Chief Executive Officer of Artiva Biotherapeutics, a company that has made tremendous progress advancing the AlloNK cell platform for autoimmune disease, moving into already a pivotal trial in rheumatoid arthritis, which is super exciting and super differentiated. Welcome, Fred. Why don't you set the stage for us with Artiva and how you've positioned the NK cell platform in such a unique way in what looks like a competitive environment except for where you are.
Thanks, Josh. Thanks for having us. Look, it all started when we, together, three years ago, realized the power of the deep B-cell depletion approach, right? When we learned about this mechanism, and you and I talked about this early on, we realized that the name of the game was a deep B-cell depletion, and if you could achieve that, you could have really good clinical benefits in autoimmune disease. We first decided to go into autoimmune disease, focusing on the indications that Schett was pursuing, just because there was clinical proof of concept there. As we started to think more carefully about where we wanted to play, it became very clear that certain indications were just getting overly crowded, like lupus, for example.
When we think about the advantages of our product, is that based on our oncology experience, we saw that we can deliver a really deep B-cell depletion. Our oncology data was actually pretty compelling. We did not reach the median duration of response. It was close to two years. It hadn't been reached. So if you can deliver a deep level of B-cell depletion, if the response seems to be deep enough that you get this durable effect in oncology, combined with the safety profile that is fairly unique to NK cells, where you don't see CRS, you don't see ICANS, patients can be treated in a community setting, why not go into one of the largest autoimmune indications? We felt that a lot of companies were not pursuing RA as their initial indications because there's a lot of drugs that are approved in RA.
Many of those modalities cause CRS. Many of them are still being used in a hospital setting today in order to get treatment. Because we were not constrained by that, we could think about going into these broader indications. So today we're in a phase III trial that has paid off because we believe we are ahead of everyone else. Nobody else has announced a phase III trial. Nobody else has announced a phase II trial. So we really do think that if things go according to plan and we deliver in our RCT as we expect, efficacy continues to look strong, safety profile continues to be accepted, we could be the very first deep B-cell depleting product to enter the RA market since RINVOQ was approved actually in 2019.
Okay, excellent. There seems to be an uphill battle around sentiment for the NK cell platform. This view that they are not as powerful an approach as CAR T and that there may be some shortcomings here. You kind of juxtapose that with the execution and your ability to get patients treated and find a path to navigate. How do you kind of reconcile that perception investors have versus the reality of the execution and progress you are making?
Look, I think we mistakenly talk about NK cells as if they are very similar. Let us remember that there has probably been three or four sizable enough trials for people to make determinations as to whether durability is there or not. We have had iPSC-derived NK cells. We have had CAR-NKs. Those are all very different than what we are doing. We are using NK cells that are not genetically modified, and because we do not genetically engineer them, we use a monoclonal to actually do the targeting. We believe, based on our internal work, that that activation of NK cells via the Fc portion of a monoclonal is one of the most powerful ways to activate NK cells. Based on our data generated in oncology, which is exactly the place where people first became disappointed with NK cells, that data was actually really strong.
Just like we do in every other area, you have to look at each product individually. Given that we think we achieved a really deep level of B-cell depletion, which explains the durability in oncology, this is why I think we are seeing pretty compelling data in autoimmune disease. I think that now that we are a phase III RA company, the NK cell is just the how we do it. But what matters is what does the data look like? What does the safety look like, and can we really be first in a compelling new market?
What gives you the confidence as you move into RA as the lead pivotal, where others have not, that there really is still an unmet need to address there, despite, as you kind of point out, quite a number of different mechanisms and modalities for those patients?
Well, I think that can be ascertained just by speaking with physicians. RA is interesting because historically, take the development of RINVOQ, for example. It took over 1,000 patients required to be treated in order for RINVOQ to get an approval. This is because historically, most of the drugs that have been approved have been approved either for right after you fail methotrexate or for after you fail, for example, a TNF. Those are first-line settings, second-line settings, where your opportunity to have such a much better result than the available agents are actually fairly low. If you're a company targeting a first-line agent in RA or second-line agent in RA, you have a very long development path ahead of you because you have to demonstrate that you're better than other agents that work pretty well.
What we know from the literature and speaking with physicians and registries and a lot of the papers out there is by the time you have failed two distinct biologic or targeted synthetic DMARDs, your opportunity for a response is actually very low. You talk to a physician and you ask the question: what is the unmet need in RA? There are two different ways they look at it. As you know, Josh, a lot of times when patients come to a physician, they want to leave there with a script. If that is their objective, you can always give them a new drug that has been approved in RA because there's been many of them that have been approved.
But if you ask them the question, after a patient has failed two targeted classes, do you have high expectations that they'll respond to a third, a fourth, or fifth? They don't. That is exactly the population that we're going after. Now that we ran the phase II trial and we saw the pretty high ACR50 rates that we're seeing in this refractory population, we feel really convicted that if you are the first to get into that market targeting this refractory population, that you are addressing a big unmet need. The final thing I'll say is we're beginning to share more information on our specific patients that are being treated. For example, our very first patient, now we have more information about her background and lifestyle. This is a patient that has had RA for over a decade.
They have been on two or three different biologic or targeted synthetics. Leading up to our trial, this patient had 11 knee taps. Then they were on our drug, and as of the last update that we provided in April, they had not been on any drugs for 18 months. They were back riding their motorcycle, using their hands. It really is a big unmet need, but you have to ask the question: what do you do, physician, if your patient has already failed two distinct classes? What are your hopes of them getting a response? That's where drugs targeting refractory RA can have an impact.
Part of the AlloNK product profile does include preconditioning or fludarabine and cyclophosphamide. It feels like this is a shifting pendulum, and I am not sure which way it is necessarily likely to head, at least for the CAR T programs, whether they can navigate without fludarabine and cyclophosphamide. Maybe you can talk a little bit about the inclusion of that, the importance of fludarabine and cyclophosphamide, and why you do not think it may necessarily be a significant concern as we think about the AlloNK profile in RA.
Cyclophosphamide and fludarabine. We have to understand how this notion of separating cyclophosphamide and fludarabine from these regimens and talking about them in a vacuum first emerged, right? Because historically, what we do in biotech is clinical results come out, you look at the efficacy, you look at the side effects, and then you talk about the regimen. Here, because you have some therapies that use Cy/Flu, therapies that do not use Cy/Flu, we started asking people in industry and physicians, what are your thoughts on Cy/Flu? That is a difficult question to ask, because if you have the same exact efficacy and the same exact tolerability, but one product uses Cy/Flu, the other one does not, who is not going to want the product without Cy/Flu?
But that is how we ask the question, because physicians right now, because they go to conferences and they see all the modalities out there showing their best data, they have this impression, well, I can have whatever I want, right? That is why you are asking me the question. But what I would argue is if you now think about it differently, you think about our product generating efficacy data, safety data, we complete our RCT, and now we are coming to market with this product.
That is when you ask the physician a question. Look, what do you do for your patients that have failed already two distinct classes? Here is the target product profile of a product that is entering the market. Do you think that your patients could benefit from that? I think in that context, the tolerability of cyclophosphamide and fludarabine would be a lot higher, right?
For us, we think that there is a very acceptable profile utilizing cyclophosphamide and fludarabine, which is why that is why we are driving our phase III trial using cyclophosphamide and fludarabine, because we have established that it works that way. Not too dissimilar than Cabaletta , who is using cyclophosphamide and fludarabine in their lead indication in myositis. Now, do we think that there is a role in trying to understand what is that minimum level of Cy/Flu that is actually needed? Because we do not want to give Cy/Flu if it is not needed. There have been efforts by other allogeneic cell therapy companies trying to eliminate Flu or not using Cy/Flu. I personally have not seen the same level of deep B-cell depletion as one sees with the Cy/Flu.
If there is an opportunity to reduce the cyclophosphamide and fludarabine, which I think there is, it's going to take us a little while as an industry to understand how low you can go. It's something we're interested in doing, but we just don't feel that you need to do that before bringing a product that has a good target product profile into the marketplace.
I guess one interesting dynamic is that there's almost an assumption that another deep B-cell depleting modality will be on market to compete with as we kind of frame the AlloNK program, because relative to what's approved for these patients, not a lot of competitive dynamic as you've outlined. Do you see certain programs that are moving most quickly in the alternate B-cell depleting modality space in RA? Who might that be that you're most closely keeping an eye on?
Yeah, I think it's really important to actually think deeply about who else we're competing with, because oftentimes investors are asking me about the competitive landscape. Whenever you ask the CEO about the competitive landscape, not surprisingly, I'm going to have a favorable response. But let's think it through in terms of the modalities. Who is running an autologous CAR T trial in RA in the autologous CAR T space? We had BMS, we had Novartis, but those programs have been halted, right? The only other trial is the IIT by Kyverna. So that's an IIT, and Kyverna's mostly focused on going into neurology. So in the autologous CAR T space, we don't really see any programs that are seeking approval within the same timeframe as we are. If we look at the TCEs, it's important to remember that the TCEs operate through CDER.
Through CDER, you first have to establish a dose. Once you establish a dose and a regimen that you want to use, typically you go into a phase II trial where you are testing two different doses to then choose the final dose that you're going to go into a phase III trial. So far, nobody has announced that they're going into a phase II trial. If anything, we are waiting data later this year, some first data presentations on the first couple of TCEs that are coming in. We don't really see them getting an approval within the timeframe that we're operating in. Then you can look at the other allogeneic cell therapy companies, and really, RA has not been an area that has been a focus for most of the other ones.
Adicet has an IIT in China, which they talked about six months ago, so we will see where that goes. Nkarta recently announced that they have an interest potentially in RA. But again, we are significantly ahead starting a phase III trial. Then finally, you have the in vivo approaches, which I am not sure that they have dosed an RA patient yet. So the competitive landscape is actually quite favorable. I think if you just have an assumption that what we are doing works out, which time will tell if it does, and if everybody else, based on the data that they are disclosing, that that is accurate, then we really are fairly well-positioned to have that first opportunity to get to market. Now, let us say that you put that aside and you just ask about the target profile in general.
Cy/Flu is certainly something that people would prefer if our therapy did not have, right? But when you look at the regimens that do not use Cy/Flu, whether it is like TCEs or whether it is in vivo, there is CRS. So I think that the grand debate, you are asking where the pendulum is going. I think down the road, the pendulum is going to go into a discussion of what would you rather have, CRS or Cy/Flu? And I think it depends on the setting you are in. If you are in a hospital setting, tertiary care center, where there is a monitoring infrastructure in place, you will not care about CRS because it is not really your problem, right?
There is a team that is actually monitoring it. If you are a practitioner in a community practice, it is very much your problem because now you have to monitor for the presence of CRS. And the problem with CRS is you can say it is just a simple fever. Well, that is if you treat it right away with tocilizumab.
But if that escalates, it can be pretty serious, and it is not one that you can just wait for a day or two before bringing the patient in. So it does create significant monitoring requirements. We, again, I like coming back to what you always say. This is a really big market. There are going to be people that if our RCT works, are really going to like our product, and there are going to be people that are not going to like our product. If we just have a small piece of that market with a label that nobody else has, which is refractory RA, with a really large population, I think we could do really well as a company.
You just preempted a whole bunch of questions I was about to ask. Thank you for that. Do you envision a potential to replace fludarabine and cyclophosphamide with a different agent? If so, what is Cy/Flu accomplishing? Is it B-cell debulking? Does it have other immune system dynamics that are favorable, and how might you replicate that with a monoclonal-type add-on instead of Flu/Cy? Because you already have Rituxan in the mix. Is there something else that you could include to help shift away from the Flu/Cy concerns?
Those are really good questions. I would say that today we don't exactly understand what is the most important role of Cy/Flu. There are several that could be at play. Number one, it could help with debulking. Number two, it can prevent the host from attacking the cells. Number three, it can be adding supportive cytokines that actually help the cells actually remain persistent and be very active. We don't know. This is going to be one of those trial by error where you start reducing the dose of Cy/Flu, you start introducing other agents to see whether you can get the same PK effects, PD effects, and ultimately the clinical effects. I always come back to HUMIRA, right? HUMIRA did not launch as a $20 billion drug. The product profile actually had a lot of infusion-related reaction.
There was a lot of optimization that AbbVie did in order to get that drug to the point where it became the preferred drug in RA. Similarly, I look at our regimen in a very similar way. I think that the target product profile that we have today, that we aspire to have by the time we launch, is good enough to address a big unmet need. But there will be many opportunities to actually optimize it and make it that much more attractive for patients. But it'll take a little time to actually figure out exactly what are these alternatives to what we do today that could actually provide the same benefit or close to the same benefit, but with less of the issues. But we have to remember that the issues that we are dealing with, a lot of them are hypothetical in nature.
A lot of the concerns that people have around Cy/Flu come from the oncology experience. We're not treating patients with those same doses of cyclophosphamide and fludarabine as in oncology. I actually do think that when you show up with 100, 200, 300 patients that have been treated with our doses of Cy/Flu in our context, I think that that starts to paint a picture of how tolerable it is that we just don't have today because most physicians don't have experience using Cy/Flu at the doses that we're actually using today.
What's interesting, and it must at times for you feel like investors are pitting you against a ghost, because as you pointed out, there's no deep B-cell depleting competitive regimen moving into RA anytime soon, and yet it kind of feels like you're being pitted against those modalities despite them not being competitors anytime on their horizon. So I'm guessing that might be a little bit frustrating at times. Well, maybe we can turn to the RA data that you have generated that has led to the pivotal trial design. Give us a quick snapshot of what you've reported thus far, and you just came out with a press release articulating what else we may be looking forward to over the next few months.
Yeah. Our last data set, which we shared at EULAR, was around 21 patients that had been treated with RA, but only 13 of them had actually reached the six month mark. What we guided is that by the end of this year, we are going to go from 13 patients that we had presented to at least 20 patients that will have been treated with at least six months of follow-up. Importantly, at least 10 of those 20 patients will have all of the criteria from the phase III trial. Because the phase II trial was a little bit more permissive. We allowed patients that had only failed one class of b/tsDMARDs to enroll in the trial. Turns out the physicians ended up treating patients that had failed two or more because that is where the unmet need is.
In our phase II trial, we enrolled patients that had failed rituximab, and we demonstrated that failing rituximab does not predict that you are not going to respond to our drug. But in the phase III randomized trial, we are going to be randomizing patients to our drug and rituximab, and so we are not including rituximab failures because physicians are a little uncomfortable randomizing somebody to rituximab if they have already failed rituximab.
So by showing specific data in the specific cohort that we would be enrolling in the phase III, that will give investors insights into how that data is evolving. We will also have an opportunity to see how the patients that had reached the 12-month mark and six month mark, how they are doing several months later, and that is an important question that we will be uncovering in time. Then there is going to be data in other indications.
We share data in Sjögren's and scleroderma, and we will be sharing more data on Sjögren's and scleroderma.
Okay, great. In the data set you presented earlier this year, it looked like there was actually some improvement between three months and six months. So what do you attribute that to, and do you have any expectations for what happens beyond six months? Especially because at that point, the effect of the Rituxan may be wearing off, and so in theory, you may start to lose a couple of patients as you follow out longer.
Yeah. The efficacy deepening from three to six months has also been seen in autologous CAR T-cell experience and in the rituximab experience, and this has to do with the specific mechanism. You see, when you're giving a JAK or you're giving a TNF, you're just stopping the inflammation right there at the site of action. Whereas with deep B-cell depletion, that's not what you're doing. You're getting rid of the B cells, and there's less autoantibodies, there's less antigen presentation, there's less cytokines. So it takes a little bit of time for that effect to trickle down to seeing the efficacy. So we expect that six months is actually the optimal time to actually be measuring that ACR50 because that's when you're likely to see the maximal effect.
In terms of how long that effect lasts, we're targeting a median time to the next treatment of between 12- 24 months. You see, when we discuss durability in this field, we discuss it a lot. This came a lot from the autologous CAR T-cell space where you treat a patient, and you really are only going to treat that patient once they lose response with a whole other regimen. So it's very important to know how long it can last because that's your opportunity to be within the control of that one drug. In our case, we can redose.
We feel that if you have a period of 12- 24 months that you're off your other medications because you're receiving a clinical benefit, then you have an opportunity to be retreated at that point, we can measure durability on our drug over the course of multiple infusions. Ultimately, we think that that's attractive commercially, and it gives us a chance to give patients a benefit that doesn't fully just require on that single treatment that they receive upfront. As we are releasing data, it'll take some time. The RCT is happening in parallel. We expect to be sharing data in that by the end of 2028. In parallel, what do investors want to know? They want to know, well, number one, are you likely to hit your primary endpoint in the RCT, which is the ACR50?
Having more patients where we can show ACR50 will be important. The second question is, you're targeting a median time to next treatment of 12- 24 months. What does that look like? We're following patients, but we have to follow them long enough to actually see what that looks like. The next question is, when you retreat these patients as they're losing response, are you able to actually benefit them again? When you do, how long does that last? It's only once you answer all of these questions that you have a complete picture of the target product profile, and that's what we're hoping to achieve in parallel to the RCT reading out. Normal development, you have one RCT. All that matters is the results of that RCT.
In our case, it's all of these little pieces that point towards a target product profile that could be really attractive.
There were a couple of patients who didn't respond with rheumatoid arthritis to the AlloNK regimen. Do we have any idea why not, and does that in any way inform the potential to re-treat a patient who did have an initial response, given that key point that you highlighted?
Right. Look, the ACR50 of the best approved drug in the label was actually RINVOQ in a first-line patient, and that was in the 46%, 45% range. Which tells you that there's a ceiling effect on how high the ACR50 is, how high you can be a responder. Why is that? Part of the reason, number one, is patients may, and physicians may think that a patient has RA, when in reality, that's not what they have. They have fibromyalgia, they have other pain syndromes. The drug is not going to do anything for those patients.
The second element is, after you've had RA for a long period of time, you start to develop structural damage in your joints that even if you kill the inflammation, because this is all these B-cell depletion approaches can do, is they can kill the inflammation, you may still have lingering damage that are not going to all of a sudden improve, or they won't necessarily go back to what baseline is. This is different than in patients, for example, lupus, where lupus, a lot of what's happening there is based on your autoantibodies that are floating around. It's the inflammation that's happening, and if you get rid of the inflammation, there isn't a lot of other structural damage that you're necessarily worried about.
We believe that several patients in our trials will not respond because either they don't actually have RA or they've had RA for so long that even though you're killing the inflammation, they're still left with some lingering pain and structural damage that you can't completely eliminate.
Yeah. In those patients who didn't respond, did you see that set up where, wow, they did have a lot of joint damage and perhaps evidence that it was more destructive process than inflammatory?
The problem is you can measure the inflammation. You can look at, for example, swollen joints. You can look at ERP, ESR, and CRP, and as you know, those are not super specific. A lot of times it becomes one of those clinical judgments where you treat them, and if they don't respond, you'll ask the question, well, was that really RA? But you don't know for sure.
Okay.
What you can do when you're enrolling in the phase III, you can have stricter criteria that will enrich for patients that have actual inflammation as opposed to fibromyalgia. Looking at elevated levels of CRP, making sure that the swollen joint count is above a certain point, looking at X-ray evidence of damage. These things can help you enrich to a population that are more likely RA than something else. But as you know, it's very hard to know for sure.
Okay, got it. For the phase III pivotal program, is that now underway enrolling patients? If not, what are the final steps before it kicks off?
Yeah. We're using the word initiating since the activities are initiating, but what we guided is that before year-end, we would provide more updates on either site initiation or timing for enrollment to begin. The idea is that we would be sharing top-line results, that's what we expect, by the end of 2028.
At least in the CAR T landscape, cadence of enrolling patients has been rather slow. You seem to have found a path to much more rapid enrollment. As we think about barriers to enrolling patients in a pivotal trial, what do you anticipate you might need to navigate?
I think it's just more sites. We've been really pleased with how good enrollment has been, particularly given that we're doing it in a community setting. I think that the fact that we enrolled. In our last update, we had shared that we had enrolled over 70 patients. That was as of the end of April. The fact that 95% of them had been enrolled in the community practice just shows that this has actually been quite manageable for these physicians to actually do. It also shows that despite having the site Cy/Flu and despite all of the warnings of what can happen, patients are very interested, which demonstrates that there's a big unmet need. All the patients that we have shared information on have been patients that were treated in the U.S., and earlier in the year, we started activating sites in Europe and in Latin America.
The whole idea was to actually do this as part of the phase II. That way, we would already have familiarity with the sites, and they would have familiarity with the product in order to allow the RCT to enroll faster. We really just think it's like a numbers game. More sites and continuing to do what we have already been doing.
How many concurrent pivotal trial type indications do you think Artiva would be able to run? Do you anticipate moving another program into pivotal, say, next year?
We haven't guided when that second indication would come. We do see a lot of value in actually having additional indications because if somebody's going to embrace your product and learn about it and learn how to use it would actually be great for them if they could actually use it across a number of different indications. But as I mentioned to you before, this isn't a typical phase III program where you just run one program and you can forget about it. This requires understanding retreatment, understanding optimization, and so we want to make sure that we're nailing RA before we are embarking on additional phase III trials. There's also capital efficiency. I think one of the things that makes our story attractive is that we have enough capital to get into 2029.
That gives us an opening to actually invest more in additional indications, but we're trying to remain fairly capital efficient. At some point, as the capital becomes cheaper, then we can think about spreading ourselves out even more.
You've made progress, as you've noted with Sjögren's and scleroderma. Those would seem, I would imagine, seem to be prime candidates as you're thinking about where your next pivotal program may be. But between the two, does one resonate a little bit more proximal or more reminiscent of RA, and the criteria that you ultimately wound up choosing RA for as you think about next selection?
Right. Look, between those two, Sjögren's certainly looks a lot more like RA. When you think about the size of that market, the fact that patients are spread out across the community. That's a little different than scleroderma, where there's less patients, and many of them are found around academic medical centers. They're similar to RA. There hasn't been a lot of competition in Sjögren's with B-cell depleting agents. That is an area that if we go into, we have an opportunity to be ahead of most. Unlike in scleroderma, where there has been more activity by autologous CAR T-cell, by other allogeneic cell therapy. On the flip side, there is more of an unmet need in scleroderma than there is in Sjögren's. There's a lot of products that are about to enter the market in Sjögren's. There is a number of considerations there.
What I would tell you, and it's actually a good thing, is that RA really does feel across all of these indications as being the ideal choice of indication for us to go into. And I'm really glad that that's our lead indication, as opposed to many companies where they're starting somewhere, but they have to quickly go to that second indication because that's where the biggest potential is.
You talked about data updates by end of year. Is that ACR or are there going to be other updates around ACR for the LOX?
We will have a presence at ACR. I think that the titles of the talks and posters have just come out. Whether we present at all around ACR or whether we have separate disclosures, we're still figuring that out.
All right. A lot to come. Fred, thanks so much for joining. Looking forward to-
Thank you for having us.
catching up soon. Thanks, everyone.