All right, well, good afternoon, everybody. Welcome. We've got Nkarta with us tonight, Paul. And David, thank you for joining us in Miami. Really appreciate having you.
Yeah, happy to be here.
Excellent. Well, I'm just going to jump right into it.
Go with it.
So, obviously, the focus of the company has transitioned predominantly into the I&I space, where market focus now has shifted dramatically into CAR-Ts, and then just as dramatically out of them and towards bispecifics over the past year. But I'd love to hear you guys talk a little bit about how your program has differentiated from some of the other cell therapies in this space, where people have maybe lost confidence and maybe position that relative to the bispecifics, where the focus is currently.
Let's just start with everything that's shifted has shifted based on minimal amounts of data.
Two patients.
Two or three patients. I think you have to keep everything in that context. To be differentiated right now is to have a dataset that has a robust and meaningful number of patients rather than we've announced we're not going to announce one or two patients' worth of data kind of stuff. One of our differentiators is that we will not do that. We've guided to 25 to present data from both Ntrust-1 and Ntrust-2, our LN study and our basket study in myositis, vasculitis, and.
Sclerosis.
Scleroderma. So I think that's where we'll be differentiated. In terms of the cells, I think that's Dave's department, where he wants to get into the differentiation between why we have an ideal product for an outpatient setting.
Yeah. So to the first part of the question, the differentiation on cells, I think you're right. Lots of enthusiasm early because of the potential for such a dramatic impact on outcomes and the paradigm in the way these diseases are treated, and some of the things that really made the market and sentiment retract, we feel we're sort of well-positioned to address, first and foremost being safety. Some of the earliest events and some of the biggest movers have been high-grade toxicity events, whereas what we know in this group of diseases and autoimmune disease and chronic diseases, sort of differentially, sort of less immediately life-threatening diseases, safety becomes much more paramount. As an oncologist, we're a bit more cavalier about just push it until no pain.
Don't say cavalier, Dave. But yeah, I understand.
Yeah. So no pain, no gain. So whereas here, safety really is paramount, right? I think you have one safety event, and everybody says, well, OK, this is not what we signed up for. So as an NK cell that doesn't expand, you won't see expansion-related toxicities. We've been dosing this drug as an outpatient for a long time. We've never seen a case of ICANS of any grade and never had any life-threatening CRS. And so we think that's a differentiator built into the biology of NK cells, is that the avoidance of expansion-related toxicities. Also, accessibility of an allogeneic off-the-shelf cryopreserved product allows us to get to centers and patients in a way that doesn't encumber those sites, physicians, to do things like tapering of immune suppression for apheresis, readministration, et cetera, whereas we can decide from screening to treatment in a relatively efficient way.
So you obviously opened your studies recently this year. We've seen other folks in the cell space in I&I have INDs open for a very long time, struggle to enroll patients. You already announced first patient in recently. And I'm not asking for an enrollment update. Don't worry. But I would love to hear what your feedback has been from docs on the ground. Are the practitioners enrolling patients in these studies receptive to those messages that you just told me, David? Are they aware of the differentiations between your programs and maybe some of the cell treatments that they've ostensibly been investigators on and not put patients on trial?
Yeah, it's an education process, right? I think there are still oncologists that when we talk to them about our studies, they'll say, oh, this is the CAR-T NK, or this is the CAR-NK T cell. And so having that education process is constant. And that's on us to really push and highlight the potential benefits of an NK-based approach. And so like I said, it's a work in progress. It is, I think, as you alluded to, it's busy out there. It was a huge opportunity into the I&I space, a lot of movement into the space. And so obviously, there are challenges with finding sites, finding investigators that are engaged and excited about this, because it really is about the investigators. If you have it open at a center and you don't have investigator buy-in, it doesn't matter. As you said, they sit and don't enroll.
And some of these trials are two-year studies. And making decisions on whether or not you come on or off these therapies can, the disease kind of waxes and wanes. And sometimes you hear about patients like, I think they're going to be eligible. I think they're going to do OK. And that's the thing with chronic diseases of deciding not so much when do you want to tweak your standard of care, but when do you want to make a real inroad and make something like this that can be more disruptive. So it is constant education. It's getting on the road, making sure we're in front of the docs. We're at the sites. We're always there discussing these things. So yeah, I think it's resonating. It's taking time to soak in.
So to add to that, networks are going to be important. And if you look at everything through the lens of the patient, the patient goes to the big centers to be worked up. Patients get treated in the community. So the advantage that Dave talked about earlier that we'll have ultimately will be the ability to get out of FACT-accredited centers to go into the community and treat the patients with their clinical trials where they're being treated in the community. And so asking a rheumatologist to give up a patient in their practice to be able to go into a clinical trial is going to lose time at work, and they're going to have to sit around a while while they're being not only worked up, apheresed, and then dosed, and then followed up for toxicities. We're going to have some major advantages there.
But we've got to get there, right? We've got to get to that point. And that's where we're aiming to do. And that's where we think there'll be a massive differentiation between a CD19 CAR-NK and, say, an autologous CAR-T, even an allogeneic CAR-T.
Makes sense. Now, one of the things that I recall you talking about extensively when we first started talking about the I&I programs getting off the ground that I haven't heard you mention is the advantage of having a reduced-intensity lymphodepletion regimen, a fludarabine-free lymphodepletion regimen. So how has the feedback been from investigators and from practitioners on that front? And not to be too aggressive about it, but why didn't you bring that up when I said, what's the differentiation? Why wasn't that the first thing out of your mouth?
I think these others are sort of more resonating in terms of I think it falls under the safety and accessibility of it all, because one, safety, I think, falls under the toxicity of fludarabine. And that gets bundled in. And we've certainly had investigators say, listen, I've had 10 different CAR-T companies come to me. I'm not giving fludarabine. This I'll do. Or I don't want to do this. And/or some that are interested and maybe even have had experience with we've talked to investigators that have had toxicity events associated with Flu/Cy in early CAR-T patients and are interested in that approach. So yes, I think it's a secondary getting them excited about doing cell therapy and NK cell therapy. So yes, that's resonating as well. That's an important differentiator. I think for us, it's not only a safety advantage.
We think it's a regulatory advantage as well. We have a lot of data on what Cyclophosphamide monotherapy is capable of doing.
In these lupus indications.
In autoimmune indication. And so in the discussion of that is still kind of out there, depending on the approach, is what's the Flu/Cy doing? What's the cell doing? What's the monoclonal antibody that may or not be added to that doing? And is it just sort of like one big combined therapy? And that raises the bar on not only the expectations of response, but also entry into the study. If you say, I'm going to enroll this patient, but I know they've got to be inpatient for seven to 10 days. They're going to get a chemotherapy I've never heard of. They're getting rituximab on top of that, injections of IL-2 or whatever. Or if you say, listen, you're giving Cy, you know that's going to put about 1/3 of your patients into renal response.
You add one agent, and that gets you to 50, then it's way better than any other drug on the market, right? So Benlysta, voclosporin, and those things built on a background of therapy, baseline cyclophosphamide or MMF, incrementally add a few percentage points and approved agents. And it takes away from that idea that if it's not Schett, it's not 100% drug-free remission, it's a bust.
And that's a really important point, because I feel like that is where the market is so focused, where investors have become so focused. And maybe it is important for an auto CAR-T, where you have to do severe conditioning, where you have repeated apheresis and repeated cycles of challenging therapy. Not the case for you.
Yeah, we think it changes the TPP pretty considerably, because if you, as I said, not only just the expectation and need for response, it's who you might enroll into the study, because cyclophosphamide or MMF is really part of first-line therapy, right? So to hit these patients up front. And so if you can demonstrate activity using that level of conditioning, you've really got potential to impact and get into an earlier, less sick population.
Like broader assessment.
Which you won't be able to do like CAR-T in oncology has moved up the line, because you're going to get chemo no matter what. But justifying, say, a 19-year-old woman who's just been diagnosed with lupus nephritis, guess what? You're going to get Flu/Cy up-front therapy. It's just not going to happen.
Very challenging.
So we still think it's a benefit. And part of it is just the numbers of things that pop up in your mind when you think about this. But I can tell you, because we just came back from ACR, one very well-known scleroderma investigator said to me, "I have 10 patients waiting for manufacturing. This sucks, right? Don't like this. So I'm excited about your product." We all have the stagger, right, in our trials. That in and of itself is difficult enough, because you're asking patients to wait for another patient to get dosed and followed up on before they get to be enrolled in the trial. But when you add that other element of the manufacturing, there's just so many things. Should this have the same efficacy as an auto CAR-T?
And again, when you compare auto CAR-T to what we might do, I wouldn't look at Schett's data, because they were very.
Very picked.
Very, I mean, good for them, by the way. If you can dose 19-year-olds and treat younger patients, their immune system is going to be intact. It's going to be easier for them to respond. But in the clinical trial setting, you have a heterogeneous group of patients. So something south of that and north of 20%-30% that they're seeing today in these diseases is where you want to end up. But if you don't have to wait for manufacturing, and you don't have to give flu, if that's ultimately where we go, which we hope we will, then it's going to be a major.
Yeah, it's a good point that the bar ought to be different for a true allo outpatient off the shelf than it should be for a CAR-T.
Yeah. Well, even an autologous CAR-T isn't going to have. They're not going to see in a clinical trial setting in the U.S. the same data.
The same 100% response, yeah. So you mentioned the stagger pulse. So why don't we talk a little bit about that? Obviously, cell therapy development has always been slowed down by these required patient staggers. Can you remind us what your requirements are for the NK program and when you could start coming off that stagger and enrolling a little more aggressively?
Do you want to talk about what the stagger looks like, what the qualifications are and then?
Yeah, so in the Ntrust-1 study, we have one indication. So FDA has really mandated across the board that everybody's going to get this sort of 28 days between patients on any given dose level. And then once you decide if you're going to go up on a dose level, also another stagger on top of that. On the Ntrust-2 study, we have three separate indications that Paul mentioned already. And those run in parallel. So the stagger is intra-indication, but not Ntrust-2. So we could theoretically enroll a patient with lupus nephritis, a patient with scleroderma, a patient with vasculitis, and a patient with myositis all on the same day.
Sure. But all of this is independent of the fact that you've dosed now many people with this product in an NHL setting.
Right, because you're in a different disease, and they're going to want to, by the way, I think it's wise to be careful in the beginning, and while we don't like to be lumped in right now, differentiating CAR-NK from CAR-T, we have work to do, and we're doing that, but the focus on safety is probably a good thing. We haven't seen, in all of our experience in NHL, any of the ICANS or cytokine release syndrome that people are seeing in autoimmune disease with the auto CAR-T, so I think that's a good sign, and if we can keep that, then that, again, is going to be a major differentiator, and so the stagger is what it's going to be. The sad thing about the stagger is it slows down enrollment, but it also discourages patients from wanting to travel to line up for therapy.
So you've got to coordinate all that stuff. And it's challenging across the board, but we're all working through it.
All right, so let's get off of patient enrollment now for a second. I would love to ask a more mechanistic biological question, and that's about durability requirements for the cells and the pressure on the B cells. Now, obviously, we know that the NK cells are non-expanding. Durability of the cells in vivo is lower than it would be for a CAR-T, but there's some sense that you may require prolonged B-cell aplasia to drive the so-called reset. Do you have a sense how much pressure you have to put on B cells and for how long it has to be to get to high efficacy numbers? Does anybody know that at this point?
Yeah, I struggle with the concept that you need to have a reset for a period of time. It's not like you're trying to stop bleeding or something. If you're resetting and you're eliminating these pathologic B cells, you should only need to eliminate them once, and so we believe really the focus is depth and not really duration, and much like in oncology, duration ends up being a function of depth. The farther, longer, deeper it goes, the longer it takes to recover, but so far in the CAR-T data, there's been wide variations from 30 days to sometimes not recovered in six months.
You mean the aplasia?
The aplasia, yeah. But it doesn't seem that there's been much, if any, correlation between that duration and response. And it's clear autoimmune disease is different than oncology, because the PK associated with CAR-T is so much different. And the B-cell suppression is so much different. Instead of a year and a half, on average, with NHL, you're looking at a month and a half, if that. So some of those things are less relevant, we think, in autoimmune disease. And it's sort of long-term surveillance that the idea of a reset is not sort of a slow, continuous reset.
A heavy wipe at the relevance.
Reset, right? Control, delete. But you mentioned sort of durability of response. I think that was one of the other things that starting at EULAR and then again at ACR, kind of they're like, well, there's going to be patients that relapse. That changes the idea here. And we came out of EULAR initially, we were like, oh, can you believe in a patient relapse? And we're like, it would be really nice to be able to redose them. And we're like, yeah, it's built into our protocol. And giving another dose of Cy and another set of cells off the shelf, patients are used to getting six monthly doses of Cy already. So if you have a patient that responds and then loses response, you can simply dose them again.
That's where we think, again, some of that pressure, some of the sort of shine that's come off the idea of cell therapy really has actually sort of tilted back sort of in our favor, more safe, off the shelf, outpatient, redosing, reduce toxicity, fludarabine free conditioning. Those kind of things are like, OK, this is starting to sound like more like a rheumatology drug than an oncology.
Sure, sure, sure.
Right, not constant infusions all the time.
Yeah, absolutely.
Now, one thing I wanted to pick up on there, you say you would expect that the duration of response and the benefit to patients would be related more to the depth of aplasia than for duration of aplasia. I think that makes good sense. But we know from the oncology space that the NKs, in general, are a little bit less potent than the CAR-Ts. I think it's fair to say. First of all, is that a reasonable statement?
I don't think it's a potency issue.
Paul's shaking his head, OK.
Yeah, I would push back on the idea of potency. There are different diseases in the idea that you have to eliminate trillions and trillions of malignant cancer cells.
Very different.
And sometimes complex tumor architecture, et cetera. And so the idea in that idea that they're not as potent is often a sort of you run out of ammunition, right? So sometimes the tumors will shrink, and you just don't have enough pop initially to drive and to get that sort of depth. But eliminating a big tumor mass versus eliminating circulating B cells and those in lymph nodes, and another reason why we think why you probably see that sort of smaller PK peak in CAR-T and less persistence. There's just not as much CD19 around.
Exactly. Now, I asked that question because we know one of your competitors in the NK space recently added a bispecific on top of cells, presumably to goose efficacy further, to push B-cell aplasia deeper. Can you maybe contextualize that choice for us and think about and I asked that in the context of the previous question, the assumption that less dramatic aplasia or less potent cell requires some T-cell engagement, some T-cell intervention for some reason?
Yeah, I mean, hard to say. I think we're going to have to come away from the idea that more is more. The same kind of argument comes up when you say, well, you've got to target the LLPCs using BCMA, or you're never going to get rid of all these autoantibodies. Yet the biggest data set now that exists is in CD19 CAR-NK and the Ruijin data that was a late-breaker at ACR. And so far, there's been a lot of success with 19, and it hasn't been these breakthrough poor responders. So I would push back on the idea that more is more and that you necessarily need to eliminate every last possible cell to go along with it.
Yeah, those approaches are going to lead to randomized clinical trials versus if you have the option of going in a single-arm study by maybe it's not 100%, maybe it's 50%, maybe it's 60%, then that's going to be an advantage. And so just adding things and not accounting for what you're adding and differentiating what you're adding versus what the cells are doing, I think you can do it, but you probably want to keep looking at cells by themselves with lymphodepletion.
The bar becomes higher for provability.
Absolutely, absolutely. Now, we're basically out of time. But before we fully run out the clock on the passing period, I'd love to ask, you've got sufficient cash to run out a fair amount of data here?
We do.
What does the runway cover? What do you hope to be able to share with folks? Paul, you mentioned not coming to the market with insufficient data sets. What's your bar for sufficiency to come and discuss with us?
So start with the cash. Cash takes us to late 2027. We should be able to do proof of concept, Ntrust-1, Ntrust-2, ISTs on that. It should be fine. So we're in good shape there. Glad we did what we did when we raised money last time, because it helps us in the situation we're in, given the movement of investors in and out of the space. Meaningful to us means more than one or two patients at a time, right? And I made a commitment, and I will keep that commitment. We're not going to talk about one patient or two patients. We're going to talk about five patients or more, right? So that's kind of our goal, is to make sure that it's a robust and meaningful data set. When you look at it, you can at least say it's not just anecdotal, incremental data.
Particularly when you look at autoimmune patients, the heterogeneity in autoimmunity with lupus alone, lupus nephritis, right? If someone's in a flare, the difference between how that patient will respond versus someone that's in less of a flare, it could be very dramatic. You're not going to know that unless there's a large enough number of patients to be able to differentiate. Otherwise, you're just looking at a bunch of noise. That make sense?
Absolutely. All right, well, obviously, first data coming from both Ntrust-1 and Ntrust-2 next year.
2025.
As you say, and we look forward to seeing it. And obviously, it's going to be a big year in general for autoimmune space, I think, in these indications. So there'll be a lot to discuss next year.
Awesome. Thanks, John.
We'll see you then.
See you then.