in a second indication. Look out over the next, not only six months, but 12, 18, 24 months, on updates across these different indications.
Yeah. Makes sense. You mentioned the FDA gave you feedback and agreed upon the intended trial design for the registrational study. Maybe walk us through a bit more detail about what that trial will look like and timing around getting that up and running.
When we had the discussion with FDA, we wanted to propose having an active comparator because it is tricky in many of these autoimmune indications, where patient responses can be so variable, to actually feel so confident about the efficacy signal in the absence of an active comparator. We wanted to use rituximab as the active comparator for a couple of reasons. One, because rituximab is part of our regimen, we know that people would always wonder, "Oh, I wonder what the impact of rituximab alone would be versus your full regimen." We can answer that question. The second reason is rituximab works as well as any other of the approved agents in this refractory population.
The idea is, if we could use ACR50, which is a pretty standard regulatory endpoint, and demonstrate a very significant difference between the responses that we achieve on our therapy versus rituximab, that we would settle the question as to how much more active than the standard of care we are. The FDA agreed to 150 patient, single randomized control trial. We would randomize patients in a two-to-one fashion with 100 patients receiving AlloNK and rituximab, and 50 patients receiving rituximab. We would use ACR50 at six months as the primary endpoint, and then at six months, patients would have the option to actually roll over into the AlloNK arm. In addition to that, we will continue to generate data in the basket study.
The totality of safety from this randomized control trial with the safety that we're generating in the basket study is the safety database that would support approval at the time of BLA filing.
Yeah. Makes sense. You spoke a bit before about 50% ACR50 being a good bar for success. Is that still the same case for going into this registration trial? Are you expecting that rituximab control arm to be in that 10%-20% that you spoke about earlier?
Yeah. We expect rituximab to be in the 20%. For our statistical calculations, we are assuming somewhere in the 20%-25%. Just as a benchmark, rituximab has an ACR50 of 27% in their label, but that was done in patients that had only failed the TNF. We're dealing with patients that have more refractory disease. We think that 20%-25% would likely capture the range of possibilities for rituximab, and we're planning to achieve a north of 50% ACR50 in the AlloNK arm. Which would represent a 2X improvement over rituximab, and indirectly a 2X improvement over the standard of care in that patient population.
Makes sense. How are you thinking about the market opportunity for that third line, let's say, of refractory RA population? With competition that's emerging, how do you see that potentially playing out as-
Yeah. The market today for the branded, biologics and JAKs and drugs is in the $20 billion just in the U.S. 25% of patients that ever get started on a biologic, approximately, end up becoming refractory to targeted therapy. That means that there's today a $5 billion market with patients that are actually taking approved drugs that have a very low ACR50 by the time you become refractory. This is a very large, maybe the largest autoimmune opportunity with refractory patients. We certainly think that there's room for a lot of different players. I would say that our differentiation is, number one, we are likely to be first to market. We're the first ones to start a phase III trial. Our phase III trial is a pretty efficient trial.
We expect that to make a difference when you're first in class across any modality. The second is, we use cyclophosphamide and fludarabine as part of our conditioning, but we have no CRS. When you look across the entire field, competition is going to come from other allo cell therapies, which very likely are going to have a similar target profile as ours, though they're starting one to two years behind us. You have auto CAR T, which we know is not necessarily a scalable solution, and that comes with the CRS and ICANS. We have TCEs and in vivo that don't use cyclophosphamide and fludarabine, but we are seeing CRS. I think at the end of the day, when you think about the target product profile, it's going to come down to what is the level of efficacy?
I would argue our efficacy has been as strong as anything else that has been demonstrated in RA so far. Then it's the safety profile. Yes, we use cyclophosphamide and fludarabine, but we demonstrate that that has been pretty safe. The other modalities that are going to be coming in without cyclophosphamide and fludarabine have a risk of CRS, which is going to make it a little bit more challenging for adoption in a community setting because of the higher requirement for monitoring. There's room for a lot of players. We plan to be first, and we expect that by being first, and given that all the other products out there have some compromise, that there's room for a lot of players, including ourselves.
Maybe for your second indication, are you looking for similar market where you might be first to get there, or is it based on market sizing? Maybe just walk us through a bit how you're thinking about that.
The other three indications in our basket are Sjögren's, scleroderma, and myositis. There's attractive elements in these different indications. Sjögren's looks a lot like RA. You have a very large population. If we did pursue Sjögren's, there's an opportunity that we could be one of the first, if not the first, to start a phase III trial. Because of the safety profile and the scalability, that could make a lot of sense. It would be a very similar call point. Sjögren's patients are found where RA patients are found, which is in the community setting. Scleroderma and myositis are interesting because there's a large unmet need there. There's been very few products approved, if any, that work really well, and so the unmet need there is more significant.
There's an opportunity for perhaps a faster path to market, like we are seeing Cabaletta and a couple others talk about pursuing. We will still be making data-driven decisions as to which indication makes the most sense. The good news for us is the drug does appear to be active across indications, so we would like to bring something to market that could be utilized by the same call point across a variety of different indications.
Right. Okay. Maybe to end the discussion here, if you could give us a bit of a summary of upcoming catalysts and milestones that investors should be looking out for for the next 12 - 18 months.
Yeah. Over the next six months, we will be starting that RCT. That RCT is expected to read out in the second half of 2028, so roughly a little over two years from now. We have cash into 2029. Okay? Walking backwards. In addition to that RCT running in the background, we will be sharing updated data from our basket, and as we talked about before, there's going to be RA data as well as data on the other indications. Within RA, particularly if we look beyond 2026 and we start looking at 2027, we're going to start seeing ACR50s in a large number of patients, and we're going to start to see the first patients get retreated and an opportunity for us to see how well they do once they are retreated.
Because that will close the arc on the full target product profile of this product, which is a product that you take infrequently, and you could keep somebody in a good response over a very long period of time.
Awesome. Thank you so much, Fred. Good luck with all the progress, and thanks everyone who's been listening in. Enjoy the rest of your day.
Thank you, Emily.