Good morning, everyone, and thank you for joining us at the H.C. Wainwright Global Investment Conference. My name is Emily Bodner, and I'm an Equity Research Analyst at H.C. Wainwright, Inc. I'm pleased to introduce our next presenters, Nadir Mahmood, President, and Sean Rose, Chief Medical Officer of Nkarta. We'll be doing a fireside chat format. Maybe to start, for those who are newer to the story and given some of the challenges we've seen in the cell therapy space, can you give us an intro to your CARN-K allogeneic cell therapy platform and ongoing programs?
Yeah, so morning, thanks for having us at the conference this year. Nkarta is an autoimmune disease company. We are focused on developing our LEAP program, which is a CD19-directed CARN-K for B-cell malignancy, B-cell autoimmune-mediated disease. This is an area that's really grown significantly over the last few years. We've seen some incredible data coming out of academic centers as well as a number of different companies now targeting CD19 in these autoimmune-mediated conditions. We think this is an incredible opportunity where we've seen not only the decrease in B-cell numbers, but these incredible drug-free remissions that have been happening in patients for whom there's really no other therapies. It's been a transformational opportunity, and I think the movement that we've seen for companies to move into this space is really predicated on a lot of the exciting data that's been coming out of the autologous CAR-T space.
We think that these are a set of indications that are really optimal and kind of tailor-made for CARN-K cells. When you think about NK cells, these are allogeneic and off-the-shelf. That means they're scalable. They're available when patients need them. They don't have the long-term persistence, which is something that we believe is a feature of autoimmune-mediated diseases. There's a safety profile here that we believe has the opportunity to be truly differentiating from the CAR-T space. When you put all those different pieces together, what you really have is a more accessible therapy, one that we want to get in the hands of the rheumatologists, the nephrologists, the clinicians that see patients in these various indications. Our LEAP program, NK-019, as I mentioned, is a CD19-directed CARN-K cell. It's got the chimeric antigen receptor for targeting. It has a membrane-bound form of IL-15 for enhanced activity and persistence.
We are currently investigating this in two INDs. We have NTRUST-1, which is in lupus nephritis and primary membranous nephropathy. We have NTRUST-2, which is a basket trial with systemic sclerosis, myositis, and oncoassociated vasculitis. We have a couple of ISTs as well. These are collaborative investigator-sponsored trials, one with Columbia University in systemic lupus, and then we have one with myasthenia gravis with UC Irvine and Kansas University Medical Center.
Great. There's obviously been a lot of interest for cell therapy in the autoimmune disease space, given the Dr. Schett data, which kind of spurred this interest. Obviously, now we're seeing a bit more data coming out. Maybe taking a bit of a step back, what is the role of CD19 in autoimmune diseases? How do B cells kind of contribute to disease pathology?
CD19 as a target, when one thinks about this, you think about efficacious, clinically validated, and importantly, that's regardless of modality in which it's been tested thus far. We really like this platform for CARN-K cells. It was initially shown by Dr. Schett in a small trial of lupus nephritis patients about three years ago, and now showing durable remission across that population. Dr. Schett and colleagues, as well as others in industry, have now published with this target across a wider swath of indications. We think the potential remains high with this approach.
Yeah, there's obviously a number of differences with CARN-K cell therapies versus CAR-T therapies, but maybe walk us through a bit more in detail on what some of these benefits could be and why it could potentially be a better suited approach.
There are a number of differences, and we really see advantages with the CARN-K cell approach. First, as Nadir mentioned, from a safety perspective, you have sometimes serious and potentially life-threatening events like cytokine release syndrome and neurotoxicity that can happen with autologous approaches when the cells are expanding. You don't have that expansion with NK cells. We see as one of the benefits the absence of these life-threatening events. From a second standpoint, NK cells are short-lived. These cells do their job and exit the body quickly. Importantly, you also have the potential for re-dosing. We've seen this actually in oncology with a small number of patients in our non-Hodgkin's lymphoma cohort with NKX019. We were able to re-dose them successfully for those that had fallen out of remission and regained that remission, and it has been durable thus far. That's another advantage. In addition, it's a practical approach.
Our allogeneic therapies are off the shelf. Importantly, that's putting it in the hands of potentially clinicians more broadly in the community in the future. They're also gentler. When you think about what's necessary for autologous approaches, there's a procedure called leukapheresis, and that's time-consuming and very uncomfortable for patients to undergo. They have to wait to get their own cells engineered, whereas with an off-the-shelf approach, you can deliver the therapy immediately, and the patient doesn't undergo that procedure. Putting it all together, that safety advantage and the practicality, we think, are key differentiators for an NK cell-based approach.
Great. Can you discuss some of the translational work that you've done and the results that you've seen relative to what would be expected with autologous CAR-T therapies?
Yeah, we're really focusing on five pillars from a translational approach. Certainly, the first one being B-cell depletion. We want to see robust depletion. This is, you know, the shift that we've made to flu-si lymphodepletion was because of that angle. Importantly, we're looking at things like cytokines and chemokines. These are cell products put out by B cells as well as other immune cells. We're looking at autoantibody production as another marker. The holy grail, of course, in the translational space for us is immune reset. We're looking at a number of markers of immune reset to demonstrate after therapy that the immune system takes on a more naive phenotype. We'll also be looking at disease-specific biomarkers in all the indications that were outlined by Nadir.
Great. With your NTRUST-1 trial, maybe touch a bit more on the design there and what endpoints are kind of most important here, including biomarkers.
Sure. NTRUST-1 is a lupus nephritis trial. There we're focused on the kidney. In that trial, there are a number of markers that are important that are surrogates that give you access in thinking about real-world outcomes. For example, you have serum creatinine where you're measuring this protein in the blood. You've got protein in the urine. We measure levels of protein, which is a negative indicator for bad outcomes. Importantly, we're also looking at filtration ability of the kidney by a measure called GFR. When you look at those collectively, these associate with long-term outcomes in renal diseases such as lupus nephritis and primary membranous nephropathy. For example, the progression to end-stage renal disease, you can also have mortality as an outcome there, and things like the need for transplantation or for dialysis. These markers are actually leading indicators of those hard outcomes that are clinically important.
Yeah, maybe to touch on lymphodepletion a bit, can you discuss some of the differences between using cyclophosphamide alone versus flu-si, which is kind of the more standard lymphodepletion regimen that we've seen with CAR-T therapy?
Yeah, I mean, I can sort of walk you through how we've approached this. We recently, earlier in the summer, modified our lymphodepletion regimen from a cyclophosphamide only to a fludarabine plus cyclophosphamide. When you look at the space and you look at the data that's been generated to date with these autologous CD19 CAR-T cells, this has all been done in the context of fludarabine and cyclophosphamide. We believe that that regimen is probably part of some of these really transformative responses and drug-free remissions that we're seeing. For us, the thinking was really going back to trying to give our product the best chance of success and really making sure we're maximizing that opportunity for the cells to go in and do what they need to do. Our program is now focused where both trials and the ISTs are in fludarabine and cyclophosphamide.
We still have the ability for some patients to receive cyclophosphamide-only conditioning. Those are cytopenic patients, and we'll continue to be flexible and adaptable as the data emerge. We're really kind of focused on both fludarabine and cyclophosphamide. I don't know if you want to talk to differences between the approaches too.
Yeah, look, I think it's when you think about it as a tailored approach, as Nadir outlined, right? The flu-si is the gold standard in cell therapy. We think that's a really good move, and we look forward in the future to sharing data on that. I think the other is that when a patient comes in lymphopenic already, we want to give them the right regimen that's tailored toward them. The cyclophosphamide alone approach is something that we're also considering in the appropriate setting.
Actually, what's been interesting, I think, that we've seen over the last year or so is rheumatologists getting more and more comfortable with the fludarabine and cyclophosphamide because they're seeing this continually growing body of data for patients suffering from these same diseases. I think they're like, all right, if this is what's giving them the best response, let's make sure we're doing that. I think that's been a change as well that we've noticed.
Great. You've also looked at different dosing regimens. You've looked at three doses over two weeks and three doses over one week. You've now standardized your trials to be three doses over one week. What's the benefit of doing the doses more quickly rather than spacing them out a bit?
Yeah, this was a data-driven decision. I mean, we based that on the PK that emerged out of the data as well as pharmacodynamic responses. The goal, of course, is to extend the PK as long as possible, but also importantly to drive deep B-cell depletion. There's also a practical element to it, right? It's friendlier for the patient. They're coming in, it's three doses over the course of a week, and that's it, right? You're done. That's helpful for both the clinical care team who's delivering the therapy as well as the patient. There's a practical angle to it as well.
Yep, makes sense. You've also announced that you'll be having data for this trial and also NTRUST-2 later this year. How should we think about the bar for success for NTRUST-1, particularly given some of the other autologous CAR-T data we've seen in this indication?
Yeah, so look, it all started with Dr. Schett's data, right, where we were seeing, you know, in the initial paper about three years ago, 100% durable remission in a single center study. Now, of course, that's evolved. As an industry, we now have a number of companies who are running different modalities, right, in these cell therapy trials. We're not seeing 100% remission. We think that's not surprising right now. These trials are multi-centered. They're at centers dispersed also geographically often throughout the world. That introduces a lot of heterogeneity in terms of the populations that are being studied and the approaches that are being taken. That said, this approach really has potential to be transformational. When you look at the body of evidence for this, we are now seeing responses and remission rates that are, you know, well exceeding the standard of care, which is inadequate.
The approach is undoubtedly exciting. We're kind of moving forward with that.
Great. How do you think about durability longer term in the autoimmune space, given we've seen some patients have one, two plus year durability of remission? Do you think that that's potentially something that you might see in your trials?
Yeah, we do believe we have the potential for durable responses here in the autoimmune population. It's an important concept. Again, in the early initial trials that we're seeing now for a year, about two, and even approaching three years now of data with Dr. Schett's data, it's truly remarkable. We anticipate having durability. I do want to highlight that one of the benefits of an NK cell approach is should someone slip into relapse after having previously had a complete remission, you have the potential to dose again. That's different than the autologous CAR-T approaches that are being taken. We think that's a potential advantage. In fact, we had a handful of participants in our non-Hodgkin's lymphoma cohort where we re-dosed them and were able to recapture durable remission even out to two years.
Maybe on that topic, how are you looking at retreatment in your trials currently? How do you kind of figure out when the right time is to retreat a patient?
Yeah, so it's something we're actively evaluating. We have the potential to do that in the context of the trials and look forward to sharing that in the future should we have that situation. I think just one of the things that sort of brings this back to the point I made earlier is that accessibility feature.
I think that's where the retreatment, because with the CAR-T, with all its benefits, the idea is that's a one and done, but it comes with that side effect profile and that toxicity profile. If you can get away from that, like Sean said, with the safety, but then also moving to outpatient like we did in oncology, all that really bundles up to something where you just have greater access and opportunity to go in and retreat over time.
On your investigator-sponsored trial in SLE, how do you kind of think about efficacy in the broader population compared to LN?
SLE is a condition that can affect any organ system in the body. Lupus nephritis implicates the kidney. In SLE, how I would compare that to LN is that, you know, if we're seeing response rates there across different organ systems, it suggests a broader effect of the therapy compared to LN targeting the kidney.
On your NTRUST-2 trial, which is looking at a number of other autoimmune diseases, how are you kind of thinking about potential opportunity for DIS? What is kind of your plan for narrowing down some indications to focus on?
Yeah, right now we are in the dose escalation part of the study. It's really thinking right now about identifying that optimal go-forward dose, finding the indications in that basket trial where we're seeing the most meaningful responses, and then also really looking at where we can get to data in a reasonable period of time. Those factors will ultimately all come together to inform us and give us information about which ones we want to focus on. It could be different, like some of these will have the onset of remission that just takes much longer. The follow-up time needed once you have delivered some deep response could be different. We're going to take all these different factors into consideration. I think one of the things here is these are, this is a pioneering new way of looking at treating these various indications.
I think we have an incredible opportunity through this approach of looking across these various indications to really see how the biology of this drug works in this context of these B-cell-mediated autoimmune diseases and then utilize this initial data set as the catalyst to say this is the indication or set of indications that we're going to move forward and hopefully eventually advance to more pivotal trials down the road.
In terms of the data update later this year, what should we be looking out for in terms of patient numbers, how much data you're planning to present?
Yeah, so this will be our initial kind of first look in the autoimmune space. It's going to come across the IND, so multiple different indications. There's going to be patients from a variety of different indications. There's going to be different follow-up periods of time across those. When you factor in the switch to fludarabine and cyclophosphamide on lymphodepletion, that was more recent. More of the more recently dosed participants would be sort of under that. It's hard to say exactly numbers-wise what that's going to look like, but it's going to be sort of this mix of patients across different indications with different follow-up times. I think really what we're going to be looking at is building out sort of a set of data around safety, B-cell depletion, and then whatever response and potential follow-up that we could have by that point in time.
What might a pivotal trial or pivotal program look like in the autoimmune disease space? Obviously, we have several other companies that are kind of approaching that point currently.
Yeah, I mean, I think we're starting to see some really exciting stuff coming out from some of the other companies that have been able to move forward, whether it's in myositis or sort of a 15-patient pivotal trial. I think in indications like myasthenia gravis, some folks have reported 50 or 60 participants there. I think we're starting to see this a little bit more of a spectrum, but more narrowing in terms of what the expectation is. I think with the potential that cell therapies have here, there's an incredible opportunity to potentially move faster than a lot of us maybe anticipated, sort of taking some of that oncology framework that we'd previously seen and starting to apply it in this setting. Sean, any additional comments?
Yeah, I mean, the only thing I would add is that the transformational potential here is truly striking.
The fact that we're even talking about that now and the concept of durable remission in these trials is unbelievable, right? Two, three years ago, you wouldn't even, that thought wouldn't have even popped in your head. The potential here for cell therapy and the streamlined approach toward development and the partnership that health authorities are taking around this and recognizing that potential is truly striking.
Great. Maybe to close out, if you can comment a bit about your cash position currently and also give us a summary of upcoming catalysts and milestones you're expecting in the next year or so.
Yep, from a cash position, we have runway into 2029. That gives us a lot of flexibility and opportunity to advance the program, look at the different indications from the dose escalation part and hopefully more advanced studies, and really not have to worry about raising cash in the near term. From that perspective, we're very fortunate. We've been guiding to an update in the second half of 2025 as our initial update, so stay tuned on that.
Great. Thank you very much, Nadir and Sean. Thanks everyone for listening in. Enjoy the rest of your conference.
Thank you.
Thank you, Emily.