Good morning, everyone. Thank you for attending Jeffrey's Healthcare Conference. My name is Kelly Xu, one of the equity analysts here on the Biotech team. We are very pleased to have Dr. Fred Aslan, CEO of Artiva Biotherapeutics, join us today. Welcome, Fred.
Thank you, Kelly.
Maybe let's first start with a big picture question. Many cell therapies in the autoimmune space originated from oncology, and Artiva also has three autoimmune trials and two oncology programs. Could you share what you have achieved in oncology programs and how they inform the clinical trial design for autoimmune?
Thank you. Yes. Artiva was founded around five years ago. We are a spinoff of a Korean company called GC Cell that has developed a highly scalable process for actually generating NK cells. We started in oncology, as did most of the other cell therapy companies, because in many ways, we were chasing the really strong clinical signal that was emerging from Auto CAR-T, but with a therapy that is off the shelf, with lower COGS, more tolerability. We did have an opportunity to actually have the product evaluated in two different oncology trials. One was a trial in NHL, where we used our NK cell in combination with rituximab. The second one was a trial in Hodgkin's lymphoma, which we carried out with Affimed using a CD30 targeted biologic.
Just to remind the listeners, AlloNK, which is our lead asset, is a non-genetically modified NK cell. We combine that with a targeted therapy, either a monoclonal or an NK cell engager. That way, without having to engineer our cells, we have the ability to target those cells and to be highly cytotoxic. Having generated this data in oncology, we noted that the therapy actually works quite well in that setting, meaning when you compare our efficacy compared to what you would achieve with the biologic alone, whether it is rituximab or AFM13, which is the CD30 targeted biologic, we get a much more enhanced ADCC response, which led to really interesting efficacy with a safety profile, which we always believe to be much safer than the other cell therapy products where we have seen a correlation between high efficacy and the rate of CRS.
With that proof of concept in mind, when we also came across Schett's data, where he demonstrated that deep B cell depletion did have this big impact in autoimmune disease, we felt that we had already demonstrated that that mechanism of action was very much in place for the product in cancer. And so we're evaluating it now in autoimmune disease.
Fantastic. Also regarding the progress made in autoimmune programs, you originally planned to report the initial data for the AlloNK in the first half of this year. Recently, you decided to postpone the initial efficacy readout to the first half of 2026. Maybe could you provide some additional color on what drove this decision?
Yeah. When we first started evaluating the data that was emerging from Auto CAR-T, particularly from Dr. Schett, it was noted that in every patient that he would treat, one would see all of the clinical improvements. The hypothesis for the entire field is that if you just had two, three patients, that that would be enough for you to have a sense of what that signal is. One of the things that has been very encouraging from all the data generated from Auto CAR-T is that when you look at all that data set in totality, it is very clear that the signal that one sees is much better than the standard of care.
If you line up each one of those patients one by one, it's very noticeable that whereas there are a few patients that you see all of the same features of Schett's patients, where you see clinical improvement, you see deep B cell depletion, you see reduction in autoantibodies, as well as removal of steroids, you don't see that across every patient. Even though in totality, I think investors in the field should be very encouraged that a lot of Schett's signal is getting validated, patient heterogeneity and those results point to a situation where if you just come in with few patients, you won't truly be able to seek out the signal, because what happens if your first two, three patients are very good, or whether they're very bad, that doesn't tell you what that looks like.
I think what we're learning is in order to derive meaningful information from the trials that are being conducted, one can only really pool indications if you're looking at things like B cell depletion or safety, because there it doesn't matter whether you're treating a myositis patient or lupus patients, an RA patient, but when it comes down to efficacy, you need to be benchmarking that efficacy against the standard of care in that indication with enough N, with enough follow-up. What we felt is that if we came out with results in the first half of this year, they wouldn't be as interpretable as if we wait until we can actually have more N with more follow-up. The way we have divided up our guidance is we plan to present by year-end data sets where you can actually pool across indication.
Again, we will look at all the patients that we'll have treated, and we will show what the safety overall look like, as well as what some of the translational markers look like. We will also announce by year-end what our lead indication will be, because we feel that efficacy is interesting in the context of your development plan, to have a lead indication defined. What we will do is to present the initial efficacy in that lead indication in the first half of 2026. That way, over time, investors have a better understanding for what the potential target product profile for the product will be and in the specific indications that we're prioritizing.
This is a great point. You feel overall the data provided by the industry for tackling autoimmune from these cell therapy players are actually on the right track, but individually you saw some variation. Curious, what are the learnings from those data sets that could actually shed light on how you manage your clinical trials, for example, in terms of patient baseline selection? Any new implications you plan to do for the next 12 months as the industry provider insights, continue to provide insights?
Yeah, I would say that what we're beginning to learn is that patient selection is actually pretty important. I think we are learning that the younger you are, there's an advantage in the response you will have, because these diseases are not just about the inflammation. The inflammation is what originates a lot of the pathology, but there's usually one or more organ systems that are involved.
If you've had the disease for a long period of time and you have a lot of fibrosis and scarring in that organ, whether we're talking about the kidney in lupus nephritis, whether we're talking about joints in the context of RA, the longer you've had the disease and the more beat up the organ is, whereas these therapies appear to be very effective in eliminating the inflammation on its tracks, the degree to which the underlying organ is going to get an improvement will be dependent on how long you've had it for, how damaged it is, and how young you are. Since the younger you are, the higher probability that your system can actually regenerate. If you are Dr. Schett selecting patients for your trial, you understand exactly what the mechanism of action is.
I think that he was very appropriately selecting patients where he felt, if I eliminate the inflammation on its track, can I get a clinical result? You translate that into real world, where a lot of the physicians that are coming into this are learning how these therapies work. Oftentimes, these therapies are usually given and offered to the patients that have been your least responders. You have your practice, you have patients that you've tried a lot of therapies on, they've had the disease for a long time, and now you have an alternative that you didn't have before to try it on.
I think the patients that we're seeing in the real world are actually a lot, let's say, more heterogeneous with a lot higher disease severity than what we can see in a pure play academic study where the focus is on the inflammation and that's what it is. I think what we are learning over time, and I think this is true for the whole field, is that most of our inclusion criteria are actually quite permissive. I'll give you an example from lupus nephritis. If you have failed two therapies, that is sufficient to enter our trial. For example, you could have had a course of steroids, you could have been tried on a biologic or voclosporin, that would be enough for you to be eligible for the trial. In the real world, that's not what we're seeing.
We're seeing that a lot of the PIs are taking the patients that they have tried a lot more than just that, because there's many more patients. I think over time, as we establish safety with the product, we will all start to tighten that inclusion criteria, because the ideal patient is one that is having significant disease activity, but one that if you do cure the inflammation, then you can see resolution and remission from that pathology.
I see. Super insightful. Also regarding selecting the lead indication by year-end, curious, what efficacy benchmarks should we use across different indications? For example, what % of patients are achieving drug-free remission could be considered as positive data? Maybe any other endpoint, excuse me, other endpoint, or maybe even biomarker studies you're going to leverage in thinking about the most promising indications to move forward as the first?
Yeah. Thinking about which data points are very relevant. Again, I go back to, I'm going to go in the order in which we are sharing our data. First of all, we need to see evidence of B cell depletion across the board. That is the one constant that seems to be necessary, but not sufficient, because even with patients with Auto CAR-T where you have eliminated all the B cells, there are still occurrences where you do not actually see all the clinical improvements as you do in other patients. That is important to know, because that seems to be, again, necessary, but not sufficient.
The second piece that's really important is the safety profile, because there are a number of different modalities coming into this space, but ultimately, the type of modality and the safety profile of that modality is going to really move the needle in terms of what the commercial potential is. Finally, we get to the efficacy piece. Now, the efficacy piece is going to be very different depending on the indication, because on the safety side, you're looking for evidence of the generic things. Are you generating CRS? Are you generating ICANS? Do you have to hospitalize the patient? If you don't hospitalize the patient and you treat them, how often do they have a fever that is strong enough for you to hospitalize them? There are a number of things that are cross indications. It's very informative and you can pool.
On the efficacy side, it'll be indication specific. For example, you have to take the best available therapy or best experimental therapy out there, and then you need to be a lot better than that, given the complexities involved in cell therapy or the side effects from T cell engagers. In LN, I think today one would look at obinutuzumab. We have to remind ourselves that obinutuzumab is being used on top of steroids and on top of MMF. One could either look at the complete renal response of obinutuzumab on top of all those meds and look for similar efficacy, but in the absence of steroids and with a really clean side effect profile, or you're looking for significantly better efficacy in the context of these other advantages. If you're looking at RA, you're looking at patients that are refractory to multiple different mechanisms.
You're asking the question, once you are refractory to different targeted mechanisms, and now you're receiving your third line or fourth line, how often do those patients respond compared to the responses in your own trial? The goal of actually announcing what indication we will be prioritizing by year-end gives us an opportunity then to spend the subsequent few months educating investors on what success would look like for us in those indications.
Fantastic. Maybe also could you provide an update on the status of patient enrollment in your clinical trials? Compared to 12 months ago, what are the new learnings given actually more competing programs? How do physicians think about putting patients on each different mechanism of action?
Yeah. What we've learned is when we first entered the clinic around 12-18 months ago, the Auto CAR-Ts were the first movers in that space. There is no doubt that by the time the off-the-shelf approaches arrived, they were in line, given that the other Auto CAR-T approaches were being tested. We have learned that you can't just rely on the Auto CAR-T centers, because when you think about the number of clinics that are out there that could run a clinical trial and would run clinical trials for biologics, it's multiple factors compared to Auto CAR-T centers. Given the safety profile of our therapy, one of the possibilities that we have, and that does give us a first mover advantage, is to actually go beyond the CAR-T centers.
That is very appealing for the non-CAR-T centers, because in many ways, the non-CAR-T centers have been blocked out from the cell therapy revolution because they're not in a CAR-T center. At the same time, they would like to potentially offer this to their patients. By having a safety profile where we don't have to hospitalize our patients and where one can manage patients on an outpatient basis, that opens up the number of sites. That is what we are focused on. We have been very encouraged so far based on what we are seeing emerge that our therapy does have the potential to be friendly in the non-CAR-T center. That is where we would like to show that it's effective and that it's safe. We've also learned that it is a little bit of a numbers game.
If you had asked the CROs what enrollment rates are like, even before the Auto CAR-Ts came on board, they would give you a statistic where it would be very clear, well, you're not going to be able to enroll enough patients if you're only on five sites or 10 sites. You really need dozens of sites. To that point, I do tip my hat to some of the Auto CAR-T companies that are in dozens of sites, because that's what we all have to do. We have to be in dozens of sites recruiting at regular rates of enrollment for these indications so that we can get that data set that is needed. The final thing I'll say on that is one of the advantages of the product is that of AlloNK and NK cells in general in our approach, as I've been mentioning, is the safety profile.
The FDA in many ways has corroborated our understanding of the safety profile, because in this most recent trial that I'm sure we'll talk about, a lot of the restrictions that are usually placed in cell therapy trials were not included in this protocol. For example, we don't have to stagger our patients. There is no requirement for any hospitalization. All of these changes in a way that the acceptance of these inclusion criteria help us move beyond the Auto CAR-T centers, and it demonstrates that that safety potential advantage could be there for the product.
Fantastic. Since you mentioned the community settings, we think the potential to use cell therapy at community settings will be a huge advantage. Regarding the investigator-initiated trial you're conducting in the community setting, what kind of feedback have you received so far from physicians?
Yeah, it's the experience in that site that is giving us confidence that this approach makes a lot of sense, because what's special about this IIT, it's the only one of its kind as far as we know, is you have a community rheumatology practice. There is a community rheumatologist who enrolls patients in our trial, treats the patients in his infusion chairs, sends the patients home, and then just manages them as an outpatient. The fact that that is turning out to be viable, and we need more N in order to keep demonstrating that, gives us confidence that this approach could be well embraced by community sites and could give our product a compelling target product profile that's different from other therapies in the space.
Great. In your clinical trial design, the patients will receive two doses of monoclonal antibody and three doses of AlloNK with the initial monoclonal antibody dose injected before the first AlloNK. The whole regimen will span over 20 days. Could you discuss why this dosing schedule may achieve deeper B cell depletion and what has been the feedback from study centers?
Yeah. A lot of what we're doing, in a way, we are learning from what the Auto CAR-T experience has actually showed us. In the example of Auto CAR-T, what we see is that when Auto CAR-T is given to patients, there is a two- to three-week period when the Auto CAR-T expands, eliminates all the B cells, and then it goes away. Because NK cells don't persist for that long, we are also trying to replicate that area on the curve, if we can call it that, by actually giving weekly injections of AlloNK times three. That way, during that three-week period, we have the monoclonal on board with the NK cell eliminating B cells for that period. As you mentioned, it does take 20 days. It's basically six visits to the physician's office.
You can think about it like this: a Wednesday, Thursday, Friday is when you received your cyclophosphamide and your fludarabine. That next Monday, you come in for your first infusion of AlloNK. Just important for the listeners to know, AlloNK is cryopreserved, off the shelf. It is vialed in an infusion-ready media. You thaw it at the bedside, and it is a 5, 10-minute IV push. You come in for that, and then you come in the two following Mondays to receive your second and third dose of AlloNK, and that is it. We believe that it is a one-and-done therapy. We need to treat more patients with more follow-up in order to determine what that will ultimately look like, but that is the patient experience.
OK, fantastic. The lymphodepletion is still a necessary step for AlloNK trials. Do you have plans to evaluate the option without lymphodepletion with a modified protocol?
Yeah. There's a lot that we're trying to educate about lymphodepletion, because most investors know lymphodepletion from either the context of these being chemotherapy agents that patients are on, with cancer patients are on, for extended periods of time where they're immunocompromised for extended periods of time. That is not what's happening in our trial, or they know it from the Auto CAR-T experience where these patients typically have to be hospitalized in order to receive the regimen. What, again, physicians that utilize these therapies understand is you can give these agents as outpatients. When you lymphodeplete these patients like we are doing, we're talking about a two- to three-week period when you have neutropenia and when you have lymphopenia. During that period, you could be on prophylactic antibodies, antimicrobials, antivirals, antifungals.
We're talking about a very short window when patients are under the effects of the lymphodepletion, but then they're done. We view the lymphodepletion as not being a major limitation. There's a lot of companies that enter the field already with the goal of actually eliminating lymphodepletion. I think that at the end of the day, it'll come down to this. In order for me to convince you that lymphodepletion is actually something acceptable and attractive, first of all, I have to demonstrate that there is an efficacy advantage to using the lymphodepletion. If you don't need to use lymphodepletion and you get the same degree of efficacy, then it's fair to question, why are you using that? Because that could be unacceptable. The second thing, you would want to know, what is the safety profile of utilizing CyFlu?
Because if patients are receiving it as outpatients, they're going home, and they're not being hospitalized at a high degree because of that, then maybe it's not that big of a deal. At the end of the day, we talk about lymphodepletion in a vacuum. When I think we have to look at the efficacy of the product, we have to look at the overall safety, and then we have to compare those across modalities to then ask the question, is lymphodepletion really bad or good? I would say that what we're learning, because of that heterogeneity in the results, originally people felt, you know, everything is going to work here. So why don't we just start with the most tolerable therapy? Let's remove the lymphodepletion.
I would say, looking at the results that are coming out, every inch of efficacy counts, because nobody is generating exactly shed-like results. Again, our strategy is we have embraced CyFlu for now. We do not know whether it would work without CyFlu because we have not tested that. For now, we are trying to go for the best efficacy we can get and with a tolerability profile that we believe will be embraced by the outpatient community as long as the efficacy is there.
OK, very insightful. When we think about combining AlloNK with CD20 antibodies, you have the option for rituximab as a widely used agent, CD20 antibody. You also have obinutuzumab as an option, which actually claimed trial success in lupus recently. Curious for the new trials in RA, rheumatoid arthritis, and RM, idiopathic inflammatory myopathy, and systemic sclerosis, and Sjogren's disease. Why did you choose the rituximab?
Yeah. One of the advantages of utilizing NK cell is that you can combine it with different monoclonals. There are a number of different targets that have emerged as being interesting in autoimmune disease: CD19, CD20, BCMA, CD38. We have commercial antibodies, as you mentioned, for CD20, Rituxan, as well as Gazyva. There are commercial antibodies for CD19, a plasma from Amgen. There are also commercial antibodies for CD38. One of the advantages of our product is that without having to introduce any engineering, we can target different B cell compartments or target them in combination. Now, as a first approval for our product, because it is a combination product in the sense that there is the AlloNK as well as the monoclonal, we wanted to minimize regulatory friction by actually utilizing a monoclonal that has already been approved in that indication.
That way, if anybody or the agency is wondering, well, what is the contribution of the monoclonal as opposed to the contribution of the cell? You know exactly what the contribution of the monoclonal is, because there is plenty of clinical data with the monoclonal. If we are pursuing a path forward in lupus or lupus nephritis, we would use obinutuzumab as the monoclonal because it is likely, we speculate, that that will get approved, a recent approval in lupus or lupus nephritis, I should say. If you are working in an indication like RA, you are better off working with a monoclonal like rituximab, because rituximab has been approved in RA.
We are always trying to start in order, again, to minimize that friction with something where there is an obvious comparator, because otherwise the FDA would ask the question, need to understand the individual contribution. This helps eliminate that question.
Great. Also, with a different autogenous strategy, do you think a customized combination strategy is necessary for different autoimmune disease? For example, we have CD19, CD20, BCMA as the target for B cells.
Yeah, we are learning as a field which targets matter. I would say that every company has started with a target, and that's what they're initially exploring. We are obviously starting with CD20 because those are the monoclonals that have been approved with a lot of experience in autoimmune disease. That is, in a way, what guided our choice. There's a lot of speculation as to whether CD19 is better than CD20. Also, in which indications could CD19 or CD20 be better? We are seeing some interesting data from the CD19 plus BCMA Auto CAR-T that is begging the question, do you get better efficacy and in what indications, but at what cost of side effect profile? Since with BCMA, we've seen a greater need for IVIG and the potential for more infections. We are learning as a field.
What I would say is we will be announcing our plans with additional monoclonals in time as those go on hard rails, but we do want to exploit the advantage that we have and that we can work with different ones. In combination, though, it takes time to build that pipeline.
Yeah, it's easy and a quick switch for AlloNK platform. So last question, as we're waiting for clinical data from AlloNK programs, can we discuss about the regulatory path for autoimmune? If you make a compare and a contrast to the previous CAR-T approval in oncology, do you expect a single-arm accelerated regulatory path or randomized controller trial would be also possible?
Yeah, we're watching the conversations that the Auto CAR-T companies are having with FDA very closely. It was very encouraging that Kyverna got a path forward in SPS. It was very encouraging that Cabaletta had a good productive conversation with FDA on myositis. Autolus started to discuss some of those conversations around lupus nephritis. I think that part of what's encouraging is with SPS, that's a very small orphan indication. It's not a shocker that the FDA agreed for no control. It was actually very encouraging that in the context of myositis, which is bigger than SPS but still smaller than other indications such as lupus or RA or Sjogren's, the question is, as you get into larger and larger indications, what will be that threshold? Obviously, it'll be based on safety and the delta in efficacy compared to the standard of care.
I think we're all learning from each other as these conversations are developing. I could see there being a paradigm that is a lot closer to oncology, because most of the therapies in the autoimmune space have been incremental to the therapy that had been approved right before. The opportunity for accelerated approval when you need more N to know whether it's working or not is more limited. Again, very encouraging that with Auto CAR-T, we're seeing that the signal is quite strong. You can tell from a 10, 20, 30 patient data set that you are seeing something that patients should start getting access to.
OK, overall looks pretty promising for the regulatory path. We will wrap up our session here. Thanks again, Fred, for a great discussion as always.
Thank you, Kelly.
Thank you.