NKX019 Clinical Update @ ACR Convergence 2026 - NKARTA INC

Good day everyone. Welcome to NCARTA's webcast to review initial clinical data from the Entrust program being presented at ACR Convergence 2026. All webinar participants will be in a listen-only mode until the question and answer session begins. Following the presentation, we will conduct a question and an answer session. This call is being recorded. If you have any objections, please disconnect at this time i would now like to turn the call over to paul hastings chief executive officer of encarta please go ahead thank you moderator and welcome everyone we're grateful you could join us this morning i would like to remind everyone that today's call will include forward-looking statements and actual results may differ materially please refer to the risk factors in our most recent quarterly report on form 10q filed with the sec for a discussion of the factors that could cause those differences now i want to open today by thanking our patients and their care partners for their trust and their participation in our study without them the search for a better treatment wouldn't be possible we are here for them and not the other way around we're excited to be here at acr convergence in orlando where two world-renowned rheumatologists are presenting initial data for our investigational CAR-NK cell therapy, NKX019. Dr. Guillermo Valenzuela, founding medical director of Iris Rheumatology, shared our initial myositis data yesterday in an oral presentation. Our systemic sclerosis data will be presented in about two hours during a poster session by Dr. Dinesh Khanna, Director of the Scleroderma Program at the University of Michigan. And on Wednesday morning, our overall safety data across all autoimmune indications will be the subject of another oral presentation by Dr. Valenzuela. So here's our agenda for today's call. Sean Rose, our Chief Medical Officer and Head of R&D, will walk you through the data. President Nadir Mahmood will review market opportunities and provide an update on our cash runway. I'll come back for a quick recap, and then we'll open it up for questions. So this morning, we're presenting the first data from our autoimmune program in myositis and systemic sclerosis. These two indications will now be our sole focus as we work towards pivotal trials next year. We will carefully follow the rheumatoid arthritis patients we've treated so far and have been encouraged by responses to date for safety and preliminary efficacy, along with patients enrolled with other indications. However, the focus of our time and resources now is on myositis and systemic sclerosis. We will revisit the other indications as time and resource is permitted. the bulk of our data we'll highlight this morning are from myositis and scleroderma patients with at least 90 days of follow-up treated at the highest dose we've reached so far. That's three doses of 4 billion cells given on days 0, 3, and 7 for a total of 12 billion cells. Now at Encarta, we've always believed the safety profile of NK cells would enable patients to receive cell therapy in a more accessible and convenient way. Our engineered CAR-NK cells are administered on demand without apheresis in an outpatient setting, without an overnight hospital stay, just a two-hour observation period after each dose, without the necessity for patients to travel hundreds of miles to a major academic center, and without a hematology oncology cell therapist needed to be on call in the event of a life-threatening immune reaction. Also, our allogeneic CAR-NK cells can be redosed, a key advantage over current autologous CAR-T approaches. Now, today, we will present proof-of-concept data for NKX019 in autoimmune disease for patients given a three-dose cycle of cells following preconditioning. Now the three things that stand out about the data are first we're seeing a dose response in line with what you would see with a traditional small molecule therapeutic or biologic. Second we're seeing impressive early efficacy in a range we believe to be comparable to what has been reported for CAR-T and third the safety profile of NKX019 remains highly promising and importantly free of immune effector cell toxicities. So to date, no CRS, no neurotoxicity, no IECHS, and no GVHD. So before Sean goes through the data, I want to talk about our ongoing dose optimization work and some key translational findings that are not reported in our data analysis today. The data we're presenting today reflects three infusions of NKX019 administered on days 0, 3, and 7 following preconditioning lymphodepletion. So the graph on the left shows NKx019 exposure and the dose response we've observed. As you can see, that each step up in dose from 1 billion to 2 billion to 4 billion cells given on day 0, 3, and 7 produces a higher peak and a larger area under the curve. Now, the graph on the right shows host T cell levels recovering from lymphodepletion between day 4 and day 7. So looking back at the graph on the left, you'll notice that both peak levels and overall exposure from the final dose are reduced due to the return of those T cells. So in other words, today's data most likely reflect a reduced contribution from that third dose. So to address this, we recently amended the Entrust protocol to compress the dose schedule. We are now dosing patients on days zero, two, and four. This way, all three infusions are administered before those T-cells recover. Compressing the dose regimen is also more convenient for patients. They can now complete a three-dose regimen in five days. This is effectively dose escalation since patients to date may not have been getting the full benefits of that final dose. And as I said, we believe our early data in both myositis and scleroderma is comparable to CAR-T. We believe this data could improve further when patients get full exposure from all three of those doses. Now, we also have the option under the Entrust protocol to go to 6 billion cells per dose for a total of 18 billion cells, and we plan to exercise this option and enroll a handful of patients at the 6 billion cell level on the compressed schedule of day 0, 2, and 4. Why? Because our safety profile to date gives us that flexibility and we don't want to leave any efficacy or durability on the table. Now that's the advantage of having a cell therapy with a clean safety profile and a dose response. We owe it to ourselves and to our patients to enter pivotal development at the optimal dose. And one final point that's important to address, it concerns the recent safety news from a competitor's trial involving a different investigational NK cell therapy administered with fludarabine as part of the lymphodepletion regimen. Now, since fludorabine was introduced into NCARTA's lymphodeletion regimen, our program has had a consistent safety standard across all studies for patients that have kidney impairment. Now, outlined in our protocol, patients with compromised kidney function are required to receive a reduced dose of fludarabine as part of their preconditioning. Furthermore, beyond a defined level of renal impairment, patients are not eligible to enroll in the Entrust trials at all. So as I mentioned, our protocol also gives us the option to retreat patients, and we've retreated three patients in the study who did not respond to their first cycle of therapy. Each received a second cycle of lymphodepletion, followed by three infusions of 4 billion cells. That's a total of 12 billion cells per protocol. All three of the patients have been safely retreated to date with LDN cells with three months, two months, and one month of follow-up, respectively. So, we'll provide additional safety and preliminary efficacy data on these three patients in the near future. Now, you'll hear more on this from Sean, who will now take you through the initial data for NKX019. Thank you, Paul. Good morning, everyone. It's a privilege to present these results. Let me begin by orienting you to the Entra study design. It reflects what Paul just described. NKx019 is dosed like a traditional biologic in the outpatient setting. Patients received three days of lymphodepleting preconditioning, followed by three doses of NKX019 via infusion. Dosing began at 1 billion cells per dose. Then we dose escalated to 2 billion cells for dose and then to 4 billion. Paul already covered a recent refinement of the schedule based on our translational findings and why we're exploring 6 billion cells per dose in preparation for pivotal trials. Under our study protocol, we assess the response for up to two years and follow safety for up 15 years. On the right are the endpoints. First and foremost, we evaluated safety and tolerability. In anticipation that fludarabine levels increase in patients with compromised kidney function, Our protocol, from the start, has included a safety standard for patients with compromised kidney function. Patients with compromised kidneys function are required to have a reduced dose of fludarabine as part of their lymphodepleting preconditioning. And beyond a defined level of impairment, patients are not eligible to enroll. We also assessed NKX019 exposure and B-cell depletion and recovery, which allows us to determine whether we're achieving immune reset. For efficacy, we used established measures in each disease. In myositis, that's the total improvement score. TIS-40 is a moderate response. TIS 60 and above are considered majored responses. TIS 40 is our target because it is the ACR and EULAR-defined threshold for a moderate response. TIS combines muscle strength, patient and physician assessments, and other disease measures. So a moderate respons reflects broad improvement in the disease. The criteria are now widely used as an endpoint in myositis trials, including trials that supported approval in dermatomyositis. We also measure MMT8 for muscle strength and CDASI activity score for skin disease. In systemic sclerosis, we looked at changes in skin thickening with the modified Rodman skin score, or MRSS, and evaluated overall improvement using the R-CRIS composite score. Because the disease affects multiple organ systems, RCRIS measures skin, lung function, physical function, and the patient's and clinician's global assessments. Here, we're aiming for RCRIS 25 or higher, which means at least a 25% improvement across multiple of those five domains. A multi-domain response reflects a more holistic improvement in disease activity. That could meaningfully advance care for these patients, or typically treated with therapies that target a single organ system or domain. As is common in trials for autoimmune disease, we strongly discourage the use of immunomodulators, but they are not prohibited in our protocol. Investigators may use them if they feel it's necessary, and where that happened, it's noted in the data. There is only one patient in the 4 billion cell dose cohort being reported today who received an immunomodulator after their first response without any retreatment. With that framework in place, let's turn to the data. Let's begin with safety across all indications as of September 18th cutoff date. 40 patients across five autoimmune diseases received preconditioning with ludarabine and cyclophosphamide and at least one dose of NKX019. Overall, NKx019 was well tolerated and treatment-related events were mainly hematologic and attributed to lymphodepleting preconditions. The safety profile was broadly similar across indications, with cytopenias more frequent in the lupus nephritis group. That likely reflects differences in the underlying disease and in some patients, lower blood counts at baseline. No immune effector cell-associated adverse events were observed across any indication or dose level. We saw no cytokine release syndrome or CRS of any grade. No ICANS, no IECHS, and no graft versus host disease. The events associated with NKX019 administration were infusion-related reactions in five patients, all resolved within 24 to 48 hours without the addition of tocilizumab. That's a safety profile that makes outpatient administration possible. Turning now to the myositis results. This slide shows the myositus patients treated so far. They had active disease that hadn't been controlled by prior therapy. Median disease duration was 3.5 years, but three patients had between 14 and 30-year disease duration, two of them in the 4 billion cell dose cohort. Disease activity was clinically significant at baseline. Median MMT8 measuring muscle strength was 117 out of a possible 150, and the range went down to 85, indicating substantial muscle weakness. Patients with dermatomyositis had active skin disease as well, with a median CDASI activity score of 19. These patients had already been through a lot of treatment. 9 of 11, or 82%, had received four or more prior therapies. This is a population with refractory disease. This is the main efficacy readout in myositis, the total improvement score, or TIS. a composite score measuring overall clinical improvement. TIS combines muscle strength, patient and physician global assessments, and other disease measures into a single score. Starting with the graph on the left, five of six patients with at least three months of follow-up, or 83%, achieved a moderate or major response at the 4 billion cell dose level. As a former practicing rheumatologist, I can tell you these are the kinds of meaningful responses that matter to patients and their physicians. The responses you see here span three myositis disease subtypes. Dermatomyositis is an inflammatory muscle disease typically with a characteristic skin rash. Juvenile dermatomyositus is the same disease with onset in childhood. And anti-synthetase syndrome combines muscle inflammation with lung disease and often arthritis. One of these patients, IIM-3, who achieved a major response in the 4 billion cell dose cohort, has maintained it through six months. I also want to highlight IIM5. This patient had a major response early with a TIS response of 95, then contracted COVID-19 and dropped to below TIS-20. After recovering from COVID and a subsequent dermatomyositis flare, the patient received low-dose steroids only and has rebounded. As of the September 18 ACR data cutoff, this patient had an ACR of 95 and a Tis-40 response and continues to improve. As for the dose response curve, we see consistency and durability of response to date at 4 billion cells per dose. At lower doses, depicted in the graph at the right, we saw an early moderate response at the 1 billion dose level and a major response at 2 billion, but those responses were not sustained. You will notice that there are open circles at the later time points for the 1 and 2 billion dose patients. These represent additional therapies that these patients received for increased disease activity. We also had one patient in the 4 billion cohort, IIM4, who received a low-dose steroid taper and IVIG from a community rheumatologist outside the protocol and without the investigator's knowledge. This was not because of disease worsening. The patient had already achieved a TIS-40 response at day 37 before any additional therapy began around day 50 and went on to a Tis-60 response by day 120. Muscle strength measured by MMT8 tells the same story. Starting with the graph on the left, at the 4 billion dose level, 5 of 6 patients with at least 3 months of follow-up, or 83%, showed improvement in their MMT 8 score. The gains appeared early and were maintained through follow-ups. The one dip you see is IIM5, which coincided with the COVID-19 infection I mentioned previously. Now, an assessment of skin disease, measured by CDASI activity score. At the 4 billion dose, 4 of 8 patients, or 50%, had clinically relevant reductions, with several dropping to near zero. The other 4 patients remained relatively stable compared to baseline. The CDASI activity score spiked at day 90 for IIM5 during the COVID infection, and the score has since come back down. Turning now to the systemic sclerosis results, starting with the patients treated. Our patients had longstanding disease and extensive prior therapy. Median disease duration was 4.6 years, with some patients up to 8 years from disease onset. said. Disease activity was substantial at baseline. On skin, median MRSS was 26, with a range up to 46, reflecting severe skin involvement. And these patients had already been through a lot of treatment. Nine of 14, or 64%, had received three or more prior therapies. 86% had received conventional disease-modifying anti-rheumatic drugs, or DMARDs, including mycophenolate mofetil in nearly two-thirds of patients. This slide shows skin responses in systemic sclerosis. The graphs on the left show MRSS scores, and the graphs on the right show percent change from baseline, with the shaded area marking a 50% or greater reduction. Starting with the 4 billion cell dose at the top, we saw rapid and deep responses through day 90. Patients had a median reduction in MRSS of 15 points, with reductions of up to 29 points. Six of seven patients, or 86%, had a decrease in MRS-S. And these aren't small changes. Five of seven patients, or 71%, achieved an MRS as 50, a reduction of at least 50% from baseline. That goes well beyond a 25% improvement. There's also a clear dose response. Looking at the bottom graphs at 1 in 2 billion, we see only one of five patients reached a 50% reduction, compared with five of seven at 4 billion cells per dose. Now, let's turn to the ARCRIS composite score, which combines five measures, skin, lung function, physical function, and patient and clinician global assessments. Lung function, measured by forced vital capacity, or FVC, is a trailing indicator and can take longer to show a change. At 4 billion cells per dose, 6 of 7 patients, or 86%, achieved an ARCRIS-25 or higher at day 90, which is our target, and 5 of 7, or 71%, achieved in ARCris-50 or higher. One patient in the 2 billion cohort with the longest follow-up has maintained an ARcris-70 response through day 270. Turning now to the translational data, the data on this slide go beyond what is in the ACR myositis oral presentation and the scleroderma poster. They include all patients dosed at 4 billion cells for whom we have these data. Starting on the left, this is peripheral B-cell depletion in these patients, who were dosed at 4 million cells on days 0, 3, and 7. We see deep B-cell depletion, with the majority of patients remaining depleted through day 27. What matters most is what happens next, and that's on the right, the B-cel profiles. We have data from a small number of patients so far, but the pattern points toward B- cell reset. Memory B- cells, switched memory B-cels, and plasma blasts fall and stay low, while naive B-Cells return as the dominant population. This pattern is consistent with an emerging B-cell reset rather than B-cel depletion alone. To bring the clinical and translational data together, NKX019 was well-tolerated in the 40 patients treated with a range of treatment from 0.3 to 15.9 months and a median duration of 5 months. There were no cases of CRS, ICANS, IECHS, or GVHD, and we did not see an increase in adverse events at higher doses. In myositis, at 4 billion cells per dose, 5 of 6 patients with at least 3 months of follow-up or 83% achieved a moderate or major response by total improvement score or TIS. In systemic sclerosis, at 4 billion cells per dose, six of seven patients achieved an ARCRIS 25 or higher by day 90, and five of seven achieved an ARCris 50 or higher. Across the program, we see a dose response. PK exposure increased with dose, and the most consistent clinical responses were seen at 4 billion cell per dose. On the translational side, we see deep B cell depletion with a shift toward a predominantly naive profile among repopulating B cells. Now, I'll turn it over to Nadir. Thank you, Sean. Refractory myositis in systemic sclerosis patients have limited to no therapeutic options and a severe need. We're pleased with what our early clinical data show that this therapy can potentially offer them high therapeutic benefit, a very clean safety profile so far, and importantly, convenient administration. On benefit, the responses Sean just showed reinforce our belief in the impact NKX019 can have for these patients. That impact comes with a differentiated safety profile, free of immune effector cell toxicities to date. And it's off the shelf, ready to ship on demand, and given in the outpatient setting with just three infusions within five days. Feedback from the physicians treating these patients has been highly favorable. They're energized to bring their patients a therapy with high efficacy, a clean safety profile, and operational ease. A product that delivers this kind of value should translate into a strong opportunity to help even more patients. Our preliminary U.S. estimates put myositis prevalence at about 80,000 patients, including roughly 7,000 cases that are refractory. Systemic sclerosis is about 90,000 patience, including roughly 10,000 case that are refractory. We'll continue to refine these figures. Based on these estimates, together with feedback from payers and physicians on access and patient share, we see NK-019 as a therapy that could be widely prescribed across both indications in the U.S. That's the U-S alone. Europe represents additional upside that isn't included in these figures, and we're early in estimating the addressable patient population there. Here's what's next. Based on these data, we remain focused on advancing NKX019 in myositis and systemic sclerosis. In the first half of 2027, we expect additional follow-up in both indications and a plan to select the registrational dose, 4 billion versus 6 billion cells. We also have upcoming FDA interactions to discuss the registracional path in myicitis and systematic sclerosus. And we're well-funded to execute on that clinical development plan. As of our last quarterly update, we have $216 million in cash, cash equivalents, and investments with an expected runway into 2029 based on our current operating plan. Now, I'll hand it back to Paul. So let me recap what we just heard. NKX019 was well-tolerated in the 40 patients treated with no cases of CRS, ICANS, IECHS, or GVHD. Our protocol includes a safety standard to reduce fludarabine-related risk for patients with kidney impairment, and we have not seen serious fludiarabine related toxicity. Five out of six myositis patients achieved a moderate to major test response at 90 days. Six out of seven systemic sclerosis patients achieved an ARCRIS 25 or better, and five out of seven achieved an ARCRIS 50 or better at 90 Days. The duration of treatment across both indications is a median of 5.4 months with a minimum of 1.5 months, and the longest follow-up is 12.6 months. At 90 days, the skin responses we see are some of the largest reductions reported in MRSS. We're also seeing durability at up to nine months in one early patient who received a lower dose as of the September 18th data cutoff. And preliminary B-cell profiling shows early evidence of immune reset. Now let me talk to you about one final point. We reported data today using traditional endpoints in myositis and systemic sclerosis, and we believe our data speaks for itself. Yet, we also believe that cell therapy warrants a fresh look at scoring systems developed before next-generation disease-modifying therapies existed. That's why Encarta is co-sponsoring a companion study with Dr. Valenzuela called ACES to capture real-world Patient-Reported Outcomes. Now, the ACEs study team is interviewing study participants before treatment and after they complete treatment via Zoom in the comfort of their own homes under a parallel study to our dose escalation study. We'll update you on what we learned next year. The data we've shared today tell part of the story. The rest comes from the people who treated these patients and who saw the changes in them day to day. We're delighted today to be joined for the Q&A by Dr. Valenzuela, who is both an investigator in our study and a leading KOL in the field. He's past president of the Florida Society of Rheumatology, receiving his postdoctoral training in rheumatography and clinical immunology at Cornell. Now as founding medical director of Iris Rheumatology, Dr. Valenzuela has been a trailblazing community-based clinician running a community- based research center that, in my opinion, rivals or surpasses academic settings in conducting clinical research. His site has participated in more than 200 clinical trials, including multiple cell therapy studies in autoimmune disease. Dr. Valentzuela has been administering NKX019 on an outpatient basis from his community clinic in South Florida for several months. Thank you, Dr. Valenzuela, for joining us and moderator. We're now ready to take our first question. Thank You. At this time, if you would like to ask a question, please click on the raise hand button which can be found on the black bar at the bottom of your screen. When it is your turn, you will receive a message on your screen from the host allowing you to talk, and then you will hear your name called. Please accept, unmute your audio, and ask your question. We will wait one moment to allow the queue to form. Your first question will come from Gail Blum with Niedermann Company. Please unmute your line and ask your question." Good morning, everyone, and thanks for the very interesting updates. Maybe a quick question for Dr. Valenzuela. Just, you know, given we all saw the results today, what is your opinion on these results and how would it apply to patients in your care? Good morning. Thank you for your questions. I think this is the first take of seeing patients in these conditions having alternative treatments that traditionally you haven't been able to offer to them. As you saw in the recent presentation, the responses of patients, in my view, exceed what we normally expect from the traditional therapies we've been exposed in the past. I have the opportunity to see these results in our patients directly in our clinic, And it's also replicated in other patients who are not part of my own cohort. But I have a great motivation to continue seeing patients under this therapy because of the outcomes that we see, the personal expressions of our patients in the results. we have collected their experiences in different ways with their own personal statements that go beyond perhaps the metrics that you've seen here that are traditionally used to to gauge the response of patients so i see beyond the numbers and i see patients having changes in their life their statements and at a personal level is very gratifying as a treating physician to be a witness to their responses. Okay. And as a follow-up, just given the risks associated with lymphodepletion and the potential for redosing here, what would you consider an appropriate durability for these kinds of patients? The durability is perhaps a thing called measure to predict, obviously. To the question of the lethal depletion, you're probably relating to events reported before, but I don't think it's a changing event. I can tell you in our experience, I want to remind you of one important thing. All these treatments are provided in the convenience of an outpatient setting. In other words, our clinic has its own outpatient setting where these treatments are provided, of which conditioning meaningful depletion is one of them. The process of administering the meaningful deplete and the subsequent days after that essentially are not a major hindrance or at all a hindrance to the patients, other than the known mild side effects that they can have. So I don't have an issue in terms of the safety. I think the collective safety of this regimen far surpasses the risk that the therapy imposes to the patients itself. Not only myself, but if you see across the cellular therapies, the fludarabine and cyclophosphamide are standard therapies, and they're very well tolerated in the majority of the trials. So to summarize your question, I don't think nipple depletion imposes any significant major hindrance. I think it's mostly the opinion of physicians who are not experienced to this. However, we've been educating our colleagues. In fact, yesterday during our presentations, we showed, we expressed, we shared our experience with lethal depletion. And it seems to be very well taken once the community understands the implications of this treatment. Thank you, Dr. I would add to that. I believe the prevailing thought is that these therapies should have a durability of about 12 months. And the option to retreat with NK cells is the benefit of the NK cell therapy. The ability to retreat, if needed, is there. Okay. Thanks, Dr. Valenzuela. And one for the company, Paul. So this one's for you. So out of those 40 patients that you guys reported, how many were treated as outpatient? I don't think I saw a specific number. Sean, I don' t know if you know that number, what percentage it might be for the early patients. Yeah. I mean, I'd say it's probably at this point roughly half are outpatient. Yeah. Okay. That's super helpful. All right, guys. Thank you and congrats. Yeah, just one addition. The outpatient therapy was a protocol amendment that was recently submitted and agreed upon with the FDA about roughly, what, six months ago. Yeah, six month. Cool. Your next question will come from the line of Salim Syed with Mizuho. Please unmute your line and go ahead with your question. Great. Congrats on the data, guys. and thanks for the questions. I'll just try to limit myself to one for the doctor, maybe one for the company. Dr. Valenzuela, in your view, could you just give us your updated thoughts, just given the data that we saw this week and previously, where do you, at least in a preliminary basis, think NK cells for myositis and scleroderma could get slotted versus T cell products? And then just for the company, on the potential registrational start, Paul or Heather, what are the gating factors here to actually starting the registritional trial? And is 2027 a reasonable estimate for that? Thank you. Thank you for your question. I think this is the question that I get also from our colleagues in the space in general. First, I see that NK therapy, NK019 specifically, has a bright future in patients. I would probably say the active early patients has a pivotal role. There are patients who, as we know, have a long journey and we're trying to anticipate the chronic further progression of the disease by acting early through NK, as you saw there. and using the B-cell depletion in this data you're also seeing in the change of the behavior of the cells is very encouraging because it's essentially paralleling responses to CAR-T. Now, I think the winning point as a clinician, for example, is how we apply this concept into the administration of the treatment and the great advantage is as you saw in the presentation is the safety profile i would say you know summarizing you already seen all those numbers and second is that the practicality of the whole process i'm sure you're quite familiar with what the journey of the patient with party is and i can tell you that the journey the patient who sees mk is similar to the regular infusion therapy we have been traditionally providing for the last 20 years in our clients Oh, registrational. Yes, absolutely. So, Salim, on the registritional end, our plan, even though we're now going to 6 billion cells, we feel that the 4 billion cell dose level is giving us very acceptable early preliminary exciting outcomes. The fact that we can go to 6 billion cells is because of the safety profile. We don't want to leave anything on the table. However, we're prepared to discuss with the FDA very soon our pivotal plan. So your question about is 2027 a reasonable period of time in which we would do that and start trials? Yes, the answer is yes. Okay, great. Thanks so much, guys, and congrats again. You bet. your next question will come from the line of phil nadeau with td cohen please unmute your line and go ahead with your question good morning congrats on the data um thanks for taking our questions two from us so uh paul just on your point about the six billion versus four billion dose um levels that you just made can you tell us how you uh decide between those two doses i guess in particular how much additional talks would you be willing to put up for put up with in the case of either better efficacy or longer duration of response. That's first. And then second for Dr. Valenzuela, could you give us some sense, as we look forward to the pivotal trials, what is the minimum response rate that's necessary, do you think, to advance this to become part of the paradigm in either myositis or sclerosis? So what TIS, moderate to major response rate, or ARCRIS-25 response rates will you be looking for in the pivotal study to think that this has a place in the treatment paradigm. Thank you. Yeah, if you don't mind, Phil, I'll have Dr. Valenzuela comment first, and then I'll follow up on the response. Well, thank you for your question. Moving into a clinical process, as you're asking, what would be an acceptable or a desirable response on our end? I would start to feel very comfortable if we are starting to reproduce what we just saw on the screen. Certainly, there's room for optimization, and I'm very encouraged. I'm going to have to step back for a second. I have to give you a bit of my background. I train in immunology, so one of the reasons why I follow this very closely, these clinical responses, is because I believe that the mechanistic effect of these cells is primordial. So to your answer from the four to the six billion cells, I believe there's still an additional room for, following the PK curves that you saw on the previous charts, I think there's additional room for this treatment to be compacted and even more effective having more available cells for doing their action. So in terms of response, I would be very happy to see results in the 50s to 60% as we saw on the T-scores, I think it's quite acceptable and sustainable. That would be a very elegant outcome where our colleagues will certainly feel very comfortable of trying to achieve themselves as well. Yeah, and we believe that between 50% and 60% is a rate that would be much better than what is available today and an acceptable rate. But we also agree with Dr. Valenzuela, reproducing these data would be actually spectacular. On the level of tox, one's willing to accept. One would hope never to have to deal with toxicities. And so far, we haven't, which is nice. So the move to 6 billion cells, in our opinion, is going to be carefully monitored. And given the rapidity and the responses that Dr. Valenzuelas sees in his practice on these patients, we'll know very early whether 6 billion cells offer a significant advantage over 4 billion cells. So I predict it won't come down to tox, although we haven't hit a maximum tolerated dose. And I don't think we'll push beyond 6 billion cells, but it's going to be relatively quick assessment of 6 billion versus 4 billion. If the responses are similar, we'll go forward with 4 billion because from a cost manufacturing point of view, that makes more sense, and for these cells to be available for patients. So that's how we're looking at that, but no level of toxicity is what we would hope for, and that's what we've seen so far. That's very helpful. Thank you. Congrats again on the data. Your next question will come from Dana Graybosh with Lear Inc. Partners. Please go ahead with your question. Hello. Thank you for this. I wonder, we could talk a little bit more about the different organ scores. And it seems like you're consistently seeing a strong skin effect. Does that make sense? some more NK cells traffic. I also think NK cells are known to traffic pretty readily initially to the lung. And that's where maybe you saw, you didn't see as much of an effect, but you discussed that you nonetheless expect the lung effect to be delayed. So both just more about where you're seeing the effect across both of these studies in the organs and how we should interpret that. And also I know both of these disease types can have fibrosis involvement? And where, in terms of the specific domains, might we see that there's fibrosis that's going to be challenging with any active therapy to actually address that score because of that underlying fibroses? Right. So I'll start, Sean, with you. You want to tell Dana what the endpoint is and what the time point is for the first lung assessment in the trial that might help in terms of when we're going to see that improvement and then maybe dr valenzuela you give your opinion on what you think about how rapid this agent works at skin why that why you're seeing that versus you know maybe some of these early lung changes or maybe some of the early lung challenges you are seeing thank you for your question dana um i'll start with the organ scores uh particularly in systemic sclerosis uh we've had some very rapid and robust responses seen in the skin. We do believe and validate what you're saying immunologically, yes, NK cells traffic very readily to the skin, and we think that might be driving that early response. From a lung perspective, our data is relatively immature. We collect time points at roughly 30 days or one month after the initial dosing, and then two months out, and then three months out. And after that, it's every three months. So what you see from a lot of the data for CAR-T, for example, is they're showing data 60 days out through one year, right? And our data is relatively immature in a lot of these participants. What I will highlight is those that had no ILD at baseline, they have not seen any progression in those patients of new ILD onset. And in those who had pre-existing ILV, it has been mixed thus far. We've had a couple that have improved. We've Had a couple of them been stable and we've had a couple That did not respond at all in skin or love that had progression of long. So we think that's some encouraging early data, but premature and we really want to make sure that we are following up for durability over a six plus month time frame through one year. Thank you, Sean. And I think that summarizes the whole cohort. But let me use examples of patients. In terms of the different organ involved in these conditions, starting with the scleroderma, I have been, I would say, privileged to see some responses in patients with a rate of skin improvement, or I would almost say close to resolution in some of those, with very rapid softening of the skin, which is not what you normally see in the literature for the cycle of scleroderma that happens way, way after a number of years. These are responses that can be directly attributed to the treatment, they correlate directly with the treatment. I can picture right now three of those patients who had their very quick response of the It's getting to the scores that, if you remember looking at it first, we showed before, rapid resolution without any further damage. I would echo what Sean said in terms of the pulmonary domain of scleroderma. We see, as precisely that, we've seen some early hints towards the improvements of the fusion capacity, which is expressed as the ELCO. and we don't see translated into the patient we have not witnessed any kind of patients complaining of worsening of their respiratory capacity or their exercise quality which is quite encouraging at this early stage so I think that probably would be a better graphic way to describe or to translate what you see in the data into persons or patients as I had the opportunity to see. And I'm quite encouraged by that. And if I can do a retrospective group analysis of what we have done traditionally in rheumatology in this condition, it's quite unique. I have not seen even using the toxin out in the past these results of the skin that I've seen in these particular patients we've treated. Great. Thank you. Your next question will come from Jonathan Miller with Evercore ISI. Please unmute your line and go ahead with your question. Thanks so much for taking my question, guys, and congrats on all the data. I'd like to start with one for the company on durability. Obviously, this data is still early. You've got these great rapid responses. But what do you think are the major drivers of durability from here? Are they different from either auto cars, T-cell-based therapies, unmodified NKs? Are there different drivers of variability for your product versus some of your competitive products? And how can you get confident in the durability profile at this point in time when there's been questions in some of the competitive programs? And then maybe secondly, maybe for Dr. Valenzuela a little bit, I know that you guys have retreated at least a couple of patients so far, and that data may not be fully mature or ready for primetime, but can you speak to the retreatment results that you've seen and how patients have fared after retreatment at this point? Yeah, so let me step in for a second. So what I will say broadly is, and Dr. Valenzuela did have some of those retreated patients, we will update you on the retreatments probably in the first half of next year. We've had requests from investigators, including Dr. Valenzuelan, who treated patients at lower doses, and he can speak to that, why he wanted to retreat those lower dose patients when we got to 4 billion cells. But we'll give an update on all those patients in the 1st half of this year. And then, but why don't I have him do that first, and then we'll come back to what we believe is the right durability number and why we feel confident that the durability we're seeing so far is encouraging and consistent. And I might pitch that over to Sean and maybe Nadir could comment on it as well. So go ahead, Dr. Bell. Yeah, thank you for the question. Yeah. So that's an interesting approach that these protocols allow us. Certainly, we are aiming for a person's single treatment. However, as a clinician, it's comforting to know that we have the option of good treatment in patients, especially in the face of dose exploration when we perhaps due to the size effect of the lower doses, you may not have achieved the B-cell depletion as you would have expected in the past. So I can give you examples. It comes to mind a gentleman who's a patient who has a diagnosis of scleroderma, a construction worker who received the first cohort of doses at $2 billion, and about three months after that, the assessment pointed that he would probably that he had not reached the response he would have expected from the beginning. So as part of the rationale, as I mentioned before, in having the option to to treat this patient, and given the fact that he had not achieved the original expected goals, the patient was considered for re-treatment, which he underwent approximately two months ago, and he's starting to show now he's back to work. He's a gentleman that, again, as I said, is a construction worker. Aside from the chronic, you know, features of scleroderma that he had, he's improving with his skin, not only his skin score, but his strength and his ability to perform activities. So I guess this probably reflects the fact that from a lower dose to a higher dose and re-treatment and without any major associated complications or disruptions getting to the second regimen uh this patient is now showing signs of early response maybe i would ask you to go back to when we first treated this patient he had a response it wasn't a deep response but it was encouraging right exactly so he had that response but um shortly thereafter we noticed that it was not as deep as we would have expected in fact some areas of the skin uh did not improve but the way we wanted it with the second first we're starting to see actually can do a comparison uh the first cycle the second cycle and uh first cycle was two billion correct first cycle was two million that's correct uh the second has put the general back into um uh the workforce so uh i'm encouraged by that and again as i said before as a clinician uh not that we uh obviously what we'd like to treat patients on a cyclic basis, that having the opportunity, the availability of a re-treatment has been one of the reasons why perhaps some of these patients signed up for the trial. Sean, do you want to talk about why we think our three-month durability so far is encouraging and what we might expect to see? Yes, and thanks for your question, John. Our leading indicators that are really important here in terms of durability is what we've learned from the cell therapy field. First of all, we're seeing robust deep B-cell completion, and that's really important to see in the periphery. We are collecting tissue in skin as well as in lymph nodes, and we look forward to presenting that sometimes at a medical congress next year, so that will be another leading indicator. As you heard Paul speak to earlier, emergence of a naive phenotype of the B-cel compartment and reductions in the membrane B-sel compartment. This is referred to as B-cell immune reset. We are seeing this at our high-dose cohort at 4 billion cells, and I think this is an important leading indicator. Certainly with clinical responses, we've shared with you the data as of September 18th data cut. Now, we're six weeks later, and we look forward to sharing an update on durability in the future. However, I will say that those results continue to be encouraging. anything you would share yeah i think one of the the key points for us that we look for is trying to sort of mention around the b-cell population is just what is the reconstituted population and the immune reset so i think when we think about the early data that could guide us towards having some level of confidence of longer-term durability it truly is looking at a reconstituted population that represents a more immature, naive phenotype. And I think we have early data for that, but it supports that rationale that we're seeing the immune B-cell reset that we'd expect. Right. And the other thing that I would add, John, is that in the early days, we were having difficulty enrolling the trial. I think what rheumatologists didn't grasp, and maybe we didn't either, was that NK cells don't act like T cells. So at the lower doses, you weren't seeing the robust responses that T-cells were seeing at the first dose they were giving. Once we got to the 4 billion cell dose, enrollment picked up dramatically, and that was all over the past year. So what you're seeing is dramatic enrollment and dramatic results in a fairly short period of time. And now we owe it to you to follow up on that. We will. And with an overall improved safety profile that gives you the flexibility to potentially go in and redose at some point in the future, I think that's just an added bonus that can potentially enhance some of the attributes here. Yeah. And most of the rheumatologists we've been talking to the last few days, because we're all here at ACR, are very excited about the ability to see if you could actually maximize this dose. And so everybody's interested in going there. So we are anticipating that enrollment in the six billion cohort is going to be robust. And actually, Dr. Valenzuela is treated already. No, not yet, but he's lined up soon to treat a compressed dose four billion. 0, 2, and 4 patient. Yeah. Excellent. Thanks so much. Thanks, John. Your next question will come from the line of Douglas Sal with AC Wainwright. Please unmute your line and go ahead. Hi, good morning. Can you hear me? So congrats on the data. I'm just curious, how you think about going to the 6 billion cell dose. Because obviously, I think you've indicated you don't necessarily anticipate going out to necessarily six months before making a decision in terms of sort of your dose selection. And just given the fact, obviously, we've seen very rapid responses in termsof skin. And understandably, we're seeing a little bit of a lag in terms of the lung benefits in systemic sclerosis. I'm just curious, you know, your confidence in terms Of sort of that translational data, and whether the higher dose might ultimately result in better lung improvement. I mean, you essentially, Doug, just gave us what we've been discussing in the company, every day, every minute. So absolutely, we are with you on that. And again, our expectation, given the repetitive results we're seeing, and the depth of the results that we're seeing, the closeness that we have with our investigators, and the amount of communication that's going back and forth, which is absolutely phenomenal, we're going to know pretty quickly whether we're seeing differences very quickly. And again, at the end of the day, we want to go to pivotal. We believe that we have a pivotal dose now, and we believe we could optimize that. So we'll put together some criteria ourselves internally in terms of how do we make those decisions. But we're very excited about looking at what this does. And I would say we would have to see a dramatic difference in the depth and speed of the results we're seeing that would then hopefully translate into durability and also the B-cell depletion as well as the reset. So all things that we'll be able to see over the next few months. And if I can, I'd be curious to hear from Dr. Valenzuela in terms of sort of the translational or sort of a correlation between skin improvement that he has seen typically with lung improvement in scleroderma. Thank you. Well, exactly. So I'm eager to see those results. I think we will use that benchmark, the B-cell depletion, and specifically the reset characteristics of the new phenotype of those cells to compare them to the results that you get with CAR-T. Essentially, that's the ultimate goal. And I believe, if you look, again, I can refer you to the PK curve that we showed before, that's an achievable goal. The depth of the depletation will be, I think, achieved either in this regimen, the more compacted, or perhaps even the 6 billion people see it, I think it's very encouraging to translate what I see, what we see in the lab, into the clinical responses of the patients. And that's where I see the clinical dose response, from the 1 billion patients in the past to this current 4 billion doses. I believe I'm seeing that now apply to the patient's responses. Didier, you had some comments? Sean had some moments? Yes. Yeah, I think just the last point, Doug, around the translational data and what we want to see. I think what we look for there, obviously, is continued deep B-cell depletion and reconstitution of naive phenotype. But we're also collecting additional translational beta where you can do some comparisons looking both in lymph nodes and in tissues as well. So that's going to help inform us as to whether there's some difference that would give us confidence that the 6 billion dose might be a better dose than 4 billion. I would just add one thing. As we've highlighted before, NKX019 behaves very much like a traditional biologic. We're seeing a very clear dose response. So we're going to look at safety, of course. We'll be looking at efficacy, as you've heard. And it comes down to pharmacology as well. We'll see whether there's any increase in exposures with compressed dose regimen, especially as we escalate between 4 billion and 6 billion cells. and then many of the pharmacodynamic measures that you've already heard described. Okay, one more question. Or a group of questions from the last person is what I'm expecting. The final question will come from Stephen Wiley with Stifle. Please unmute your line and go ahead. Yeah, good morning, guys. Thanks for hosting this. I guess I appreciate the early B-cell profiling data you've provided. And I think we know that NK cells are advantaged in terms of being able to traffic into lymph and tissue. Have you been able to get lymph node biopsies from any of these patients? And should we expect to see profiling of reconstituted B cells from here? And then do you think the depth of skin score improvements that we're seeing in scleroderma patients is facilitated by this trafficking capacity? And I just have a follow-up. Yeah. So on the lymph node biopsies, yes, we're able to do them. It is still early. What we do find is, believe it or not, the capability of centers to do lymph node biopsied, particularly academic centers. Now I'm going to get to Dr. Valenzuela, who's looking at me right now, because he knows how to do these with expertise. When I see lymph node data come in, I trust the stuff that he's giving us. And when our academics are dealing with interdepartmental, whatever you want to call it, sometimes that becomes more complicated so i'd say you know getting all of no biopsies is a challenge and dr valenzuela can speak to his experience because he's done it now on a number of patients and uh you want him to talk about the depth of responses as well okay well uh thank you so um to the point of the no biopsy we incorporated that in the uh in the trial um already um having a number of subjects. I actually believe it was your idea to do that, which it wasn't, yes. Thank you for giving me credit. Sure, I think we have biopsies in several or since the 4 billion cohort in the majority of the patients, we have pre-equalization and at two different time points at the completion of the NK8019 and 30 days out. So we have three time points in the majority of the patients that I think we will be data we will we're gladly willing to to see and in terms of the the skin response I cannot I cannot answer that question I think here I think Carter would have to start looking at those biases and it's a little early perhaps to to have that that that answer for you I think will probably see changes I expect as a clinicians that will see changes in the structural practices of the skin as they surrogate for the clinical observations. But I would say it's a little too early to answer that. I wish we can find the direct correlation that would be even more supportive of the clinical findings that you're having now. You want to talk about your experience? You know how to do skin biopsies as well? Yeah, skin biopsy we do in our clinical center. It's relatively simple. Sometimes I have questions as to why many cannot do that. It's a very simple procedure, the punch biopsy. Whereas the lymph node biopsies, we try to optimize the retrieval process of the lymph biopsys. We have them done under the expert hands of any radiologists, interventional radiologists who can actually hone in the biopsis. And so far, we've been quite successful at getting enough sample for the majority of these patients in this cohort. So very anxious to, or actually very hopeful to see the results. Since it's you, Stephen, do you have any more follow-up? Or you'll be the last one? Yeah, just lastly for you guys, and I'm sorry if I missed it earlier, but how much patient data at the 6 billion cell dose are you hoping to provide at the time of next disclosure? And should we expect those patients to all have a minimum of three months of follow-ups as well? Thanks. Yeah. We're going to update on 6 billion. We would have three months of follow-up, and we would do it with a robust number of patients, probably between six and something beyond that. But that's really our goal. So with that, yeah, I want to thank you for joining us today and for your questions. I want to thank Dr. Valenzuela. I do want to highlight the question on biopsies and things like that. I think the issue and the reason that we are so excited about working with community-based centers is there is no bureaucracy and the ability to do things, simple things like lymph node biopsies and skin biopsied becomes a matter of a conversation, not a negotiation. So I want to thank Dr. Valenzuela, our investigators and study teams, and above all to the patients and the care partners who made these data possible. And we look forward to sharing more data on safety at ACR on Wednesday, where Dr. Valenzuela will be giving an oral presentation on the overall safety of our NKX019, an additional follow-up in 2027. Thank you very much.