All right. Good afternoon, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and apologies for the late start. We're trying to get Nadir patched in, but he is available through Paul's phone, I believe. There we go.
Yes, he's on my cell phone.
So, very glad to have with us in the next session, Nkarta. Paul Hastings, who you see there, is the CEO. Nadir Mahmood is the president. He's on the phone. You guys want to make any opening remarks before we jump into Q&A?
Nadir, do you want to give a little brief overview?
Yeah. Hopefully everyone can hear my voice here. Apologies that we couldn't be on video. There were a little technical difficulties. As an overview, Nkarta is an autoimmune disease company. We're developing a CD19 target CAR natural killer cell for autoimmune diseases. The cell is allogeneic off-the-shelf. We are administering outpatient, and this is in indications across two company-sponsored INDs. First one, Ntrust.
There we go.
First one is Ntrust-1. We just lost him. By the way, this is part of his CEO training, how to deal with audio-visual problems when they happen.
How you doing?
The first is Ntrust-1, which is in lupus nephritis, and the second is Ntrust-2, which is a basket study, which has scleroderma, myositis, vasculitis, and now rheumatoid arthritis. As you know, we have upcoming data at ACR. Hold on a second. Okay, you're back?
Yes.
Okay. I just-
It's okay.
Okay. All right, I just went through Ntrust-1 and Ntrust-2, so you can take it from there. How's that? Okay.
The idea here is to look at this potential cell therapy and what we've really seen from the autologous CAR T space, but really deliver this potential therapeutic benefit to patients in a therapy that is readily available off the shelf, on demand, with incredible safety profile that can make it more amenable and more accessible to a broader range of patients. We are looking forward to presenting our first set of data at the American College of Rheumatology Convergence 2026 meeting in November of this year.
Also to have the ability to redose if it's needed. One of the things we keep hearing from investors now is how safe are your cells, because of all the safety issues that we've been hearing about, and then can you retreat, and can you retreat with lymphodepletion? What you'll see is, yes, we can. We've done that in oncology. We're now doing it in autoimmunity, and we're actually seeing similar results that we saw in oncology. We'll be presenting those data either at the plenary session, not the plenary, but the oral presentations at ACR or at the company event, which we will hold at ACR as well, where we'll explain all the data that we have.
Okay.
What we think we have is a safe cell, an effective cell, and one that can be retreated if needed, which is important for patients, because it's difficult to retreat with autologous CAR Ts, et cetera. NK cells are handmade for autoimmune disease because you can do all those things with them.
Okay. I definitely want to get to the clinical data we're going to see at the ACR meeting, but maybe you can just kind of first speak to some of the operational logistics underlying Ntrust-1 and 2. I know you made a number of protocol amendments earlier this year in agreement with FDA. How have those changes impacted patient enrollment kinetics up to this point?
Oh, in an amazing sort of way. When we went from oncology to autoimmune disease, the FDA basically said to us, I don't blame them, "You have safety data in oncology, but now you're in a new patient population, autoimmune patients." As a person with Crohn's disease, I've had it since I was 13 years old, autoimmune patients are going to react differently to chronic therapies than to an oncology patient with a therapeutic. They asked us to start all over on the safety database. We actually had to go through these patient-by-patient staggers. We had to have 24 observation period once they got dosed with the cells. Originally, they had to stay within a 60-mi radius of the institution for 30 days after they got dosed. All of that is now gone because of our safety profile in autoimmune patients.
The FDA and we work together with a protocol amendment, and we now have the ability to dose patients. They can walk in, get their cells off the shelf, be observed for two hours, and go home. All outpatient administration of these cells, no hospitalization time, and the ability to actually be convenient for the patient so that they don't have to sit in the hospital for a week. They also agreed with us to condense the dosing from where it was to zero, three , and seven days, and we're looking at a new dosing schedule, which is even more compressed, which we're working with them on now, so that everything we do is for the patient and to make this as convenient as possible for the patient.
When you make the investigational agent convenient for the patient and you provide services for the patient, like travel and daycare and doggy daycare, and reimbursement for their time if they're missing work, and it's on their request alone, that makes it easier for the patient as well. When you put all these things together, enrollment started going very well compared to difficult-to-enroll patients, grabbing them from Albany and bringing them to Manhattan, or grabbing them from wherever in Kentucky to the University of Kentucky. Now it makes it a lot easier. Enrollment is up, and it's convenient for the patient. We also added community-based centers.
When you take away all those restrictions, even though we have one amazing community center, by the way, that does have overnight stays in their institution, but when you actually open up these community centers. By the way, I recently heard that Lilly is focused on community-based centers for all of their trials now as well.
I think this is amazing because with restrictions on trials, it makes them only accessible to patients, which is 5% of the patient population that wants to be in clinical trials is accessible to them when they are in academic medical centers. When you open it up to community-based centers, the dynamic gets better. As you can see at ACR, I am setting you up from logistics to actually tactics. At ACR, we will be reporting in two indications with a handful of patients in each with durable responses. We could focus on the indications, see which ones enrolled well, see which ones responded well. Now we have gone from a big basket study, and we will talk about where we go next, which will be down the path of a couple indications for our pivotal study.
All of this has allowed us to be more convenient for the patient, more convenient for the clinician in the institution to administer the cells and the lymphodepletion, and ultimately enrollment improved in a dramatic sort of way.
Okay. I might have to revisit my R&D estimates. I do not think they contemplate dosing.
Okay. Well,
So-
No, we don't want to overpromise and underdeliver. All right.
No, I know. You've dose escalated now up to 4 billion cells per dose, and this is administered on day 037. I know you have the ability to dose higher if needed. I know you just talked about maybe looking at a more compressed schedule. I'm not sure if there's-
Yep
anything that you can say there, but can you just speak to the data that you're using to guide dose escalation across all of these different disease states right now? Are these decisions being predicated just upon B-cell depletion, reconstitution, PK/PD, or are you actually looking at-
Oh, no.
clinical data to inform dose escalation as well?
Nadir, do you want to talk about what have we said about dosing publicly? I want to make sure I'm not having a senior moment here.
We're on dose 037, and we're always looking to see if there's other ways to enhance efficacy while maintaining a clean safety profile. I think dose escalation, looking at other ways of potentially compressing doses. I think the PK/PD point, Stephen, I think that's an important piece. That's definitely one consideration. The other thing that we're going to look at, because now, if you recall, we started dosing at 4 billion cells with the Flu/Cy regimen earlier this year. We're starting to see data around what that could look like. We're going to use data also on some follow-up of certain patients to help inform do we need to go higher? Do we need to do something more in terms of changing the regimen to give us an even better opportunity to deepen responses if we need to?
Those options are there, and we believe we can scale that. I don't think they're going to have limitations from the manufacturing perspective if we need to go higher.
What Nadir is alluding to is always looking for the best optimized doses possible. But what we hope to achieve here, and what we are seeing early signs of, is a dose-response curve. The thing about our cells is we like to say that our cells are just like a biologic, right? NK cells don't expand in humans as much as T cells do. The dose you give is the dose you get. Our big 4 billion dose times three, once the patient gets all those cells, is about equivalent to once T cells expand, right? That's a pretty interesting, we hope to be a therapeutic dose. If that 4 billion dose is safe, we have the option to go higher.
When you develop drugs, you want to know whether your tox profile is so good, and you want to be able to maximize as much as possible your efficacy. We probably will go higher at some point, and look to see if that higher dose is better. But when coming back to your comments about PK/PD B-cell depletion, nobody really knows today. We think that full B-cell depletion leads to durable responses. We need to do more of that. And what does full B-cell depletion mean? Some CEOs will tell you it's measuring it in blood. I say that's wrong.
Measure the lymph nodes. We're doing lymph node biopsies. We're taking the risk, working with our patients and our clinicians, to do lymph node biopsies. NK cells have different profile, PK/PD, than T cells. They traffic to different areas. But we're still doing those lymph node biopsies, and we are looking at B-cell depletion, and we're trying to figure out does B-cell depletion correlate with durable clinical responses or not? Because no one's really proven that yet. There's some correlations that are being made, but we're going to do that. We're going to look at that. But what's more important than the PK/PD and biomarkers, if you will, in this case, B-cell depletion, is how is the patient responding? The disease activity indices associated with all of these diseases, if you think lupus is tough, look at myositis and scleroderma.
Look at CRISS and TIS and rCRISS and mCRISS, and all these other disease activity indices. If you ask a Crohn's disease patient like me about the Crohn's Disease Activity Index, I'll roll my eyes and say, "Are you kidding me?" Ask me if I have diarrhea, ask me if it's bloody, ask me if I can live and not be exhausted. We're doing the same study in our myositis and scleroderma and RA patients.
Alongside each one of those studies, we're doing a patient-reported outcome study separate from our clinical study, where we call them in their homes on a Zoom call, and we ask them in their words- What their symptoms were when they entered the study, and what their symptoms are now that they've either responded or not responded to the drug, so that we can come up with the FDA, outcomes that make sense to patients, that are more patient-friendly and actually easier to understand from an investment point of view than TIS or CRISS, which is a composite of all kinds of different things. How's your skin? Is your skin flexible? Can you raise your arms? Can you eat? Can you swallow? How are your taste buds? Can you taste food, in the case of scleroderma? We're doing all those things in parallel.
PK/PD and B-cell depletion, critically important. Equally important are patient-reported outcomes in these highly subjective autoimmune diseases with these patients, and the durability of those patient-reported outcomes alongside with those scales that they use, which is essentially asking the patient to take a pencil and put it on a line about how they're feeling today, right? These things they're not ideal, but we're working on that with the FDA, and with our patients, and with our clinicians.
Okay. I know you also have a couple of ISTs that are enrolling, looking at myasthenia and also lupus, with or without lupus nephritis or-
SLE, yes.
SLE, with or without lupus nephritis. Is the dose escalation that you're able to move to in the Ntrust-1 and 2, are those incorporated into the ISTs?
In some-
And some of the protocol amendments have been incorporated into those studies as well?
In some cases. But let me tell you what we're going to do by the end of this year. We're going to tell you where we're going next, and we're going to go from a huge list of indications down to a very specific list of indications. We may revisit the ISTs, the other indications that we haven't enrolled as many patients to have as much meaningful data as possible. But we're going to take the data we have and focus in a couple of different areas so that we can take the capital we have, which we have plenty of, and get these things through as close to pivotal trials, if not all the way through, with room on the other side.
So we're going to focus first in the key indications we've got great data on with durable responses in large numbers of patients, focus on that, and then revisit over time these other indications. But we will start with a very focused group of indications so that we can actually focus the company, focus the supply, focus the clinicians in a couple of different areas. And we expect that those areas will be relatively easy to enroll refractory patients who really want a therapeutic, and where it's not so crowded that you can't enroll more than one patient every other year in an academic medical center. So that's where we'll go next.
Okay. Maybe getting to the ACR presentation specifically, I know that you're a bit limited with respect to what you can say here, but maybe you can just provide a high-level framework of what we should be expecting to see in terms of patient numbers, duration of follow-up, and then just some of the specific efficacy metrics that you hope to share in an effort to provide proof of concept.
Yeah. Nadir, do you want to take a crack at that, and I'll add to it if I need to.
We have three presentations at ACR. The first one is an oral presentation on myositis, and we have a poster presentation on scleroderma. Then there is a third presentation, which is also oral on the last day, covering safety, which is unusual to have a safety-only presentation at a major conference like this. But it's really an opportunity, I think, to demonstrate, especially given what we've seen with the autologous space recently, the potential for a truly safe outpatient therapy in the setting. In terms of data, as you can see, we are focusing our presentations on two different indications from the six that we have across the two IND studies. The whole idea here is this is where we're driving our focus and our emphasis right now.
What you can expect there is, as Paul mentioned earlier, about a handful or more of patients that have about three months or more of follow-up. The idea there is to start having not one or two patients, but we've always wanted to have a meaningful number of patients at a clinically meaningful dose with some relevant amount of follow-up that we can share to talk about why we are excited and what we're thinking about those particular indications. When you think about this process that we've gone through, right, not your typical cell therapy dose escalation, but more like a traditional pharmaceutical or biologic style dose escalation, going from 1 billion cells to 2 billion cells, now to 4 billion cells.
Now that we are at where we believe sort of is a dose that can deliver data that we can talk about in terms of what we think the program can go, that's really what we want to present and what we want to have in the myositis presentation, in the scleroderma poster. Then the safety is going to cover sort of the entirety of the program across all indications, all dose levels, to sort of show what we've been able to see from a safety perspective.
So we'll have a community-based academic, Dr. Valenzuela, presenting the myositis data in an oral presentation. We'll have Dr. Dinesh Khanna, who is world-renowned in scleroderma, present the scleroderma poster the next day. Then imagine getting an oral presentation on a safety database, right? This is why this is so important to ACR and important to rheumatologists to understand how safe these cells are. We got an oral presentation, which Dr. Valenzuela will give. It is important to note that Dr. Valenzuela is the highest enroller in our studies community-based center, right? Academic, academically trained, owns his own community-based center. He will be giving that oral presentation on that last, actually, late-breaker day is when they gave us an oral presentation, even though it is not a late breaker. Because we submitted the protocol, the abstract at the time.
One oral on myositis, a poster on scleroderma, and an oral on safety across all of our indications. Not oncology. Then a company-sponsored event, which we'll do, where we'll pull it all together. Then I want you to pay attention to the dose response because we'll have patients. You asked about durability, Stephen. There are patients that were on 1 billion, 2 billion cells. If they're responders, they're going to have more durability. You can connect the durability of responders at lower doses to where we are at higher doses. Then you can look at not a lot of retreated patients in autoimmune disease, but maybe one or two that have been retreated. Did we deepen the response the way we did in oncology? In oncology, we had patients that came out of CR that we retreated, put them back in CR.
Are there patients in autoimmune disease that maybe weren't a TIS 50 or greater that we then retreated with a higher dose and got a TIS 50 or greater after the first cycle of dose? We're going to see that. What we hope you'll see is a dose response like a traditional therapeutic, which I think people will be excited about. It is a cool story. Then you'll see the ability to retreat, not the necessity, but the ability to retreat, and why that's important if patients don't respond the first time. What if they respond somewhat the first time and maybe have some unforeseen circumstances in their life and their disease regresses a little bit and then we retreat them? What happens then? We'll show that data as well. Whoops, you're on mute, Stephen.
Apologies for that. I know you kind of acronymed out some of the endpoints relative, or relevant within the context of myositis, which is TIS, and in scleroderma, which is CRISS. I think we've seen some CAR T data.
MCRISS and rCRISS. Yeah.
Yeah, correct. How do you think about the CAR T data that we've seen there as kind of an efficacy benchmark that investors might be holding you hostage to?
I love it. We want to match their efficacy and give a better safety profile. Simple as that.
Okay. Then-
And their durability. I want to match the durability.
Yeah.
We like durability. Yeah.
What can you say about background therapy in the context of Ntrust-1 and 2? I know
Yeah
for instance, if I look at the Cabaletta data, for instance, I think they had patients drop all immunomodulators prior to dosing. Are you allowing for stable background therapy, and how should investors think about that if you are?
Yeah. We are allowing a certain dose of steroids if they need to use steroids. They come off all their other therapies, though. I have heard some CAR T companies allow methotrexate and other agents, particularly in RA. We right now, right, Nadir, we have no immunomodulating therapies or background therapies other than steroids. Is that correct?
That is right.
Yeah. When a patient comes on therapy, think of an RA patient, and by the way, we are excited about RA because we think CD19 is a great target for RA as well as the cells. We're not as far along there because we just started doing that. If you think about an RA patient, an RA patient comes into a trial, and you take them off everything that they've been on, and they might actually have a bit of a flare. You don't want to see that flare, so you want to keep them on a low dose of steroids to kind of prophylax against the flare while they're getting their cells. That's something that we do allow.
Okay.
Up to a certain milligram amount.
How much additional data, say like in myositis and scleroderma, which you've highlighted, how much additional patient data would you like to generate from Ntrust-1 and 2 before you feel comfortable pivoting to registrational development?
Well, look, one question we want to ask ourselves is, because you don't want to leave anything on the table, is should we go higher or not, right?
Yeah.
And get deeper responses. That is hard to do when you have got three months of follow-up, but we are going to think about doing that. We want as much data as we can get, so we are going to keep Ntrust-1 and 2 going anyway to collect the data, but we would like to have. What I am anticipating we will do is over time, maybe one of those retreated patients will become a case study at the next medical meeting. Maybe the next set of data is presented next year at the meeting with more durable responses after you see three months durability, maybe get six, 12 months durability. I think we will always be looking at Ntrust for the durability factor because people want durability. You give people three months durability, they want 12 months. You give them 12 months, they want 24 months.
We want to keep that going, then starting enrolling the pivotal trials as well.
Okay. I know the FDA has been pretty friendly in terms of kind of the patient data requirements, number of patients that have been required for some of these registrational cohorts. I think the Cabaletta myositis registrational development effort in that disease is what? 17 patients, right?
Yeah. We want to go forward. Our goal, and I have told our clinical people sometimes they do not like it, single-arm trials. We have been invited by the FDA to do these kind of trials in cell therapy. Single-arm trials. Why give someone a placebo if you do not need to, right? I am a little skeptical of this registry concept where you go get a registry of data and try to compare that registry to your population in your trial because you have to go to these registries and negotiate all these ridiculous contracts. But if there is a way to look at standard of care and make sure that your results are better than standard of care through the literature, you want to do that.
But in myositis and in scleroderma, you can probably do that given the lack of therapies in those diseases and what's available, IVIG, for example, and other things. Look at that, look in the literature, and be able to compare that and make sure that your responses are durable.
Okay.
They've been great in terms of number of patients. They basically said, "If you dose escalate and you've got efficacy and safety, we would welcome you to consider a single-arm trial." I think you're seeing a lot of these single-arm trials being encouraged. They have a whole initiative at the FDA on speeding the discovery to development effort, and they're being very friendly to cell therapy, and we're grateful for that.
Okay. What's your level of confidence around potentially being able to initiate a registrational effort before the end of 2027?
That's next year. Pretty good. Pretty high. Yeah.
Okay.
Pretty high, yeah.
Okay. I guess I've always kind of thought about this first update as being important for a number of reasons we just discussed.
Well, you don't get an oral presentation at ACR.
Yeah
Because you got shitty data, right?
But it seems to me that the update in 2027 that you mentioned, right, in terms of
Yeah
additional follow-up
Oh, yeah. No, look
durability and more patients
I think we'll be able to tell you at the end of a. A little bit of a lack of trust right now around these patient deaths, not just with investors, but with the FDA. We got to make sure that we're doing the right thing and showing the safety profile. Everybody, I think we all will, whether that's a manufacturing issue or just a rapid expansion, a release of cytokines, a release of interferon gamma, release of macrophages, who knows what that is, but that's going to be important for all cell types.
Where NK cells are going to come out is you're not going to see any of the hyperimmune syndrome because we don't have that rapid expansion in the patient and the release of all those cytokines and the ICANS and the cytokine release syndrome that comes with it that then releases the interferon gamma, the macrophages, and all that stuff. That's what we're hoping for NK cells, but the proof will be in the durability of responses and in the durability of the lack of these unfortunate toxicities, which are fine in oncology patients and may not be good for autoimmune patients.
Understood. That's all we have for time. I know we're a bit over, but thanks.
Well, thank you for putting up with.
Thanks. Yeah, thanks for patching him in. I appreciate it.
All right.
Sorry, everyone, for the technical difficulties and thanks for joining.