Welcome, everybody. My name's Dana Grebosh. I'm the I/O analyst here at Lyric Partners. We are in the club. The last time I was in here was approximately 12 years ago. So nice to be back with you.
Not low sticks at the time.
Yeah, pretty much. Something like that. I'm really excited to have a couple from the management team of Nkarta, David and Nadir. Maybe I'll start, just let you just quickly introduce yourselves and your roles, and then we'll get into our chat about your programs.
Nadir Mahmood, I'm president.
I'm David Shook, Chief Medical Officer and head of research and development.
Great. I'm going to jump right in and state the obvious. The equity markets have been pretty challenging for cell therapy generally, whether it's in oncology, autoimmune, whether it's autologous, whether it's allo-. Why do you think we've had these recent challenges, and why should Nkarta specifically—why should we still be excited about that, given the general sentiment about your company?
Yeah, I think the challenge is particularly magnified in the cell therapy space right now. Unfortunately, it seems like we're not seeing much to take us out of that. It's going to take more data over time. I think some of the headwinds that we've faced in the space have been people are looking to recapitulate what George Shett's group has done. I think the expectation of a 100% response rate is probably not a realistic one. That's what we're seeing with some of these larger studies done by some of the other companies in the space.
That, coupled with some of the side effects that we're seeing that are attributed to the autologous CAR-Ts, I think that sours some people in the space and sort of thinking about, OK, how do you actually take this paradigm-shifting approach, but actually get it deployed and utilized by rheumatologists? Not just in cell therapy clinics, cell therapy centers, but in the hands of the rheumatologists where the vast majority of the patients sit. That's where we think Nkarta, as a CAR NK company, has a unique opportunity to really differentiate from the competition. We know from our experience in oncology that this product does not cause any ICANS or life-threatening CRS. We deliver this in an outpatient setting in oncology.
As we think about the opportunity in the rheumatology space or in the broader autoimmune disease space, I think that's really the properties that we can leverage to sort of unlock our ability to move into the sites where eventually we believe the vast majority of these patients actually will be.
Yeah.
I think broadly speaking, there was a lot of enthusiasm about these treatments being cures initially or long-term remissions. I think that the struggle has been the space going from the idea that these are cures to that they're drugs. Once they become drugs, it becomes a more challenging idea. You have to start thinking about, OK, if it's a drug, what does your label look like? What does your target product profile look like? The initial kind of enamorment for cell therapy and autoimmune disease was not for five patients in lupus nephritis. It was, broadly speaking, what it can do to this field of can we cure a bunch of autoimmune diseases.
Now when you see small data sets coming out from whether auto CAR-T has been more or less validating what we already know from the Shett data and the Ralangan data, I think now we know targeting CD19 with cell therapy can result in remissions. What are you going to do with it? How will that, how will it be prescribed? Who will use it? In what indications? In what line? In what setting? Those are the questions that these small data sets, regardless of the outcomes or response times, are not addressing. How do you make these into drugs?
I think what you're both lining on is it's going to take a lot more data and maybe different types of trials. Would you guess at a time frame for when we start to sort of get through this transition and get to these larger data sets where people can see this real drug path forward?
Personally, I don't think that there's a mass of data or a critical mass of data or a length of data that the market says, well, when I see 12 months, I'll be happy. Or when I see 12 patients, I'll be happy. I think generally more is more, and more is better. I think why some of these data sets may not have been rewarded in small settings is how does that get us incrementally closer? I think what will help and what we hope to get to is how do you start to imagine what's your point of view? What's your TPP or POV for your drug? And to say, we know challenges to the space are the interactions between rheumatologists or autoimmune physicians and cell therapy or bone marrow transplant oncology physicians.
That referral between one physician group or one center to another physician group or center has been probably the biggest gridlock in the space. Not necessarily competition, but really the logistic challenges of it just gridlocking the space. Rheumatologists are saying, you know what? I know how to use rituximab or belimumab, and now obinutuzumab. I can integrate that into my clinical practice. I know how to prescribe it. I can control it. I follow these patients longitudinally. When you're talking about a cure, have a conversation with me. Sure, they have to get fludarabine and be in an inpatient and get ICANS and all these other things, but they're cured. That's a different discussion than saying, I've got a drug, and these are the side effects.
What we're looking to do is establish this as having a profile that is conducive to the kinds of drugs that get approved in this space and get adopted in the space. Start to look like a biologic. Start to have outpatient infusions. Be controlled and infused by rheumatologists. To not have things like ICANS hold over you. To not have things like prolonged inpatient observation or delayed toxicities hang over the space. They're used to using these drugs. The rheumatology and autoimmune community, and not just rheumatology, because you see it in myasthenia as well, is the physician groups are very comfortable using safe, accessible drugs that have incremental benefit against standard of care. The space changes, as one of my mentors used to say, by evolution and not revolution.
Got it. Let's talk about your product, so NKX019, a CD19 CAR NK. How do you think it will stack up against the clinical signals we've seen from the CAR-T side, just to set our expectations? I think you really well described the potential to stack up sort of commercially and process-wise, but how do you think it's going to stack up on the efficacy side?
I think there's no reason to believe that targeting CD19 with an NK cell-based therapy would have less potential benefit than targeting CD19 with a T cell-based therapy. That's how we've leaned in. My preamble about how you would use these drugs is not to say that we'd be happy with an incremental improvement in standard of care, only to say that if that exchange rate of getting in, of just adding one drug to cyclophosphamide, for instance, gives you an incremental benefit, that's more acceptable. I think I would expect that our Paul, our CEO, likes to say, better than standard of care, less than Shett. I don't think that's fair. I think everybody wants that. I think right now you saw what will likely become a new standard of just using sort of contemporary data.
You saw the obinutuzumab data come out, and will likely be rapidly incorporated into the standard of care for LN in the same way that belimumab and voclosporin have been sort of introduced. I do not think you, and that was an 11% benefit against standard of care and on 7.5 milligrams of steroids, like nothing too terribly. There is growing sentiment that that will become the sort of new drug. I think if you have a drug that gives you a 60% response rate and the same kind of thing, you'd easily become the best drug on the market. You go into 70%, 80%, then you're talking about real disruptive kind of responses. We'd love to see CAR-T-based or the kind of response rates that you're seeing and feel like we've got the asset to do it.
We won't be held hostage to that kind of bar either. I think the largest data set we have in the space actually is in the CAR NK space, in terms of one of the largest number of patients treated, I think 21 or 22 patients in the Fate Therapeutics trial of a CD19 CAR NK. You see 50% DORIS remission there, so pretty stringent measure. I think that, again, demonstrates that you can get these deep responses in the right patient population. That, we believe, is maybe not as powerful an engineered NK cell, given it doesn't have armoring the way that ours does. Also, that trial used fludarabine in the lymphodepleting conditioning, and we have cyclophosphamide only.
Opportunities for us to demonstrate, hopefully, something that can get us to where the Shett data are closer to that, but also with the accessibility features that make NK cells so attractive.
I wanted to ask about Fate next. You beat me to it. Let me ask a little bit more about that. You said you have armoring and they do not. Can you specifically tell us what your armoring is and what gives you confidence, either preclinically or from your oncology trials, that that is going to give you a boost? On the flu side, I think the flip could be, they had flu, so maybe that gave them more homeostatic IL-15 and gave them room longer. You might have, that is better on the accessibility side to remove flu. Do you have a clinical risk vis-à-vis the Fate data?
Just talking about IL-15, it's your invention.
Yes, I'll speak to that. Our armoring is membrane-bound IL-15. It is IL-15 on the surface without a receptor fusion, and it is not secretory. It is all maintained on the surface. Actually, the majority of it is internalized. It is all autocrine signaling. There is no additional IL-15 into the serum or into culture, even at large doses. Essentially endogenous autocrine signaling for IL-15. To answer the other half of the question of why we feel like that really enables fludarabine-free conditioning is because fludarabine's predominant role, at least on the autologous side, is to eliminate that sync of lymphocytes, sort of eliminate cytokine sync, allow predominantly IL-15 to be bioavailable. On the T cell side, there is a very clear correlation between IL-15 bioavailability and both PK or expansion of CAR-T cells and response. In our oncology data, we have seen no such correlation.
We measure IL-15, IL-6, IL-2, et cetera. For one, we do not see any elevations of IL-6 at all. Owing to the sort of lack of any CRS or high-grade CRS or ICANS, we do not see any really bump in IL-15. When we do, it is not correlated to response, whereas that kind of dependency on endogenous cytokines that you mentioned is there with fludarabine. If you come loaded with what fludarabine provides, we feel like it is less relevant. You can see that in one of their doses, but also in their PK, which is pretty transient in Fate Therapeutics.
Got it. You don't have that risk of not getting the cytokines from not having flu because you have it on board. In fact, that's probably giving you an even better signal and better therapeutic response.
Right. You certainly get more direct IL-15 signaling when it comes endogenous. Now, do you see is there a risk of fludarabine itself causing B cell depletion? I think that's probably the one that gets called out more because the vast majority of the CAR-T cells, by the time that they're infused, B cell count's already zero, right, because flu C wipes out B cells pretty dramatically. We don't see the risk of the endogenous IL-15 signaling being an issue.
Got it. Let's talk about peripheral B cell depletion. It was pretty robust. You mentioned the obinutuzumab data. We saw Roche's phase III regency trial, and they had robust B cell depletion. As you also mentioned, the relative clinical benefit over placebo, I'd say, was modest. I mean, does that tell us anything about B cell depletion in lupus? Is it a warning signal for the likelihood that the pharmacodynamic depletion that we know happens is going to translate to durable benefit with your NK cell program?
We've seen B cell depletion for a while. I mean, rituximab's pretty good at depleting B cells. Even in the historic LN data, you see a lot of B cell depletion with a lot of different agents. It has not always correlated to response. I guess I agree with you that this was not sort of an incremental benefit in standard of care. I think it was, what, 33-46 or something like that, 41-33, not all that impressive. Those patients were still on steroids. In terms of that question of does that pose a risk, I don't think it's a warning sign so much. It's just a reminder. We don't have that signature quite sorted. You and I have talked before about what is going to be that biomarker signature, what's going to be the predictor of response.
Is it probably not B cell depletion strictly. Is it immune reset? Doesn't look like it's autoantibodies because there's been patients with long-term responses with persistent autoantibodies. I think there's more to it than just wiping out every single last B cell because there are plenty of drugs that don't wipe out every last B cell that have clinical effectiveness. I think it's a reminder. I don't think it's a warning. I think it's a warning if you say if you're leaning strictly into B cell depletion. I think there's more to it. These are about modulating immune responses. We highlighted before, we're not curing patients. These patients are still the same patients before that developed lupus before, may develop lupus flares again. We need to have drugs that can modulate that immune response, not just eliminate all the B cells there.
Got it. Maybe another competitive view here. I think a lot of people believe the T cell engagers are going to be this nice bridge, so more potent than using ADCC or ADCP with something like obinutuzumab, but not as logistically challenging as autocar T. Sort of what's your view on T cell engagers as competitive for your CAR NK?
I think data is still pretty early for T cell engagers. I mean, I think the key attributes there are that they sort of pitch are no lymphodepletion, right, and the accessibility sort of of an antibody-type dosing regimen. While those are there, I think the big questions and outstanding questions are, is the level of B cell depletion going to be sufficient? Tissue penetration going to be sufficient? I think you still have to deal with some of the CRS and other tox profiles that still emerge. I mean, we still have black box warnings. Can we completely get away from some of the questions that they're supposedly addressing on the T cell side to some extent, but probably not all the way?
I think that's where a CAR NK can sort of find that sweet spot where potential to have that deep immune reset that drives the clinical response, but with the accessibility and convenience that you can get with an antibody-type therapeutic.
I do think they're still relatively limited to specialized centers. We've had T cell engagers on the cancer side for a while. Belimumab has been around for a while. Even in the ALL space, it's not disrupting the CAR-T pipeline. Those are still in referral centers. I think where we need to be is in the referring centers. TCEs are, as you know, I still do this for a living. They have provided a good tool. They are not, they're not the, as I said before, the wooden stake through the heart of cell therapy. They are going to be a tool that we use. What is going to really, especially on the autoimmune side, they are not going to be available for your sort of everyday rheumatologist.
They do, they're sort of one click above and of sort of the ADC kind of approach and one click below. That kind of leaves them in no man's land of where will those drugs be prescribed? Who will be prescribing them? Are they going to referral centers? Are they able to break into referring centers? I don't see them getting there. Plus, as Nadir mentioned, the B cell suppression kinetics are not so great. Again, we don't know whether or not what B cell kinetics are really are mattering. We will see what the data are and have them play out. I think there's a lot of reasons to believe that they won't be quite as disruptive as they've been made out to be.
Yeah. Let's talk about lymphodepletion. You already mentioned that you use a Cy only approach, taking out flu, which has its own risk. You're one of the first companies to do that. Many other companies have followed using various sparing strategies, both allo and auto. I wonder, why are you, is this just you're the head and it's going to work for a lot of different products? Why is this relatively more likely to work for your product than some of the others?
To be trendsetters.
Yes.
It would not be the first time we have been inspirational for other cell therapy companies. No, I think I do think that, one, we did it intentionally, right? This was not something that we backed into. We, speaking with rheumatologists, and we were investigating getting the autoimmune space a year before we had our first IND, understanding what kind of drugs and treatments people were looking for. The answer was always, we do not need cures, we need drugs. The drugs we have do not work. Can you get us something that makes progress? What are the things that really hold up? Nobody seemed excited about giving fludarabine. It is not a drug that is being used. It introduces problems on the regulatory side with contribution of component. You are introducing a new physician group and a toxicity profile that you are not understanding.
Yes, we feel we knew from a TPP standpoint that that would be the way to go, that fludarabine would become an issue. And biologically, as we mentioned, we knew that the predominant reason fludarabine was there, we had engineered a solution for it. Still need some LD to get our immune suppression since it's an Allogeneic product. But fludarabine seemed to be the piece that we could remove in a way that was consistent with what the kind of product we wanted to deliver. As there have become more challenges in the space in terms of enrollment or adoption of these therapies, I think people are looking at things like lymphodepletion and saying, how do we make this more user-friendly? Not just less toxic, but real more manageable and more accessible. Fludarabine gives you both toxicity and trouble with accessibility.
I think what you probably see now is more companies shifting away from that and looking at these different regimens or lymphodepletion-free. I think you see that now because in the early days, we just wanted to recapitulate the SHET data as much as we could, right? I think that's where the auto CAR-T companies started was how do we get to those effects? Now as we've gone past that and we're starting to learn more about the interaction and how rheumatologists view the world and their practice and how that's very different than how oncologists view it, I think people are starting to realize that you probably need to change things up a little bit to make it more accessible for this population because it is vastly different than going into a cancer patient.
Let's talk about rooms in your trials. I think all the trials have been difficult to enroll here. I wonder if you can give us an update on where you are in getting patients and how you see that improving over time and why.
Just as a quick refresher, we have two INDs right now, NtrustOne, which is in lupus nephritis, NtrustOne, which is a BASCA trial in systemic sclerosis, onco-associated vasculitis, and myositis. We have two ISTs, one in systemic lupus at Columbia and another in myasthenia gravis at UC Irvine. We have six different indications that we're looking at right now. We have announced that we had dosed the first patient in the lupus nephritis trial, and we had open enrollment in the BASCA study. We will have more updates later in 2025. Do you want to talk about sort of engagement?
Yeah. I mean, it's a challenging space. I don't think that for everybody. We've faced headwinds that I think the initial thought was this was too much competition and that there were too many things to choose from and that it was being spread around evenly. I think what you're seeing is everybody's saying it's competitive. It's not everybody's getting a little bit of the patients. It's everybody's getting very low number, like less patients than they expected. It's challenging. We do feel like we have the right product TPP to overcome those challenges. Where we see that going is we really believe in the same way that an autologous CAR-T has talked about it for years now in oncology, is you have got to get into the referring space and not the referral space.
There isn't mom-and-pop shops or something, but really non-academic medical centers where the majority of these patients are treated. The referral center that have the KOLs that we all talk to, that RPIs, et cetera, are not the big enrollers. It is centers where we can have these drugs become more accessible. We are on a very intentional journey to go to centers that do not have experience or as much experience in some cases in using cell therapies to show that you can use this as easily as you can use a biologic. Where we feel like a really disruptive update would be rheumatologists are using this and cell therapists are not involved at all. Now that is our use case. If you can demonstrate that, all of a sudden how much data you need to see to be impactful changes, right?
If I could say, hey, I've given you a handful of patients, they look like everybody else, but instead of being admitted and going to a hospital by seeing an oncologist, a rheumatologist saw them, decided to treat them, gave the cyclophosphamide, gave the cells themselves, and it was all done without another physician in sight, that's where we know we need to get to. We think that the update that the field is waiting on.
Can you get to that in your phase one?
I believe so, yes.
When? How close are you to signing up a site like that and dosing a patient in a site like that?
We're going to give a clinical update in 2025 on both NKX019 and NKX101. We hope to give an update on where we are in the study and strategy as well.
Is the update going to be data or it's going to be more like which sites we've started and when we're going to track towards more significant clinical outcome data?
We've talked about presenting data in 2025. It'll be a heterogeneous mix across different patients, different indications if we put the two together. You will have a spectrum of durability from those that may have been enrolled early to those that were enrolled closer to the date of the announcement. We do want to have some initial data that can give us some direction and idea of sort of where we want to go with the program.
Yeah. One minute and I have two questions I really want to ask.
Okay.
What's the first one? What's the regulatory path? Let's just say in lupus nephritis, if you're hitting your TPP.
Single arm study with using cyclophosphamide monotherapy is a path to approval for voclosporin, path to approval for belimumab, cyclophosphamide plus one drug. Where cyclophosphamide plus one drug, they showed a 5%-6% improvement in standard of care against cyclophosphamide and were easily approved and widely adopted. In lupus nephritis, we think there's a clear path to a single arm study.
Got it.
Is that fast enough?
That's fast enough. Okay.
I could give you a better one, but that's.
You're an allo cell therapy, which is why you have to keep using SI. You were in oncology looking at other allo evasion strategies to maybe get SI.
Yes.
Okay. Can you just give us an update on where you're at that, when that will be in the clinic?
I would say that we're still evaluating it. It'd obviously be a new drug because it's not in our current drug. It would be a new IND. It would be sort of resetting. I think we're very interested in it. That is the holy grail, if you will, of being able to deliver cell therapy without any LD and have it be impactful. I agree with you and we've talked about this before. Immune evasion will be a part of that. It has become more tangible. Before it was a bit sort of pie in the sky. I think the technology is becoming more effective. I think we're getting a better sense on what kind of immune evasion strategies could work. Still very much on top of mind for us.
Right now we're focusing on execution and 019 as it is.
Okay. We're in the red, but I have to follow up. Why thank God you're an allo? You said thank God you're an allo and not an auto.
I said thank goodness.
Goodness. I'm sorry. I'm sorry.
Not to offend anybody. Because autologous therapies are just not meant for this space. I mean, they require too much handing over of patients from one site or investigator to the other. This is like one side says, well, we're the experts in the process, in the therapy, so we'll be in charge. One side says, well, we're the experts in the patients and we've been managing these patients for 10 years, we'll be in charge. They sit on either side of a divide and no patients get helped. Yes, autologous therapies are challenging in oncology. We use them. We use life-threatening pain in the neck treatments for life-threatening diseases. For these diseases, it's about safety. It's about accessibility. It's about getting to as many patients as possible. Auto is just never going to get there for autoimmune disease.
It is not just the auto part, but the NKs. It is the safety aspect of it too that we believe is not just the allo part of it, but the safety aspect that is a big differentiator.
Awesome.
It's got to be off the shelf.
Thank you very much.
Thank you.
Thank you.
Always a pleasure.
Always.