Thank you everybody for joining us. We're here with Nkarta today. Very excited to host you guys. Obviously, it's been a very exciting past couple months for you, so I'm really glad to have you in person to go over it. Been an exciting morning in the CAR T space, frankly. W hat? Before we even get into your day, let's start with that.
Okay.
Because I feel like that's top of mind, even just getting myself a soda out in the lobby, I just spoke to three different people about this. So, so do CAR Ts cause T-cell lymphoma? What are we going to do about this, and how much of an issue is it for any particular CAR program?
Yeah, I mean, we're learning like you are. And so I think it does highlight a potential risk of using an autologous product that's genetically modified, right? Especially a long-lived cell, like a T-cell. So this, t he potential risk that's being highlighted here is that the virus is then inserting itself into a place that immortalizes these T-cells because the FDA has called out that there's been CAR-positive lymphoma or leukemia lymphoma. And we're building a big experience now. We've treated thousands of patients with CAR-modified cells. I do think this is less relevant for an allogeneic cell a nd certainly less, much less relevant for a short-lived, sort of, easily rejectable cell, like a T-cell.
Presumably, I mean, there are NK malignancies as well, but, presumably, with an allogeneic product, you, it's easier to. Would you expect it to be easier to spot that in advance?
Well, I think it's.
QC for it, I guess?
Well, it's not so much the QC as that we expect some degree of, we count on our cells being rejected by a host immunity. What we have long highlighted as an advantage here is these cells get in, get out, they don't cause, sort of indefinite, long suppression of the B-cell compartment and aren't. W e don't worry about it as much for immortalization because there will always be that selective pressure from host immunity.
Yeah, that makes sense. That's great context, that sets maybe your platform at least a little bit to the side of what's crushing t he cell therapy space.
Yeah. Yeah, I mean, I think generally a rising tide raises all ships and I think the cell therapy space is going to come under, some degree of investigation, I think, or?
The sinking tide.
Increased interest.
I guess.
Yeah, that's what I'm saying. There's the opposite.
The sinking tide beaches all birds.
Yes, exactly. So I think, again, we feel it's probably more relevant for autologous cells and more relevant for T cells, but we're.
Makes sense.
Watch this space.
All right, well, let's transition there to exactly the same question, except about autoimmune. Obviously, we've seen a ton of interest in, well, lupus specific, but in autoimmune generally from CD19 CAR Ts, also some bispecific, some TCRs, allo CAR T approaches as well. But you're the first of the NKs to whole hog go into the space o r at least announce an intention to do so. So, can you talk a little bit about what you view as the selling points for an NK-based approach in the autoimmune space relative to a T-cell based approach?
I'll tag you. Keep going.
Yeah. Yeah, I think, first and foremost is accessibility and safety. I think an accessibility of having an off-the-shelf product that allows patients and and facilities to avoid the sort of burdensome infrastructure associated with autologous CAR T in a space that's largely treated as an outpatient. And so we, we feel not so much the rapidity of treatment, but the ease of access. T his is given as an outpatient in the malignancy , in the oncology space, we have a big a large safety database on this drug, so we can give it safely. So reduced inpatient admission, off-the-shelf availability, no apheresis, no infrastructure at the sites. We think that accessibility issue is huge.
And then from a safety standpoint , this, today's news notwithstanding, we know that NKs have a clean safety profile. Nobody has ever said that NK cells are not safe, and so no high-grade CRS, no ICANS, those sort of expansion-related toxicities, if you will. But the other thing that comes with that is the ability to have a disease-specific lymphodepletion regimen. So CAR Ts require sort of a specific secret sauce to get them to expand and take off. Our cells don't need that. Those cells come in active. We don't depend on in vivo expansion, so we can tailor conditioning regimens to the disease, and in this case, avoiding fludarabine, which itself has a risk of MDS, secondary malignancy prolonged cytopenias, et cetera. So, we think very big accessibility, and safety benefits here.
Yeah, I mean, I would just add to that, that if you're an autoimmune patient, it's a different profile. You're walking around, you're going to work every day, you're not feeling well, you're looking for relief, you're not interested in sitting in a hospital for two weeks in a clinical trial. So from a clinical trial point of view, we're hoping there's going to be an advantage there with a push from patients who understand the difference between , maybe needing to be observed for a couple of weeks versus maybe for short-term observation. The other thing is,
They already miss a lot of work, so missing more work for either a clinical trial or, waiting for, their auto CAR T or what have you, we think that there's a place. If we can show efficacy that's similar, and we have this profile, this NK cell, which we've been talking about, as Dave mentioned, the short acting nature of the cells, the quick one-two punch that the cells have, then we feel like there's some really nice patient advantages as well as for the clinicians in those medical centers.
Oh. So also, apart from, you know, accessibility or allogeneic aspect, in autoimmune, we're looking at an immune reset. So, how would you say, you know, CAR NK cells are better suited for an immune reset in these patients compared to, say, CAR T?
Yeah, I mean, well, first and foremost, I don't think we need to best what is being seen in CAR T once you get you know, 100% response. I think what we're looking to do is to recapitulate those data, and I think we're well positioned to do that. Really, the more CAR T data that we see, the more it favors an NK approach. CAR T in malignancy and CAR T in autoimmune disease are clearly different entities. In the malignancy space, you get massive expansion driven by lots of tumor antigen, high expansion-related toxicities like CRS, ICANS, big explosion of T cells, long-term persistence, long-term B-cell aplasia.
Whereas in autoimmune disease, now we've got at least a couple, almost a couple dozen patients out. Everybody's getting very low-grade CRS, very low-grade expansion. Nobody has long-term persistence. B cells are recovering very quickly. This is the NK profile, right? This is saying, you don't need long-term persistence.
You clearly don't, because these patients don't recover their B cells quickly, they never, they don't require immunoglobulin replacement, they don't have impact on vaccine responses. If you were to hear it, that's NK. T is long-term suppression, B-cell aplasia, in the malignancy space, we use recovery of B cells as a negative prognostic indicator, as you know.
Here, they're recovering very rapidly, so it's clear what's required in malignancy is different than what's required, and certainly what's seen. You know, now we're seeing 1, 2 years of drug-free remissions after a relatively short duration of- B-cell, B-cell suppression, that immune reset. Now, how long that takes and what an appropriate duration for reset, I think we're, we'll, you'll find out, but it's clearly not that long. So, so we're actually very encouraged by the CAR T data- because they look very similar to ours.
Yeah. Now, in the antibody space, before everybody started jumping into CAR T for lupus, there was a clear relationship between amount of B-cell reduction or amount of suppression and the disease response to the benefit to the patient. But part of what what strikes me with the CAR T data is to this point, you get into this, to your point, you get into this reset. B cells come back. You don't have disease remission, or at least, the expectations for disease remission are that it'll be.
Yeah.
Much longer, take much longer to come back. So in that context, do we know yet, do we have any suspicion what the key level is? How deep do you have to get down into the, you know, low single digits, the sub-1% amount Of B cells? At what point do you feel confident you've gotten the clones that are causing you issues, and, do you expect any relationship... Once, once you've hit that reset level, do you expect any relationship between potency at target or potency of, of B-cell removal. A nd durability or you know, efficacy? You know, 100% response rate, let's.
Yeah.
Let's take that as a baseline. Efficacy beyond that would mean something like durability. You know, what do you. Do we have any knowledge of what those key levels are, what the dependencies are?
Yeah, I don't think we know yet. I think people are taking a pool of clinical data and kind of reverse engineering and saying: Well, these people got better, and they only had a very short window and sometimes, you know, a month or two of B-cell suppression. I do think the historic data on B-cell suppression has largely been with the antibodies, as you mentioned, and, you know, as the bispecifics kind of wander into the space, I do think the target is important. CD20, probably, you know, probably not the right target here. There's some certainly CD19 positive, CD20 plasmablast floating around that may be contributing. Again, I think I don't want to do what I'm accusing everybody of doing, of kind of reverse engineering. What the mechanism is here, but clearly targeting is important. The target is important, 'cause.
What do you think of BCMA?
Yeah, you know, I think it's an interesting idea.
I don't think there has been. Again, there hasn't been a hole in the CD19 data thus far to say you need a different target.
Yeah.
You probably will get a, you know, a more complete, you know, may target different B cells. Whether or not that's necessary or good even in a, in a you know, in a... If you can avoid taking out normal B cells, you certainly want to do that. There seems to be something important about hitting CD19 positive cells, but also where those cells get to, because antibodies seem... You know, patients in, say, lupus nephritis, treated with rituximab or obinutuzumab, get peripheral B-cell depletion, get kidney biopsies, and there's local antibody.
But they're still. Yeah.
And so it's clear there's something about tissue penetration, too. The antibodies are getting there, you know, it, there's likely a cell the one of the benefits that the cells are providing is being able to have a local effect, and you see rapidity of reversal of proteinuria and those things that feel like there's probably a targeting effect as well.
If you think longer term, just like we say with oncology, with the disease-specific lymphodepletion, you can always have the option of re-treating later. It's available. We don't know whether we'll need it or not, but we know the NK cell, again, is exquisitely. It'll let you. You can set up to do that.
Yeah.
Right?
I had one last question in the lupus. So there are a limited number of patients in the lupus a nd a lot of companies are moving in this direction.
Yep. Sure.
Is there any, you know, concern of, like, enrollment issues, or how are you thinking about that? Or, given that this is allogeneic, it would be different. Any thoughts on that?
You know, I'll take a stab at that, and then Dave will add to that. There's always concerns about enrollment, no matter what disease you're in. You know, you want to make sure that you're fulfilling the needs of the patient, as well as making sure that they're getting the right therapy and making sure that the clinicians are enrolling the right patients. But there are a lot of patients with lupus, and there's a lot of unmet medical need there. And when we went to ACR a couple weeks ago, we spent a lot of time with physicians and with patient groups, which are incredibly well-organized.
So, you know, between the pull from the physicians and the push from the patients, if, again, we have this idealistic profile that then shows similar efficacy, I think we're going to be in a good place there to be able to do that. I think what's really important, I think, for this patient population, and I spent a lot of time... I started the Patient Advocacy Committee at the Bio Board, where we interact with these patient groups. They're educated, looking for things that are going to make their lives easier. So the easier the therapy is, the better it's going to be for them.
I think we just have to keep making sure that we're filling the needs of the patients, that we're not asking them to come in and do things that are going to, you know, reduce their quality of life and make them have to stay out of work longer and do all these kinds of things. I think there's some-
From a trial perspective, from a trial con-
Well, from a trial perspective, but even from a treatment perspective, right?
Okay.
So if what they want to know, if they're going to go on something that's new and different, right? How safe it is, whether my physician wants to use it on me. I've heard from patients that they like being in clinical trials 'cause they get better care, background care-
Yeah
In a clinical trial than they get in their community-based setting. If we can bring the degree of academic care in the community setting with NK cells ultimately, then there's a lot of room for expansion there and working with patient groups and working with community-based physicians, and these-
CAR T approaches might not have access to.
Right. And rheumatologists haven't classically had access to drugs like these, and so getting that community used to using these, working with oncologists and hematologists to do that, I think there's a lot of room for collaboration and some pretty good experiences here. But again, caveat, we've got to show.
Yeah.
Got to show that it works first.
Of course, right. Lots of auto CAR T, very little allo NK, so I think we can leverage accessibility and safety, pretty, pretty handily.
Well, we look forward to seeing where that program goes. But I guess in the last couple minutes, I do want to talk about the last cohort in the malignancy space, this compressed dosing schedule. Can you talk a little bit about what, you know, maybe the decision to add that cohort, not pivot entirely to autoimmune? What are you hoping to see in compressed dosing that might bring you back into malignancy in a more direct way?
Yeah. Well, let's start with why we did it, 'cause I think that's important. We did it for the platform, right? We did it for the platform first and foremost to see if we could compress dosing, if that was going to be something that would be advantageous across the platform. We had lots of experience in NHL with CD19 CAR, CAR NKs, and so the opportunity to do compressed dosing there, where, you know, we've retreated patients in that trial, if we can compress dosing there, will that have an impact on how many patients might need or not need retreatment? That's something we want to look at. We also realize that with NHL, it's a hugely competitive market, so we'd have to have an edge there, and this could give us an edge. So it could give us an edge there, so if this looks really interesting.
You know, we didn't pivot to autoimmune. We expanded, right? We have multiple shots on goal now. We have NHL, we have autoimmune, we have AML with 101, and then we'll see how all the data play out, and wherever the value is created the best for the patient, for the physician, for the investor, that's where we'll go.
Great. Maybe since you mentioned 101, in the AML landscape, we've seen more cell therapy approaches starting to come in, not all traditional CAR Ts, so a lot of edited grafts or other plays on, on in transplant setting. Where do you view cell therapy as providing the, the big opportunity in AML versus stem cell transplants, bridging therapies, add-on therapies? Where does, where does cell therapy fit, and, and where does NKX101 fit?
Ask the transplanter.
Yeah.
Yeah, is everywhere an answer? But, no, so I think there's always room for safe, effective therapies, and this is a place that we're able to leverage the disease-specific LD. And so using something like fludarabine here, which is well known by our investigators, has the opportunity to move up in different lines, et cetera.
I think we view transplant as a part of the, a part of the treatment landscape. Don't consider getting somebody to patient bridging, that's standard of care. So we feel like real opportunity here to add on to what is a space that really needs novel therapies, and not necessarily getting too, I think adding on to the additional therapy that patients are already getting, patients that are this is similar to cyclophosphamide in rheumatology. Fludarabine is a regimen that patients, or patients and providers know. So that's we see that sliding into the landscape as is, rather than trying to upend the standard of care.
Makes sense.
Cool.
Well, I think we're officially out of time, but if you want to steal some of our passing period for a final thought, please, what have we missed or, or what are investors missing when they think about Nkarta's path forward?
I think, you know, we have to go back to basics and look at why NK cell therapy is a good cell therapy across the board, and I think, you know, we're starting to see that play out. I also think it's important to remember that when you're in phase one, you generally find things about your therapy, and we have found some things, and we've made some adjustments, and that's what you normally do in phase one. We're very excited. We've got cash until 2026. We'll be able to get proof of concept in all these areas and be able to make decisions on where we want to go next based on that.
So I think we've got a lot of optionality, we've got a great cell profile, we've got allogeneic off-the-shelf, on-demand cells, so now we've just gotta show that they work, and we have to do the experiments to, you know, optimize them as needed.
Excellent. Well, appreciate the time, guys, and we look forward to seeing where these 3 shots on goal take you in the next year.
Great. Thank you.
Us, too. Thank you.