Right here.
No, you're pressure there.
I don't know if I'm going to put a space between us or not.
You're the person to ask. I should direct everything towards you.
We've already been manipulating.
Oh, OK.
Ask questions.
All right. We'll see how it goes.
All right. Good afternoon, everyone. Thanks for joining us at TD Cowen's 45th Annual Health Care Conference. I'm Jeannie Ahn. I'm on the biotech team. I'm delighted to be hosting this fireside chat with Nkarta. Here with me today are Paul Hastings, CEO, and Dave Shook, CMO and Head of R&D. Paul and Dave, thanks so much for joining us.
Thanks for the chance to be here.
Great. I want to start off really broadly. Just now that you've pivoted towards autoimmune disease, what are the benefits specifically of using this CAR-NK approach for tackling autoimmunity?
Yeah. We always say that autoimmune disease is handmade for NK- cells. These cells are off the shelf. They're allogeneic. They have a safety profile that fits perfectly in the autoimmune space. There's no CRS. There's no ICANS. Compatibility with the rheumatologist in the fact that we're using cyclophosphamide alone for lymphodepletion. That's a drug they use every day. We have the benefit of that, along with our membrane-bound IL-15 that's incorporated into the product, so we don't need the fludarabine. We have a product that's handmade for the disease, but it's also handmade for the rheumatologist. We think that should we have data that's similar to other cell therapies, but with an allogeneic, off-the-shelf, convenient NK cell, this should be a major advantage.
It could be used instead of cell therapy centers in a rheumatologist center that has an infusion chair and someone that could handle the thawing and handling of cells. Very straightforward. It can be redosed. I think I just about got everything, right?
Yeah, I think that's it.
Yeah. Yeah. I mean, clearly, NK cells have a lot of advantages over our kind of CAR-T approaches for autoimmunity. Obviously, NK cells come or CAR-NK comes with its own drawbacks. There's a kind of a worry about how persistent they're going to be. How does NKX019 actually kind of address those specific drawbacks of NK cells traditionally?
You probably aren't going to need the kind of persistence in autoimmune disease that you need in cancer. You need a rapid elimination of B cells, bad B cells. You need good B cells to come back. You need, and you know, we have Cmax at day zero. You get a nice pulse of drug or cells that are engineered along with the lymphodepletion they gave him, that's, again, modified for the patient and for the rheumatologist. That's how you overcome that. That's how you compete with other modalities that aren't going to work as well, but will be easier to administer, like bispecifics, PrEPs, or TCEs, et cetera, et cetera.
Right. I said that or you mentioned earlier that you will have this very nice kind of reduced lymphodepletion that only has a cy instead of flu, which obviously is going to be easier. It has a better safety profile. Can you explain in greater detail why this is possible with NK cells?
He'll do that. Sure. There are really two reasons why we feel like a fludarabine-free conditioning really is good for specifically a cytokine-enhanced, armored NK cell. The first is that cytokine piece. We know that fludarabine is required for T cell-based products, even autologous products, which inherently is not something that you would think about because you think of lymphodepletion as immunosuppressive. These are autologous products where they're made from the same patient that will receive them. There shouldn't be an immune barrier to overcome. Yet we know they don't work without lymphodepletion, and especially the inclusion of fludarabine. That's been well documented. What was discovered over the last 10 years or so is that fludarabine really is most important for eliminating host lymphocytes, which are consuming cytokines.
When you eliminate that cytokine sink, all of a sudden, a bunch of cytokines are freed. The T cells can feed on those cytokines and proliferate. This elimination of the cytokine sink, the generation of cytokines, especially IL-15, enables those cells to proliferate. Now, NKX019 is armored with a membrane-bound form of IL-15. It is not dependent on host cytokine support, so either exogenous or endogenous mediated by fludarabine. Fludarabine, its main goal of kicking up cytokines, we do not need those because the cytokines come pre-armored. Secondly, fludarabine has a prolonged immunosuppressive effect. Its impact tends to come on, it peaks about day 13 in terms of its nadir and function. By that time, most of the NK cells are gone. NK cells do not proliferate in vivo once they are infused. They will be at their highest dose at day zero.
It is sort of a more traditional sort of decay kinetics rather than CAR-T, which are infused at a subtherapeutic dose and then expand around day 10. CAR-T would require the peak immunosuppression to be closer to day 10 when the cells are expanding, whereas we want peak suppression to be closer to day zero when the cells are infused. Cyclophosphamide's impact is more immediate. The combination of lack of need for cytokine support and lack of need for prolonged immune suppression.
Great. That makes a lot of sense. Also on lymphodepletion, some investors and physicians might be wondering whether lymphodepletion itself accounts for some of the activity that you see with kind of CAR-NK or, sorry, CAR-T in autoimmunity. What are your thoughts on this?
Yeah, I think it's a problem the field will have to come to grips with because at some point, these drugs will have to be approved. They will need to go through some evaluation of contribution of component. I think, much like there was in CAR-T in oncology, there's some question of how much the Flu/ Cy versus the CAR-T cells are actually contributing. When you look at the CAR-T data, either the original Erlangen data set or the follow-ons that have come, that's not just the CAR-T's effect, but it's CAR-T plus fludarabine plus cyclophosphamide. To be able to get those and prove those drugs are active and how much they're active, it's going to make things like regulatory path more challenging because you're now introducing a more contribution of component. For us, we and I think, broadly speaking, more chemotherapy is more.
You give more cells, they're going to kill more cells. Or give more chemo, you're going to kill more cells. Yes, it will be more active. Yes, you'll kill some cells. In fact, you look at the CAR-T data or the Flu/ Cy data, the majority of B cells have been eliminated by the time the cells even go in because if you look, there's a predose level, and then it kind of drops at conditioning. By day zero, most of the B cells are already gone. There's the elimination there.
We think that that cyclophosphamide-based approach, one, eliminates the toxicity associated with fludarabine, but also gives us a much cleaner path towards approval because the last couple of drugs that were approved by in lupus nephritis, for instance, belimumab and voclosporin before it were approved on studies that compared standard of care therapy plus the addition of one drug, their drug in question. Cyclophosphamide was an option, so was MMF. You look at cyclophosphamide alone versus cyclophosphamide, say, plus voclosporin, and you go from sort of a 35% response rate to a 38%-39% response rate. It's cyclophosphamide plus one drug or cyclophosphamide plus one drug. We think that's a very approvable path, potentially as a single arm using either real-world evidence, historical controls, and be able to get a nice, clean, fast approval.
I think because of that, we still have a much straighter path. Multi-benefits, not just for the patients, but for the drug as well. In multiple indications.
Right, right. We'll get to your multiple trials across indications soon. I guess kind of the big draw initially for the kind of cell therapy approach, whether CAR-T or NK cells for autoimmunity, is this kind of lasting response without the need for prolonged B cell aplasia. What kind of data have you seen so far, like early data, that suggests that with kind of NKX019, you might be able to see this kind of immune reset occurring?
With NKX019 specifically, we had the advantage of it not being a first-in-human drug, right? We treated 40+ patients with this drug, various B cell malignancies. We were able to not only draw on our safety database, but also our clinical data and translational data. What we did, we pulled all of the data from our previously treated patients and looked at its ability to deplete B cells. In fact, we showed that back a year and a half ago now to show that, yes, indeed, targeting CD19 is very effective at depleting both malignant and non-malignant B cells. We also had samples from those patients in recovery and able to look at the immune reconstitution and showed very similar data as what was being shown at the time by Erlangen and now mostly others showing that same immune reset.
We've done that in our oncology population. Now, again, there's the same caveats of this is oncology. It's not the same. We have been able to see B cell depletion with immune reset using our drug. Now we aim to repeat those same data with patients with autoimmune disease.
If you look at the data that's available now in autoimmune disease, the largest data set is with CAR-NK from China, from RuiYi, right? There is some, it's still data from another country. We still got to see more about that data. It is as robust as the data that they have with CAR-T. It looks very comparable, very favorable.
We're going to get to that at the end. Just to start off with, kind of obviously, we have a lot more data or not a lot more data. We've had data throughout the years trickle out from CAR-T across indications, SSc, SLE, and myositis. Pretty promising efficacy. The problem is that we've seen some relapses. There is a question on durability. How would you summarize the data that we've seen overall from CAR-Ts and then kind of get into where you see the area for differentiation with CAR-NK?
Yeah. The biggest error is trickling out data one patient at a time, in my opinion. I think it's hard to assess drugs based on that. We haven't done it for years. All of a sudden, we're doing it quite frequently now. I think that's one flaw in the data. I think what it's telling you is that no one's going to see shit-like data. It's not going to be 100%. It's going to be north of what Dave quoted in terms of what's standard of care today, north of 20%, 30%, and south of 100%. Where it lands is anyone's guess. It'd be nice to land in the higher numbers. That would be a really spectacular result for cell therapy. I said it before, and I'll say it again.
is no reason to believe that CAR-NK should not work as well as CAR-T in autoimmune disease, but with a much more favorable safety profile. If that is the case, then it is very competitive in that space. Those data are early, preliminary, but encouraging.
Right. Just in general, how much durability do you think you would need to justify kind of using a cell therapy overall and in particular for using CAR-NK, as you say, because it comes with this benefit on safety, this benefit on kind of administration, this lack of.
Sure.
Infrastructure that you need for this? Do you think the bar is lower on how much durability you need to show?
Look, the best durability would be 100% durability for years and years and years, right? That's what we'd like, 100% efficacy with durability one and done, right? The beauty of CAR-NK, again, is that you can redose. If there's a need, you can use those cells again. They're off the shelf. They're easy to administer. Where's the bar? The bar is anywhere from 20%-100%, right? It's hard. I mean.
Not 20%, but.
Right, higher than 20%- 100%, right? 30%, let's say 30%, right? You have to beat it. You have to beat the lower end of the bar. You have to be somewhere north of it. It depends on if you're in the same vicinity as an easier-to-give therapy that could be more convenient. I mean, I might argue that CAR-NK cells could be just as convenient as any antibody in terms of being off the shelf, manufactured, easy to administer, maybe the thawing, but maybe less tox profile. You have to be able to have a durable enough response that is beyond where people are today. If you need to retreat, you can.
Yeah. I think across the portfolio, now, as we mentioned, we have six indications across four different studies. The bar for each of those is going to be different, right? Each of those indications we've selected pretty intentionally because they evaluate different aspects of drug paradigms. I think what I'll add to it is whether it's the 30%-40% in lupus nephritis, or it's the 0% or whatever failure progression scleroderma, I think whatever has been seen historically has been judged or the bar has been based on continuous administration. Take the model of voclosporin, which is added on to standard of care and now considered upfront therapy in lupus nephritis. That's a drug you have to take every day. It was evaluated on a one-year and two-year endpoint.
If you say, OK, the bar is one year of renal response, I think we'll remain flexible. We'll continue to push the agency about how to compare a drug that you give, say, once or every nine months or every six months and say, what's the exchange rate on saying, could I get six months of drug-free remission if I gave this drug every nine months, if I gave this every 6, 12, 18 months, whatever it is? That should not be judged in the same way as, say, an obinutuzumab, a Benlysta, a voclosporin that you have to continuously dose for the rest of these patients' lives. We think that it's meaningful and important to look at historical bars. That's what people will, I think we've kind of, the field has come off as thinking these are cures and now thinking that they're treatments.
What we're interested in and will be continuing to push is to know that these drugs should be and will be evaluated differently because they offer prolonged drug-free remissions. They do not just add to the pile of medicines that patients are taking.
Right. Considering this kind of dosing strategy, at what point do you think it makes sense to redose? What is enough? You get this long period, but you do have to redose. Where's the balance there for you guys?
Yeah, I think this is where I'll sort of reference historical bars where many of these endpoints, whether it be lupus nephritis, scleroderma, vasculitis, something where the period of time of remission is probably in the six months to year range. I think everybody's looking at a year and saying, we kind of want to see that as durability. I think I'd love to hit it. As we said, I think we're looking at making it sort of an indefinite, long-term drug-free remission. At the same time, I don't think it's untenable to think every six, nine months of being able to say, hey, you come in twice a year. Other than that, you're never on any other drug. That's possible. I think just have to see how the data play out, see what this space evolves.
We have heard over and over again from rheumatologists, if you can get people off of medicines, off of steroids, that's a huge win, not just to continue adding to these piles of medicines that patients are already taking.
I think you start with relapse, too, right? I think you start with the most severe, which is patients' relapse. Then you work your way back and say, could you prevent a relapse from happening down the road, right? A little bit of relapse and a retreatment, we saw that in NHL when we saw progression. We retreated, and we were able to convert those patients back into CRs. One might start there in the clinical trials and then branch out into, OK, how do you prevent that relapse from happening? Maybe it's when you see dsDNA. Maybe it's something else, right? You could retreat then. That's probably the next stage of development.
Yeah.
Yeah, we got some work to do on biomarker development. I think the space is anxious to find that sort of MRD equivalent, which is to say, how do you find impending relapse? How do you find high-risk disease and treat patients that have a lower disease burden and salvage function before they have toxicity? I think the retreatment question will be in combination with the development of biomarkers.
Got it. To move on, there's some debate as to whether CAR-T or B cell depletion with CAR-Ts or kind of antibody or bispecific antibodies will be better in terms of deep tissue penetration. Where do you think NK cells fall in that kind of spectrum?
NK cells live in this evolutionary space between sort of the innate and adaptive immune system and have a wide purview and can penetrate any tissue in the body, including privileged sites like the CNS and reproductive organs, and do so even more so in times of inflammation. NK cell infiltrates have been seen in the brains of patients with multiple sclerosis. They're involved in, like I said, they've been implicated in fertility, et cetera. NK cells go everywhere. Tissue penetration is not a concern. We have, in the oncology setting, shown relapses from patients with widespread extranodal disease, disease in the kidneys, in the liver, in the bones, bone marrow. We know NK cells and we know NKX019 can get to tissue. Tissue penetration and trafficking we're not concerned about. In terms of depth, as I said, you get in the tissue.
You should be able to drive those remissions. We've seen that in the oncology setting of widespread disease on PET scan and then eliminated. I think there is a question, outstanding question on tissue penetration for biologics. I think the rituximab and, to a lesser extent, obinutuzumab has had less tissue-level B cell depletion than expected. That's been a story that's come up as patients get these drugs, have really deep peripheral blood depletion, but still have active disease. When you do tissue biopsies, you see tissue-level infiltration from B cells. There is some reason to believe that and these antibodies get there because they're smaller than, it's not a size thing. They're smaller than cells, obviously. There's something about them penetrating and being active in tissues because you often need another cell infiltrate in there. I think the jury's still out on antibodies.
Bispecific T cell engagers or NK cell engagers, et cetera, need to get there. The cells need to be there because they do not work without the cell infiltrate, too. What we have seen, the translational data on the bispecifics and engager molecules have been a much different kinetic of response. The B cell depletion tends to be sort of smeared out over time, over months of dosing. It seems like as soon as you stop, it jumps right back up. I think depth and kinetics of B cell depletion, I think, are still outstanding. I think there is evolving data on the cell therapy side. The other modalities, wait to see.
Got it. You guys opened your first study, the Ntrust-1 study, in the first half of last year with initial data expected sometime this year. You'll be using a three-dose cycle at days 0, 7, and 14 after lymphodepletion for kind of lupus nephritis. Endpoints are going to be safety, renal function, antibody serology. From this study, what are you hoping to see? At what time points do you think the efficacy is going to be meaningful from a clinical and from a study viewpoint?
Yeah. Firstly, this was our first IND that we opened in autoimmune disease. At the time, our oncology program was dosing on 0, 7, and 14, so three doses in two weeks. The program subsequently moved to three doses in one week, a 0, 3, and 7 dosing schedule that we adopted for Ntrust-1 and our ISTs. We intend, in short order, to harmonize the platform. Although Ntrust-1 is 0, 7, and 14, we expect that one to be 0, 3, and 7 very soon. That is more semantics. Yes, all the platform is essentially one dose of cyclophosphamide, three doses of cells within a week. For Ntrust-1, similarly, the data we expect them to be kind of iterative.
Early in this data update, we're going to look at impact on biomarkers, things like B cell depletion, immune reconstitution, autoantibody production, serum renal function, serum markers of renal function, proteinuria. Then we'll look at more prolonged things, looking at durable drug-free remissions, impact on immune suppression, impact on steroid dose, and such. We'll be looking at those at a lot of different endpoints because, as I mentioned, we feel like the way these drugs will be evaluated will be and should be different than drugs that are administered continuously. We think early, we'll look at some of that biomarker stuff and to see how well it translates to efficacy endpoints.
I don't think we need to be necessarily tied to historical endpoint evaluation because it just doesn't necessarily apply to say, hey, you've got to wait a year to see whether or not this drug is meaningful. I think if a patient gets a drug like this, isn't on any drugs for several months, and has no risk of ICANS, has no risk of high-grade CRS, is dosed as an outpatient with no involvement by a cell therapist, primary prescriber in an infusion room by a rheumatologist, things like belimumab prove those drugs will be taken up despite a relatively low response rate. We think that we've got that sweet spot of very accessible and safe. What the rheumatology community has shown over and over again is that they treat patients over years to decades.
They are hesitant to bring patients onto clinical trials because of that longitudinal relationship. We think that the way to be disruptive in this space is to put these drugs in the hands of the primary prescribers and the rheumatologists and eliminate the need for large medical centers. That is our intentional journey. We hope to get there soon.
Right. You mentioned, obviously, that you've changed to a more compressed dosing schedule in Ntrust-1 , even though you carried your kind of original schedule over from cancer. What are kind of the specific advantages for having this kind of shorter, more intense schedule?
Yeah, as I mentioned early in the discussion, the kinetics of CAR-NK is dependent solely on immune recovery of the patient. The closer you can get, the more proximal you can get to lymphodepletion, the less immune pressure those cells will face. What we noticed early on was the dose we would give at day 0 would get very good exposure. As the cells recovered, day 7 and day 14 were incrementally less exposure. In the oncology program, as we move them closer to LD, we got a much more intense exposure of drug. We know since these cells won't expand in vivo, which is a good thing, it just meant that we compress them closer to the lymphodepletion to give them more of an opportunity to have their impact before being rejected.
We did that, as you mentioned, on the oncology side, had good PK without any change in safety. We adapted that to our autoimmune program.
Great. For your Ntrust-1 study, which also opened last year, you're evaluating a couple more indications: systemic sclerosis, idiopathic inflammatory myopathy, and ANCA-associated vasculitis. For kind of these indications, what are the main efficacy endpoints? Do you think that any of these might be more amenable or offer a lower kind of hurdle to clear?
Yeah. As I mentioned, each of the indications we have, all six indications, they have their own little twist that we put on them. Something like systemic sclerosis or scleroderma, there's really no approved drugs. This is an inexorable march towards fatality from the disease. Most of the drugs are like, and that's generally either by organ involvement, cardiac involvement, renal involvement, or pulmonary involvement through interstitial lung disease. The only thing these drugs are looking to do is halt progression. There's no improvement in anything that's approved. We think, and that's why in that study, patients have only had to see one agent. Demonstrated progression that they can come on the study. We think the bar there is lower because there's not a line of therapy to jump in front of, right? These are patients with no option.
We have a lot of enthusiasm for that one from our sites because there's, unlike, say, nephritis or lupus, where there's lots of drugs, none of which really work, but they kind of do a little bit. This is a space where you just kind of throw everything and hope something, and you just kind of slow it down as much as you can. Scleroderma will be looking at both impact on the skin, obviously, which is the most obvious manifestation, but trying to prevent or hopefully recover some pulmonary function and interstitial lung disease or interstitial kidney disease would be a huge impact to the space. Vasculitis is a disease that's covered reasonably well with CD20-based antibody therapy. Patients are on rituximab for the rest of their life. That can sometimes mean decades.
As one of our KOLs says, you're not curing, just kicking the can down the road. While it's very well treated, we think this is an opportunity to evaluate an intermittent, maybe even once therapy against a lifetime or months to years of an alternative therapy. We'll be looking at the need for, obviously, the need for additional immune suppression, et cetera. As I mentioned, we're going to be pretty flexible in terms of endpoints. We think that the impact on reducing immune suppression and the failure of progression in scleroderma, recovery of muscle function, and myositis, we think there's a lot of good that can be done here. The autoimmune disease space is really want for safe, accessible therapies. Cell therapy has brought in a whole new promise, but it's brought in a whole new potential for toxicity as well.
That is what we're trying to avoid.
Great. As you guys mentioned earlier, obviously, we've had some data about CAR-NK from RuiYi Therapeutics at ACR last year. They presented data from 22 lupus patients with CAR-NK at five dose levels. They showed 50% DORIS remission and 60% lupus low disease activity state. What are your thoughts about this data? How kind of do you think you guys will shape up eventually?
I think if those data hold, those are really good data, right? If they get better, that would be even better. If our engineered CAR-NK beats their data, that's wonderful, too. That is a very good sign. We are encouraged by them. Early, preliminary, needs some more follow-up, but could get better.
Yeah. I mean, in that model we discussed, it would be the best drug on the market. Putting half of patients in remission for 6, 12 months at a time with a drug that, as they showed with us, like us, have no high-grade CRS, no ICANS at all. I think it was an opportunity to look and say, hey, all of the challenges and toxicities that come with T cell therapy may not be necessary. You can still put half of patients, two-thirds of patients have used LLDAS in remission. These drug patients are on very little, if any, immune suppression. It was, as Paul mentioned, a big data set.
It's a big deal.
Very encouraging. I think probably answered some questions on whether or not NK cells are capable of driving B cell-mediated autoimmune disease remissions.
Would you consider testing four to five dosing cycles the way that RuiYi is?
We don't think it's necessary. One of the things, we mentioned IL-15 and the importance of cytokine engineering. The RuiYi data were based on CD19 targeting, but non-engineered, so they didn't have cytokine engineering. Their PK is going to be much shorter. You look at their PK, more or less, as soon as they give them, they disappear. One, dependent on fludarabine for conditioning, and two, dependent on much higher repeated doses. We don't think that's necessary.
The other answer is it's still early in clinical trials. If we needed to, we could.
Got it. We did notice that in the RuiYi trial, all 22 patients got steroids. What was the reason for this?
Sometimes when patients on immune suppression are on steroids for a really long time, it's very challenging to pull them off quickly or at all. Patients develop some adrenal insufficiency and require that. And DORIS remission, which essentially says you're not on anything and you're in remission, still allows 5 mg a day of prednisone. Sometimes that amount, and you can see sometimes they give it every day, sometimes every other day. It's hard to understand. We didn't get a lot of patient-level detail with that. We're just surmising because the accompanying publication hasn't been released yet or submitted. We don't know. It was just we got what we got.
I would not be totally discouraged by low-dose steroids in some patients that have been on steroids for a really long time because sometimes patients, even in remission state, will need to be on that because their body has gotten used to seeing steroids for so long.
Got it. I think we are up on time. Thank you guys so much for joining us for this discussion.
Thank you so much for the opportunity.
Thank you.