Okay. All right, welcome to the Nkarta team. We've got everybody here: Paul, Sean, Nadir, everybody here. Thank you so much for joining us. Let's jump right into it. Paul, for much of this year, we were anticipating data from the much anticipated data from the I&I readouts coming this quarter. We pushed it out to next quarter.
Next year.
Next year.
Yep.
Can you walk us through the thought process on disclosure at this point? What's most important from that disclosure, and why did we push it out the window?
Yeah. So, as you know, and it was interesting because we just had this conversation with you last week, so I'm ready for that question. So, our original guidance was based on our original cohort of patients, which were dosed with cyclophosphamide alone instead of Flu/Cy. We had been getting a lot of feedback from physicians, our rheumatologists, that we should be using Flu/Cy. We decided to switch to Flu/Cy. That all happened in the middle of last year, right? So then.
This year.
This year, sorry. This year.
Already in 2026.
Yeah, I know.
I'm thinking about next year already. So that happened in the middle of this year. So we had the FDA approve it relatively quickly, the path forward, but then we had IRB approvals. So when we looked at the data that we'd have by the end of the year, most of it would be Cy alone. And if we present Cy alone data to people, they're going to think that's our data, right? It's not. Our data is with Flu/Cy now, comparing it to Cy alone. So we decided the best thing to do is wait until we have enough patients with Flu/Cy to be able to present a robust and meaningful data set there. And we simultaneously announced that all the patients so far that we've treated with Flu/Cy have seen complete B-cell depletion, right? The patients with Cy alone, we said, we're not all complete B-cell depletion.
So we're sort of setting ourselves up for, you've seen the data with RUI with complete B-cell depletion, which led to durable remissions. We're at an earlier part, and then you saw our interim data showing complete B-cell depletion and some biomarkers. And so we're kind of catching up to that. So sometime next year, we made the guidance broad, we'll be able to show B-cell depletion, reset, and durable responses in a robust number of patients. So that's why it was important to us not to just, you know, BS people at the end of the year with three patients or whatever the number might be, right? Absolutely. A robust data set that we can compare properly to somebody.
That you would like to see, not that you'd look at me and say, "What?" Right?
Can inform you in sort of what the potential path looks like going forward in terms of development as well.
Excellent.
Let's talk then about the clinician expectations here. I'm a little surprised to hear that your investigators were so focused on Flu/Cy as the appropriate lymphodepletion regimen there. Early development, we were talking about the potential that Cy alone might be differentiated, might be more preferred given it's a less intense conditioning. Efficacy aside, can you speak to what the investigators were telling you about their preferences?
Yeah, you know, I was surprised by that too, because you're right. In the beginning, people were thinking, "This is going to be great. Use Cy alone. You can have, you know, you won't have to have the fludarabine on board." Well, they'd all been now experiencing autologous CAR-Ts and allogeneic CAR-Ts and other NK cells where they were using full lymphodepletion. And I think they were seeing full lymphodepletion and saying, "You know what? Is fludarabine such a bad thing?" And then honestly, they came to—I mean, I spoke to them myself. They came to me and said, "You want to set yourself up for success, right? And this is how you're going to set yourself up for success." And we're okay with it. So when we switched to Flu/Cy, not one investigator dropped off. Not one.
Matter of fact, they're enrolling better now with Flu/Cy than they were with Cy alone.
That was my next question. You've seen renewed interest.
We also hired Sean, by the way. We've got to give him credit, and Sean's a rheumatologist and interacts with these folks on a regular basis.
Maybe Sean, then can you speak to the pace of how the enrollment has changed and how the patient profile has changed?
Sure. Yeah, the pace of enrollment is exponentially better than it was. And we've been very pleased to announce that we've now dose-escalated to the second dose cohort. And we, you know, anticipate being in our highest dose cohort in January. And so that's a very massive drive, right, and change that's happened. And I just want to comment that the investigator engagement is high. And their expectation is they really want to see the best possible result for their patients and really a durable goal of durable clinical effect and ideally remission. And so, you know, giving patients that best opportunity by moving to a Flu/Cy regimen, we think is a really important move.
So all the things we learned, by the way, just to add to what Sean said, all the things we've learned, compressed dosing, day zero, three, and seven, two billion cells. Now we mentioned the second cohort, right? Two billion cells, day zero, three, and seven, Flu/Cy, lymphodepletion. So those are all the things that have worked in the past. Those are the things we think we'll be able to compare. By the way, when we present our data, we can compare our data to what other people are seeing with Flu/Cy versus saying, "Well, here's what it looked like with Cy alone." And it's harder to compare that way. And if we want to go Cy alone down the road, we can definitely do that. And those patients who have cytopenia can do that now as well.
Sean, there was another change that happened recently that you announced in the quarter that you were combining the DSMB and combining some of the oversight of the two trials that you're running, which I admit I didn't understand when you told me what the impact of that could be. So could you run us through what that means for the trial conduct and enrollment?
Sure. You know, the simple thing is we have what is a basket trial, so we have five indications in our Ntrust program that were split between two different study protocols and INDs, so now what we've effectively done is the way we're operationalizing and running the trial is to have all of those patients considered in a single integrated safety database that is reviewed by our independent DSMB. This was aligned with the FDA that we could do that, and importantly, it allows us to move much more efficiently because we're truly escalating as a basket study now, so regardless of indication, you know, once we have our, it's called a three-plus-three design. You have at least three patients dosed at a dose level.
You've got an escalation.
Regardless of indication. So those were major steps forward, right? Sort of indication agnostic dose escalation. And secondly, being able to really evaluate a totality of the data set under a single united DSMB.
And eliminate that stagger too, right, Sean?
Yeah. Well, yeah, that was the other challenge, right? We previously had a 30-day stagger where we had to dose each individual patient at which 30 days until you could dose the next patient. You know, we lost some patients because of that, right? They can't wait, right? They need to get the therapy. And so now we can actually dose the first patient, we follow them for 14 days, and after that, the rest can be dosed in parallel at the same time.
We had that stagger in each indication.
Yeah. So you're doing LN, and you can't leverage progress you're making enrollment in LN for one of the other indications. Now it's looked at more holistically. So like Sean said, we don't have to wait. If we have patients lined up, we can much faster kind of get them enrolled, get them dosed, and keep progressing.
And we got on top of all that, it's kind of cool having three of us because we're remembering everything now. On top of that, we got from the FDA an indication that once we completed dose escalation, that our expansion could be pivotal depending on what the data looked like in dose escalation. So very much like other people have been guided to, we got the same guidance. So they've been very consistent in the cell therapy division at the FDA on these kinds of things. So this all happened with that one protocol amendment. I'm glad we did it.
Excellent. So let's talk then about maybe more forward-looking. When you're doing a basket study like this, as you say, you're escalating in an indication-agnostic manner. You're enrolling a wide variety of patients. Can you talk about the balance of patients that you're finding so far? Are there particular indications that are filling up your basket more? How are you competing for patients with other folks in the space who also have some overlapping indications? Do you have a sense for what the patient breakdown is going to look like when we see data?
Yeah. Well, look, we're going to guide toward that next year, right, once we have the broader data set. But we do have five indications that we're currently studying in the Ntrust program. That's lupus nephritis, primary membranous nephropathy, scleroderma, ANCA-associated vasculitis, and.
Myositis.
And myositis.
Really only some of these are overlapping with other prominent programs in this space.
That's right. Right. There are some overlaps, but also, you know, from an NK cell perspective, you know, we're really quite differentiated addressing that many indications.
So our goal would be to give enough patients in each indication that we want to present out, and then we're going to hone it down to what are we going to focus on, right? We also have a myasthenia gravis and a systemic lupus IST.
In the ISTs.
Going on as well.
Yeah. I mean, may I ask the question because obviously when data comes out, and as you say, Paul, it's going to be a fulsome data set. I and my colleagues across the cell side, I'm sure, are going to try and comp this against competitor data sets as direct and as we are.
Yeah. If you had one myositis patient and one vasculitis patient, it's not going to make any sense, right? So we're going to try to do something that's more.
Yeah. But I think also, you know, that's going to give us an indication in terms of enrollment number of patients by the time we have that update as to where we feel like we can actually push and continue to double down and really focus our efforts going forward.
Where you're going to get good enrollment in the expansion cohort.
Yeah. I mean, it's going to be a combination of data and sort of where we can actually get to meaningful data based on enrollment numbers.
Okay.
So we're really focused right now. And the one thing I would add is part of the FDA engagement, they also left the door open if we wanted to explore additional indications. They were actually very open to that.
Interesting.
Okay. Excellent. Paul, you were mentioning the differences in efficacy driven by depth of B-cell depletion between the two lymphodepletion regimens. Are there particular indications where that's more visible than others or where it's more important than others?
No, I would say.
Just across the board, you want to see as deep as possible.
Yep.
Makes sense.
I mean, you might see, and we've seen other people present data with modified lymphodepletion, and it looks like those diseases that may be not as severe or not as challenging may respond to, you know, less lymphodepletion. It's probably not something you want to do in phase one or phase two, right? It's probably something you want to wait, but that's how we look at it.
All right. Makes sense. We're also, of course, going to be comparing your progress to bispecifics with more continuous dosing or at least a limited regimen. But there's, I think the question in everybody's mind is, what is the bar for differentiation? What is the bar eventually going to be in these indications to decide between cell therapy, whether it's allogeneic or autologous, a bispecific therapy, whatever the target is? Can you walk us through your current thinking about the sweet spot for an NK cell-based therapy?
Yeah, the highest response rate possible. So I think the way it's going to look, and this is my prediction, and I'm the optimistic CEO, so I'll do it first, and these guys can correct me when I say something wrong. I think what you're going to see is traditional small molecule agents are going to have one bar for efficacy that they have now. Call it 30%. Antibodies, whether they're bispecifics or trispecifics or T-cell engagers, maybe you're going to see something more like 50 or something like that. I'm just throwing out numbers, right?
Still limited in terms of the efficacy.
Still limited in terms of efficacy because they're not seeing the deep durable. By the way, the recent data that came out with a bispecific didn't look that hot in cancer, right? Now, not that it was bad data, it just wasn't stellar data. So then cell therapy should be one step above based on so far, you know, Georg Schett's data are way up there. That's probably not going to happen, but it'll probably be somewhere in between.
Selected patient population.
Yeah. He's got a selective young patient population with great intact immune systems. So you're going to look at a heterogeneous group of patients, some my age, some young. You're going to see maybe something in between Georg Schett's data and that antibody data. That's how I would hope this will play out. And everybody was so fixated on the shiny new.
On 100%.
Well, yeah, that was with cell therapy originally. But then people went from being fixated on that 100% with that to, well, what are these cool new bispecifics and trispecifics? And now it looks to me like everything's going to be presented around the same time, right? Sometime next year. So I would be looking at this whole landscape now and saying, gee, all these zombie companies in the cell therapy space, maybe we ought to take a look at these things right now because we're enrolling patients, we've got great people helping us enroll patients, and we're going to have some results. And cell therapy traditionally, and again, if you want to look at NK cells in particular, look at the RUI data, which is robust, meaningful, long-term.
And then Artiva comes out with robust and B-cell reset, and we're showing robust B-cell depletion, and hopefully ours will show the same. And then that's what we have to show next year. That's what we're looking forward to.
I would add within the framework that Paul noted, I think there's ample opportunity for all of these players, but they're going to occupy different niches, right, in the therapeutic landscape. You know, for somebody who has severe disease, you know, severe refractory disease, or even severe, you know, newer onset disease, a cell therapy is a great option, especially if you catch them earlier in the disease course and you can redirect that trajectory and they don't have to go on this chronic therapy that they're going to have to be doing that.
Get a very durable.
Right, and getting this durable response. So I think that's a very different proposition than something that you take chronically, right?
But imagine if you are able to drive, you know, long-term drug-free remissions, and maybe it doesn't have to be five years, maybe it's a year or a couple of years, and you can redose like you could with an allogeneic therapy, right? Does the bar need to be close to 100?
Probably like somewhere in the middle there, right? I think there's a lot of room.
Let's talk about the advantages of the allo nature of your program and allo NK here. Redosing is part of Ntrust One. Can you talk about how you're approaching redosing at this point and how we should think about that as we go into the initial data set?
We plan to harmonize that, you know, so that'll be, you know, next steps, right, to really try and see that we're able to do that across the board. Yeah, I think it's important to test.
Should we expect that, to your point, should we expect to see that most patients are going to end up on not chronic therapy, but on semi-regular redosing data?
At some point next year, there may be patients that have been retreated. There'd probably be fewer because, again, we're just dosing right now, right?
Yeah.
But the ability to do that is what's really cool about this, right? So I think that's what we'll get to look at.
When we did this in oncology and we had patients that, say, achieved a PR or had a CR and then they relapsed, when we redosed them, we drove them all back into a CR.
Every single one.
For many of those patients, they maintained that for one to two years post the retreatment.
You're not losing efficacy on a retreat.
Exactly.
Excellent. Excellent. Does that extend to the, I guess, the PD properties of the cells themselves? When you redose, those cells have as long, as good characteristics in vivo as the original dosing does?
Yeah, we think so.
Yep.
We think so. And that's a differentiator from, you know, CAR-T. We know you can't redose CAR-T. They get shut off.
Yeah.
Right?
Okay, so what you need is quick B-cell depletion. That sets up the cells to do their job, right?
Yeah.
That's what the Flu/Cy does.
It's the beauty of that convenience and accessibility, but with the power of the potentially of what we see with cell therapy in this space, which others haven't shown yet. Maybe we'll see as data comes out from bispecifics, other modalities. But the standard is the Georg Schett set standard that, you know, maybe it's not 100%, maybe others are seeing 60%-70%. But it is that power. But if you have something that is accessible, redosable in a community setting, that is where the CAR-NK space, I think, is uniquely positioned in this landscape of treatment options.
Right. And with so far zero neurotoxicity, very slight CRS, you know, more.
I would have expected neurotoxicity to be modest, if present at all, given the lack of somatic expansion.
That's right. That's right.
Yeah. We never saw it in oncology in these patients. 46 patients, something like that.
The safety profile, excellent. Redosability, excellent.
Excessibility. Yep. That's right.
If you're heading to the same sort of efficacy landscape, that's a potentially differentiated profile. Absolutely.
That's what we'd like.
Excellent. Well, so in the last minute or two, can you talk about the current cash balance and runway, how far that gets you and what you would need to move into the next step?
Yeah. So we ended the third quarter with about $315 million in cash. So that gives us runway into 2029. So when you think about that in terms of what that allows us to do, what we can get through our phase one, potentially if we are able to leverage the dose expansions into pivotals, then we believe we have opportunity maybe not just for one, but maybe plus.
That runway is contemplating some potentially pivotal phase two.
Potentially we could accomplish that depending on what the size and sort of what the timeline for that pivotal looks like. But ultimately, I think what the runway into 2029 does is it gives us a lot of options and flexibility in terms of when we need to raise. We can be opportunistic. And if we want to really double, triple down in certain areas, I mean, we have runway, we have cash that we can pull in and try and get to milestones faster if we think that's a path forward.
Very important that you're not coming into data on the back foot, that you have the operational flexibility to answer that.
That's right. We did it.
Absolutely. All right. Well, thank you guys so much for joining us. A very informative conversation.
Thank you.
Thanks, John. Good to see you.