Good afternoon, everyone. Thanks for joining us today at the H.C. Wainwright Global Investment Conference. My name is Emily Bodnar, and I'm an equity research analyst at H.C. Wainwright. Pleased to introduce Paul Hastings, who's the Chief Executive Officer, and David Shook, Chief Medical Officer of Nkarta. Maybe to start, for those who are newer to your story, and given some of the recent cell therapy landscape changes, can you give us an intro to your allogeneic CAR NK cell therapy platform and your ongoing programs?
Absolutely. So we are the only allogeneic, off-the-shelf, on-demand CD19-targeted NK cell CAR NK cell therapeutic in the clinic in autoimmune disease. We discover and develop NK cell therapeutics. Our CD19 CAR NK is in the clinic for lupus nephritis in one study which is called Ntrust-1, and in another study called Ntrust-2, which is a basket study, which includes three different indications: myositis, scleroderma, and vasculitis. We also have an IST in SLE that's ongoing as well. And we have the advantage, as an NK cell, of having really nice kinetics and having Cmax at Day 0 when we dose these cells, so that when we're looking for B-cell depletion and reset, we think we're going to do that relatively quickly.
And we think we're going to be able to be very convenient for patients as well as clinicians because we're on demand, so they don't have to wait for apheresis, and the patients don't have to deal with the expansion with the other cell type, the T cell, where the expansion of the T cell sometimes leads to cytokine release syndrome or ICANS. We've seen no incidences of either one of those in our studies.
Great. Maybe discuss some of the translational work that you've done and the results that, you've seen relative to what we've seen with autologous CAR T therapies so far in clinical studies.
Yeah. So, CAR NK and CAR T have pretty similar mechanisms of action in the way that they're going to be approaching these diseases, both malignant and not, and autoimmune, which is targeting CD19. So, actually, they're probably most remarkable for their similarity, the ability to kill B-cells, both malignant and non-malignant, in the case of autoimmune disease, to be able to kill B-cells, you know, from patients with various autoimmune diseases. I think some of the more interesting translational data that we've generated has been the accompanying inflammation that happens with that killing.
As Paul described, NK cells and T cells work fundamentally differently in the way that they are dosed and the way that we use them, which is T cells are given at a subtherapeutic dose and then proliferate, and that expansion drives a lot of cytokines and a lot of toxicities, and we've shown and are most interested in the inflammatory environment in which the cells are able to kill the CD19-targeted cells.
I think an interesting point is that with CAR T cells, we see peak expansion is usually around the 10-day mark, whereas with NK cells so far, it seems to occur around Day 0/Day 1. So how do you kind of expect that to translate into clinical efficacy versus CAR T therapies if at all?
Quick B-cell depletion and quick B-cell reset, and dosing the cells in such a manner, as we mentioned before, that it's convenience for patients so that they don't have to take a lot of time out of their busy schedules, to get their doses of CAR NK cells.
Very well.
Anything to add ?
Yeah, I would add that, you know, the cells are, as we said, killing on Day 0 because there's no... They don't need to be activated in vivo, as you mentioned, and so that adds to the safety advantage. Not so much that there's going to be a necessarily an advantage to B-cells being killed two weeks quicker. We do expect them to be quicker, but not that. We don't expect that to be clinically meaningful. But what that does translate to is a lack of dependence on cytokines, a lack of potential for toxicity. And that lower toxicity barrier, we think, will really drive the uptake and accessibility of these therapies.
Because in especially in autoimmune disease, even more so than in cancer, patient population, where safety is at a premium, things like high-grade CRS or ICANS of any grade will just become untenable for you know sort of a community-type approach, which was really sort of the promise of cell therapy.
You've recently initiated a phase I study for NKX019 in lupus nephritis, so can you maybe touch on the study design and how that kind of relates to some of the other lupus nephritis studies that are ongoing now? Which endpoints are the most relevant?
Yeah. So in Ntrust-1, our lupus nephritis study is three doses of CAR NK cells given over the span of two weeks after lymphodepletion with cyclophosphamide. And then that will be looking at patients, a similar patient population to some of the other cell therapy studies, looking at patients with refractory lupus nephritis. And endpoints that we'll be evaluating, I think everybody has seen this sort of incrementally. You know, they kind of come iteratively. Initially, there's the endpoints associated with what I would say, immunologic endpoints, things like B-cell depletion, B-cell reset, and B-cell recovery, and then more sort of clinical endpoints, kidney function, kidney recovery, proteinuria. And then more traditional clinical outcomes like drug-free remission, disease control, complete renal response, that sort of thing. So it'll, they will look similar to...
Each one of the cell therapy studies has slightly different inclusion/exclusion criteria. I think we're able to get a slightly different patient population because the lymphodepletion regimen. But in general, I think that the endpoints will look relatively similar.
Mm-hmm.
That's really. I think when you look at certainly Schett data, you know, the initial wave of data that everybody was responding, and now the follow-on data, still very high rates of response. I don't think the burden is really to exceed those responses. It's how can you replicate those responses and do so more safely and more accessibly?
Mm-hmm. I think maybe just to spend a few minutes on the lymphodepletion regimen. As you mentioned, you're only using cyclophosphamide, whereas competitors in the autologous space all use fludarabine as well. So what's kind of the benefit of not using fludarabine, and what gives you confidence that you can accomplish the same results with just cyclophosphamide?
Yeah. So the benefits of avoiding fludarabine are important, right? I think it's a chemotherapy that's got both short-term and long-term toxicities that we'd love to avoid if we can, which is why we felt compelled to evaluate it first. In terms of what gives us confidence, so fludarabine really provides two main advantages or two main contributions to whether that be for autologous cells, for allogeneic cells. The first is immune suppression, right? So it depletes the number of host white blood cells that can reject cells, which is important for any allogeneic cell therapy, certainly. And then it also provides really cytokine support, even in the autologous setting, where we know patients have no immunologic barrier whatsoever, where lymphocytes can be taken from a patient and reinfused.
Those patients still need lymphodepletion, even though there's no immunologic barrier whatsoever. The reason we've found out is that it happens because fludarabine eliminates so-called cytokine sink and makes those cytokines available for T-cells to expand. NKX019 is cytokine independent, and it's engineered in a membrane-bound form of IL-15. We don't need either the prolonged immune suppression or the cytokine induction. We evaluated that in our NHL study and showed pretty comparable PK between the Cy-only and Flu/C y data in NHL. While there are caveats there, you know, different patient populations, pre-existing therapy, et cetera, we felt compelled on behalf of the patients to evaluate that first. It's also a drug that rheumatologists are very comfortable with.
They're prescribing at the same dose themselves, has some potential advantages from a regulatory standpoint. But, you know, and ultimately, if additional lymphodepletion becomes necessary, fludarabine or other agents, we certainly could adapt the dosing strategy. But for now, we felt on behalf of the patients that we should evaluate.
We're starting to see the initial data coming out from newer clinical trials in the lupus and rheumatic space. So maybe just talk about what your thoughts are on some of the latest data that we've seen from competitor studies in the autologous CAR T side, and how that kind of gives you a potential benchmark for what you'd like to see in your phase I study.
I'll start. I mean, first and foremost, we're encouraged by the data we're seeing. I don't think anyone on the discovery and manufacturing side would have felt that the data coming out of Germany from Schett would be replicated at a 100% response rate, because he treated a lot of young patients who had pretty well-attacked immune systems. And in the general population, you're dealing with patients that have all different age groups and all different severities, very heterogeneous patient population. So we're encouraged by the data we've seen so far. We are excited to be in the clinic with a convenient and safe cell that we think is gonna be beneficial to the patients, and we're looking forward to giving an update on our data in 2025.
Great. You've also announced the initiation of Ntrust-2 study in other autoimmune diseases. And in that study, you're looking at a compressed dosing schedule of seven days versus-
Mm-hmm
... 14 days in Ntrust-1. So what was kind of the background and reasoning for using compressed dosing, and do you think that that's more likely to be the dosing strategy moving forward?
Yeah. This was another lesson from our oncology program. Lots of lessons, you know, lots of advantages to this not being a first-in-human product, right? We allowed us to largely avoid dose escalation and go skip right to a therapeutic dose right away, allowed us to introduce retreatment as a function of the Ntrust-1 study and evaluate Cy-only lymphodepletion. And in the case of compressed dosing or seven-day dosing, that was something we evaluated in our NHL study in patients with refractory large cell lymphoma. And what we saw. Sorry, Gina. What we saw was similar PK or improved PK towards Day 1. So if we move that Day 14 dose to Day 3 , that we saw better drug exposure with no change in toxicity profile.
So we felt it was kind of a win-win for us to add that. Those data were not available at the time of the Ntrust-1 filing, so that was the set fourteen-day dosing. But we certainly see it as a platform-level change, and as we evaluate the data coming out of Ntrust-1, certainly opportunity to transition that to a platform.
So myositis and scleroderma are also B-cell driven autoimmune diseases that have, we've seen some positive data out of the Dr. Schett study and those indications as well, but obviously less so than we have for SLE and LN. So maybe just discuss what you would consider to be positive results in those indications and kind of the market opportunity there.
Yeah. So, I think systemic sclerosis or scleroderma is an area of huge unmet need. Unlike lupus nephritis, where there's a lot of drugs and patient, you know, a competition of a bunch of drugs that have, up until cell therapies, provided sort of marginal benefit. There's really nothing in scleroderma that works at all. They have one standard care drug that doesn't really work, and it's a slow, sometimes rapid, progressive disease that causes both skin and predominantly pulmonary dysfunction. And so the patient population there is those that are progressing, and so the hope there is to stop progression of things like skin thickening, pulmonary fibrosis, and hopefully revert those. But these are those are.
Scleroderma is a really life-threatening disease, of progressive, that we hope to avert that progressive course. Now, it does highlight challenges of using disease activity indices versus discrete endpoints. It's easier to measure proteinuria than it is to, say, measure pain or mobility, though we see it as, again, huge opportunity. And things like myositis, as you mentioned, it's also gonna have some disease activity indices, but also some laboratory testing and muscle damage. And I think some of those endpoints and the idea that you're trying to avoid progression and hopefully give some recovery has probably kept people out of that space for a while, but it's a patient population that desperately needs the new therapies.
While lupus nephritis looks to be a very challenging disease to make inroads in, and I think it's gonna be relegated to the, you know, potentially more aggressive cases. I think scleroderma is one where you could get in right away and start and really change somebody's course of their disease and life.
You've also announced a recent investigator-sponsored trial in the broader SLE indication. What's kind of the benefit of having the study being run by an outside party, and what insights are you hoping to get to potentially kind of move forward in both SLE and LN?
Yeah, our goal is to dose as many patients with autoimmune disease as we can. It's a competitive marketplace. There's a lot of clinical trials ongoing, and there are a lot of investigators that are interested in both company-sponsored IND trials, but also doing their own investigator-sponsored trial. And given the data that came out from Dr. Schett, there are a bunch of rheumatologists who are incredibly excited about doing these studies, and so we've partnered with some of them, and we will continue to do so, and we'll continue to expand our indication base and our company-sponsored trials as well. But we think the more experience there is out there between investigators who are in our IND study or doing their own study, better off it'll be for patients and for the diseases.
I think it also highlights the limitations of doing these studies, where you have to have very strict inclusion, exclusion criteria, with the hope of getting an indication of a very tight patient population. You know, we had an investigator, a very prominent lupus investigator, and said, "These are great. I got all these studies, and they all want to treat the same patient population, and I've got this whole panel of patients, and they don't qualify for any of them. There's a lot more to lupus than lupus nephritis. How about we run this study where we can get a little bit of experience in all these other manifestations of lupus?" So it was an exciting thing for us to have an investigator come and say, "You know what? This is, this is potentially transformative." Like, doing the...
You know, everybody going after the same patient population isn't gonna move the field, isn't gonna help patients, and so this was one we were excited to partner with.
How do you think about durability for autoimmune diseases, and kind of along with recent clinical data we've seen, which has shown that maybe in some patients, durability might not be as long as we initially expected? What would be an appropriate or positive duration of remission or response?
Six months would be great, and the beauty, again, of an allogeneic, off-the-shelf, on-demand NK cell is that you can re-treat.
Mm.
Unlike the autologous CAR-Ts, which are difficult to retreat, or if not impossible, we can retreat with our CAR-NK cells. There's the option of doing that, and if there is, it'd be great if you dosed once, and patients had a 100% response rate or even a 60% response rate, and it lasted forever. But if it comes back, we'll be able to redose them with our cells.
Yeah. I mean, I think the world was looking for one and done for everybody. I think we had some progression that we sort of believed was inevitable through you know, maybe a variety of mechanisms. But as Paul highlighted, what we're gonna have to be able to do is be available to have a safe therapy, to integrate into the landscape. You know, you talked earlier about the landscape. This is going to be a tool in the arsenal of rheumatologists of, of...
So it's gonna to, it'll be up to us to create therapeutics that they can deploy at the right time and say, "Hey, this is the right drug for the right patient." And these are chronic diseases, and I think we just have to be ready to settle in and say, "Hey, cell therapy may have a place in chronic disease.
Right. And if you, you know, if you take, patients who are younger and have more intact immune systems, and you're able to treat them for a longer period of time and prevent them from getting into more full-blown, autoimmune disease, that, that would be a plus, and that would- that's where we would ultimately like to go. But we'd also like to be able to treat... You know, I have Crohn's disease. I'm sixty-four years old. My immune system is gonna be different than a nineteen-year-old Crohn's. But it'd be great if I had a flare, that, and there was a cell therapy that, that would benefit, that whole heterogeneous population of patients. But ultimately, if you're able to get those patients early and prevent them from having to live thirty, forty years with an autoimmune disease, that'd be great.
That's what we'd like to do.
Great. Maybe with our last few moments, just to kind of summarize catalysts into the next twelve months.
Two major catalysts. One, we'll initiate dosing in our Ntrust-2 study this year, and we will present data from our Ntrust-1 study in 2025.
Great. Okay, well, thank you very much, David and Paul. Great-
Thank you.
Talking with you, and thanks everyone for tuning in.
Thanks so much.