Thank you for standing by. Welcome to Nkarta's conference call to review updated clinical data from the NKX019 program. At this time, all participants are in a listen-only mode. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to the company.
Thank you, operator, and good morning, everyone. I'm Kory Hartmann, Senior Vice President of Public Affairs and Investor Relations at Nkarta. Thank you for joining our call this morning. Earlier today, Nkarta issued a press release announcing updated data from the clinical trial of NKX019. This press release, today's webcast, and corresponding slides are available on our website. We're looking forward to discussing these results and our progress toward making off-the-shelf CAR NK cell therapy a reality for patients with cancer. On the call today from Nkarta are Paul Hastings, President and Chief Executive Officer, Dr. David R. Shook, Vice President, Clinical Development, and Dr. Nadir Mahmood, Chief Financial and Business Officer. We're also honored to have one of our distinguished NKX019 investigators, Dr. Michael Dickinson from the Peter MacCallum Cancer Centre in The Royal Melbourne Hospital, participating.
On today's call, we'll be making certain forward-looking statements, including statements concerning Nkarta's expectations regarding any or all of the following: the therapeutic potential of NKX019 as a monotherapy and/or in combination with rituximab for the treatment of B-cell malignancies, including NHL, the tolerability and safety profile of NKX019, the accessibility and potential outpatient administration of NK cell therapies, including NKX019, plans and timelines for the continued and future clinical development of NKX019, plans and timelines for the availability or future presentation of NKX019 clinical data, and plans and timelines regarding the future clinical development and potential of our product candidates. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements.
Interim data from clinical trials are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more data on existing patients become available. The clinical trial program is ongoing and the final results may be materially different from those reflected in any interim data we report. These and other risks and uncertainties are described in our periodic filings made with the SEC, such as our most recent 10-Q and subsequent filings. You're cautioned not to place undue reliance on our forward-looking statements, and the company disclaims any obligation to update such statements. With that, I'd like to turn the call over to Paul Hastings. Paul.
Good morning, everyone, and welcome to our call. Earlier today, we announced exciting news for Nkarta's NKX019 clinical development program in patients with relapsed and refractory B-cell malignancies. Before we dive into the clinical data, let me briefly review that natural killer cells, or NK cells, are a critical component of the innate immune system. Our platform starts with real NK cells isolated from peripheral blood of healthy donors to develop potential therapies for blood cancers as well as solid tumors. NKX019 is designed to be off-the-shelf cell therapy that can be manufactured at scale, cryopreserved, and administered on demand when a patient with cancer needs it. We're extremely proud of the Nkarta platform and its end-to-end capabilities. We recently presented data at SITC on our ability to expand donor-derived NK cells more than 250 billion fold while maintaining their integrity and their potency.
Just as importantly, with the emerging safety profile, NK cells have the potential to be administered in outpatient settings. NKX019 monotherapy findings that we're presenting today build on the success that we reported earlier this year. Today, we're reporting outcomes for 6 additional patients who were each treated at the highest dose level of NKX019, as well as follow-up on all patients from the April data announcement. We continue to see early response rates that compare favorably to the transformative anticancer activity of CAR T therapy, with durability exceeding 6 months in some of the most challenging malignancies. The emerging safety profile of NKX019 is potentially game-changing.
While occasional transient and manageable infusion-related reactions were observed, and some were even labeled as CRS by our investigators, the early onset and prompt resolution of symptoms, sometimes without any intervention at all, is clearly not the classic CRS that is seen with CAR T cell therapies. The overall tolerability profile of NKX019 has allowed patients to efficiently receive multiple treatment cycles, each with three doses of NKX019 following lymphodepletion to drive deep responses. This approach is a cornerstone of the Nkarta platform and we believe a differentiator in cell therapy. This response adaptive design allows patients to receive additional cycles to deepen and consolidate antitumor responses. In addition, patients whose disease recurs after a previous response, even if beyond six months, can also be retreated with additional cycles of NKX019 to hopefully drive tumors back into remission. Multiple patients received NKX019 on an outpatient basis.
This is the next step in our goal of breaking access barriers for patients in need. We recognize the preliminary nature of these data and the standard caveats of clinical science still apply. While encouraging, even with these additional patients, these are small numbers from an open label study distributed across different doses and different disease histologies. Time is needed for more follow-up and for more patients to be treated, but as early data go, we have reason to be optimistic.
To that end, we have recently opened multiple dose expansion cohorts to further evaluate the potential of NKX019 in the treatment of high-risk B-cell malignancies, both as monotherapy and in combination with the anti-CD20 antibody rituximab. Before Dave reviews the data, it's my pleasure to introduce Dr. Michael Dickinson, who has graciously agreed to share his views on the treatment landscape for NHL and unmet medical need faced by patients with these diseases. At the conclusion of our prepared remarks this morning, Dr. Dickinson will join us for the Q&A discussion. Dr. Dickinson is from the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital in Melbourne, Victoria, Australia, which is the largest hematology service in all of Australia. There, he is the lead of the Aggressive Lymphoma Disease Group in Clinical Hematology.
He specializes as a principal investigator in phase 1/2 clinical trials of new anticancer drugs with a current focus on aggressive lymphomas and novel immunotherapies. I'll turn it over to Dr. Dickinson and Dave to provide an update on NKX019. Dr. Dickinson, please go ahead.
Non-Hodgkin lymphomas are cancers derived from B-cells and include aggressive and indolent forms. The most common type of non-Hodgkin lymphoma is aggressive diffuse large B-cell lymphoma, which has an especially poor prognosis when it relapses. CD19 is a well-validated target employed by the approved autologous CAR T-cell therapies for large B-cell lymphoma, as well as other challenging lymphomas including follicular lymphoma and mantle cell lymphoma. While these therapies have altered the treatment landscape for some patients and set a standard for responses in those with relapsed refractory disease, safety and accessibility prevent more widespread use. Accessibility is a considerable challenge for patients, and only 20%-30% of patients with large B-cell lymphoma who may benefit from this potentially curative cell therapy are able to be treated.
This is due to several factors, including the logistical challenges and treatment delays associated with bespoke manufacturing, which result in a limited number of specialized sites being able to utilize CAR T-cell therapy. Toxicities are also common with autologous CAR T-cell therapy, with more than a quarter of patients requiring an intensive care environment. Cytokine release syndrome, or CRS, consisting of prolonged fever associated with other vital sign instability, affects the majority of patients who receive CAR T-cell therapy, and up to 49% of patients have grade 3 or higher CRS. Immune effector cell-associated neurotoxicity syndrome, or ICANS, is also common. In those that ultimately do receive autologous CAR T-cell therapy, the complete response rate for patients with large B-cell lymphoma is only between 30%-40% at 6 months.
For those patients that do not achieve complete response, there is no other option to repeat dosing among any of the approved autologous CAR T-cell products. Similarly, for those that relapse after initially achieving remission with CAR T, the outcomes are dismal and repeat dosing is not available for any subtype of non-Hodgkin lymphoma for which autologous CAR T is approved. There is a critical need for safe and effective therapies which can be delivered rapidly to patients with relapsed refractory B-cell malignancies. Thank you. Now let me pass the call to David.
Thank you, Dr. Dickinson. We're excited to present the data from the dose finding phase of our phase 1 study evaluating NKX019 in relapsed refractory B-cell malignancies. The data that we're reporting today give us confidence in the potential of NKX019 as a next generation therapy with early antitumor activity rivaling autologous CAR T-cell therapies without the safety burden and logistical challenges that have limited the broad accessibility of currently approved therapies as outlined by Dr. Dickinson. We are evaluating a high-risk, high-need patient population. The data presented today is from the first phase of the trial, which enrolled a cohort of patients with various relapsed refractory B-cell malignancies who had received at least two prior lines of therapy. Patients were required to be CAR T naive in these initial cohorts to avoid confounding evaluation of either the safety or efficacy of NKX019.
We are also now evaluating NKX019 in patients that were previously treated with autologous CAR T-cell therapy in the expansion cohorts that we recently announced had opened. Beginning on day -5, patients in the dose finding portion of the study received standard lymphodepletion comprising of 300 milligrams per meter squared of cyclophosphamide and 30 milligrams per meter squared of fludarabine IV once daily for 3 days. Patients received 3 doses of NKX019, one each on days 0, 7, and 14. This combination of 3 days of lymphodepletion followed by 3 doses of NKX019 is what we refer to as a treatment cycle. Efficacy was evaluated on day 28 of each treatment cycle based on standard disease-specific criteria. Leveraging the tolerability of NKX019, patients have the potential to receive up to 5 treatment cycles depending on response.
Having the ability to administer multiple treatment cycles gives us the opportunity to deepen responses in those patients who are showing a clinical benefit and to consolidate complete remissions with an additional cycle for those patients that achieve a CR. Another critical attribute of our trial design is that since NKX019 is available on demand, if a responding patient progresses, they are immediately able to be retreated to potentially reenter remission. As you can see, our study design is adaptive based on how patients respond, and this type of flexibility is only possible with an off-the-shelf treatment like a CAR-NK. To date, we have enrolled 19 patients on this trial. These 19 patients mirror real world CAR T patients who are heavily pretreated with a median of 4 lines of therapy and had poor prognoses. This international study enrolled 13 patients from Australia and 6 from the U.S.
14 of the 19 patients had lymphoma at study entry. Notably, 7 of these 14 had aggressive large B-cell lymphoma, 6 of which were DLBCL, and the remaining 1, a grade 3 B follicular lymphoma. 5 patients with leukemia were enrolled, including 3 previously reported patients with B-ALL and 2 new patients with CLL treated at the 1.5 billion cell dose. NKX019 continues to have a very encouraging safety profile. There were no cases of ICANS or other neurotoxicity or GvHD of any grade at any dose or any cycle. There were no grade 5 dose-limiting toxicities or treatment-related AEs leading to NKX019 discontinuation. There was a single grade 3 infection, which was the highest grade infection observed.
Myelosuppression that generally recovered as effects of the lymphodepletion wore off was the most common higher grade toxicity, regardless of a relationship, as summarized in the table on the right. 5 patients developed fever within 8 hours of NKX019 infusion, and each resolved within 24 hours. This contrasts considerably with CAR T-cell therapy-associated CRS, which has a median onset of 2-5 days and a median duration of 5-8 days. Patients with fever after NKX019 were assessed and managed differently by various investigators, despite somewhat similar clinical presentations. 2 patients were assessed to have infusion-related reactions, 2 were assessed to have CRS, and 1 patient had both assessed in 2 separate treatment cycles. There was a 1 case assessed as a grade 3 CRS in a patient with recently diagnosed pneumonia, who developed fever and hypoxia approximately 5 hours after her first NKX019 infusion on day 0.
The patient promptly improved with treatment and received doses 2 and 3 on time and without symptoms. No patients required invasive ventilation or pressor support. Of note, there was no apparent association between the occurrence of fever after NKX019 infusion and disease response, underscoring that clinical toxicity is not required for antitumor activity. We evaluated several key serum cytokines throughout treatment with NKX019. Median levels of maximum fold change throughout the treatment cycle was generally modest, rising just above baseline for most serum cytokines, or in the case of IL-15, not at all. This contrasts with elevation seen in patients who have had severe CRS as a result of CAR T-cell therapy, where multiple cytokines can exceed 100-fold increases above baseline. Here too, there was no apparent association observed between maximal elevation of serum cytokines and clinical response.
This table summarizes the responses observed in all 19 patients enrolled to date. First, take note of the top rows, which include patients with lymphoma, and the bottom rows, which details patients with leukemia. Responses were observed in all histologies of lymphoma treated in 1 or multiple dose levels. As disclosed previously, the 3 patients with ALL did not have a response. 2 patients with CLL new to this data update were treated at the 1.5 billion cell dose level. 1 patient did not respond, another achieved stable disease before coming off study per investigator preference. Looking at the lower and higher doses across columns from left to right.
Since our update in April, one patient with follicular lymphoma who was previously reported to have a partial response deepened to a complete response with an additional cycle, increasing the complete response rate in the 1 billion cohort to 4 out of 6, or 67%. 3 of the 4 patients with NHL treated with the 1.5 billion cell dose also achieved a complete response, resulting in a 75% CR rate for this cohort. In the 2 higher dose cohorts, we observed an 80% overall response rate and 70% CR rate in NHL, including a 50% CR rate for NKX019 monotherapy in LBCL. Moving now to the swim lane plot. The rapidity of responses, the advantage of the response adaptive study design, and early durability are all highlighted visually here.
8 patients have achieved complete response to date, including 5 after a single NKX019 treatment cycle. 3 additional patients deepened from partial response to complete response. Patient 1 after an additional 1 treatment cycle, as well as patients 2 and 7 after an additional 2 treatment cycles. Patient 9 had successive reductions in disease burden after each of 3 cycles and was taken to allogeneic transplant and partial response per investigator decision, and is currently in CR following transplant. In terms of durability, 5 patients had complete responses that exceeded 6 months, including patient 5 with large B-cell lymphoma, who has maintained CR for over 9 months. As we described in the study overview, a consolidation cycle is now available for patients who achieve CR after any cycle of NKX019. 7 of 8 patients who achieved CR received consolidation.
The only patient with a CR who did not receive consolidation was treated at the 300 million dose cohort before consolidation was available on protocol. 3 patients have had presumed disease recurrence, each after at least 6 months of complete response and none at the highest dose level. Each of these 3 patients and their respective investigators intend to pursue treatment with NKX019. Per protocol, they will each be treated with the recommended phase 2 dose of 1.5 billion cells per dose. All 3 will also be eligible for multiple treatment cycles as well as consolidation upon achieving complete response again. This waterfall plot shows the maximum change in tumor size after treatment with NKX019 and highlights that nearly every patient with NHL had reduction in tumor size.
One patient who discontinued therapy after a single dose of NKX019 did not have a follow-up evaluation for comparison. The two patients with partial response had considerable reduction in tumor size. As mentioned earlier, one was taken allogeneic transplant in partial response and is currently in CR, while the other had therapy discontinued following pathologic transformation of the underlying tumor, resulting in loss of both CD19 and CD20 expression. For patients with stable disease after cycle one had considerable reduction in tumor burden, and both were eligible for subsequent cycles of NKX019 treatment but were taken off study per investigator decision. The evaluation of pharmacokinetics of allogeneic NK cells is inherently challenging. Distinct from T cells, NK cells are limited in the peripheral blood and do not massively proliferate.
However, by measuring the NKX019 transgene in the blood, PK samples were drawn at several time points, and the Cmax, or peak concentration detected, was compared across dose levels. In general, higher cell doses correlated with higher Cmax across all subjects. In addition, higher Cmax also correlated with complete response at both high and low dose levels, while some complete responses occurred without detectable PK. Administration of successive rounds of NKX019 preceded by lymphodepletion is feasible and effective at achieving clinical response. Median time between treatment cycles was just over one week and was as short as 0 days. Patients are required to be admitted for observation for 24 hours after each dose of NKX019 for the first cycle, and outpatient administration is permitted for any cycle after the first, whether for deepening, consolidation, or retreatment after recurrence.
40% of such cycles occurred as an outpatient. Utilization of outpatient infusion has increased as centers and investigators become more experienced with NKX019. After we build a more robust safety experience, we plan to allow outpatient administration in all cycles as a part of a protocol amendment. We recently announced the opening of 3 dose expansion cohorts. Each cohort will use the 1.5 billion cell dose as well as an updated lymphodepletion regimen using a cyclophosphamide dose of 500 milligrams per meter squared per dose for 3 days. This change normalizes the lymphodepletion dose across the Nkarta platform and remains in line with what has been demonstrated to be safe with autologous CAR T-cells.
The first cohort will further evaluate the activity of NKX019 monotherapy in patients with large B-cell lymphoma who are CAR T naive, offering a cellular therapy option for patients who are currently unable to access or tolerate approved cellular therapy. We will be evaluating NKX019 in patients with large B-cell lymphoma who were previously treated with autologous CAR T-cell therapy. Among those patients for whom CAR T-cell therapy fails, over 90% of their tumors will still express CD19, allowing an opportunity to leverage the superior antigen recognition of NKX019 compared to CAR T-cells that we showed at ASH in 2021. We have opened a cohort combining NKX019 with the anti-CD20 antibody rituximab. Earlier this year at SITC, we demonstrated that NKX019 has enhanced tumor cell killing when combined with rituximab.
This cohort will be open to patients who are both CAR naive and CAR experienced. This concludes our remarks on the clinical data for NKX019. I would like to thank everyone for their attention and interest in NK cell therapy. I would especially like to thank Dr. Michael Dickinson for his participation this morning, his contributions along with our other investigators and their respective institutions, and most importantly, the patients and their caregivers who have trusted Nkarta with enrollment onto this trial. I'll now hand the call over to Dr. Nadir Mahmood, Nkarta's Chief Financial and Business Officer, for what lies ahead for NKX019. Nadir?
We are excited about the future of NKX019. As Dave mentioned, we have opened multiple expansion cohorts to advance this program, both as monotherapy and in combination with rituximab. We remain on track to enter potential registration-enabling studies in 2024, with the possibility of utilizing an FDA expedited program with Fast Track, RMAT, or Breakthrough Therapy designation. We ended the third quarter of this year with $395 million in cash, giving us runway into 2025. We have the potential for multiple NKX019 milestones over the next two years as the program advances through clinical development and plan to provide another update sometime in 2023. With that, I will hand it back to Paul to summarize.
Thanks, Nadir. Today, we presented data from an additional 6 patients that support NKX019 as an accessible, off-the-shelf CAR NK cell therapy candidate with encouraging antitumor activity and a differentiated safety profile. NKX019 can be available on demand when a patient needs it. It appears well-suited for use in the outpatient setting where unmet medical need is the greatest. We are already administering NKX019 on an outpatient basis in this clinical trial. The safety profile of NKX019 continues to be favorable. There were no DLTs, ICANS, neurotoxicity, GvHD, or CRS above grade 3. NKX019 continues to demonstrate encouraging single-agent antitumor activity. We had a patient with a partial response in our last update that later converted to a complete response, improving the CR rate of the 1 billion cell cohort from 50% to 67%.
With the addition of 4 new patients with non-Hodgkin's lymphoma, the CR rate for NKX019 at the 2 highest dose levels moved to 70% from the 50% that we reported in April. Out of the 10 patients now treated at our highest doses of 1 and 1.5 billion cells per dose, 8 responded and 7 achieved a complete response. 5 of these CRs were achieved after a single cycle of treatment. Of these 10 patients with NHL, 4 had large B-cell lymphoma and achieved a 50% CR rate, and nearly every patient treated with NKX019 had a tumor response. We've also shown the potential impact of using multiple treatment cycles of NKX019, with 3 patients with initial partial responses that have deepened to complete responses with additional cycles of treatment, as well as 7 patients who received consolidation cycles after achieving complete response.
Durability is early, we have already seen several patients with complete responses exceeding 6 months. The ability to give multiple treatment cycles also provides an opportunity to retreat any patient that may progress, we have 3 patients that have retreatment planned with a goal to push any patient with confirmed recurrence back into complete response. We will look at those retreatment outcomes at our update next year. NKX019 has the potential to be a transformative therapy for non-Hodgkin's lymphoma, we look forward to providing more updates in the future. Now we'll stop and open the call to your questions. Operator, if you would please review the instructions for the Q&A section.
If you would like to ask a question, please raise your hand using the Raise Hand feature button at the bottom of the black Zoom bar under Reactions. When it is your turn, I will call your name. You may unmute your line and ask your question. You'll now wait one moment while you join the queue. Our first question comes from Josh Schimmer with Evercore. Josh, you may now unmute your line.
Great. Thanks so much for taking the question, congrats on the strong data and update. A few questions for me. First, what additional data do you need to collect prior to being in a position to start the registration enabling study? A couple of other quick questions. Why were some of the patients with CRs showing tumor reductions that were less than 100%? Maybe you can help define what a CR consists of in the lymphoma setting. Why do you think you're not seeing responses in the acute leukemias? That seems to be a little bit different than the other CAR T. Thank you.
Okay, Dave, would you like that, those three questions?
Sure. Thanks for the questions. In terms of the acute leukemia questions, I think the numbers are still small. The leukemia question, the numbers are still small. I think both of the patients with CLL had some disease characteristics that made it particularly challenging to treat. I think it doesn't mean that's not, that's off the table. It's just, you know, I think a numbers issue. In terms of the regulatory strategy question, I think, you know, we're always in communication with FDA regarding the ongoing study. I think we're excited to open the dose expansion cohorts that we mentioned, and we'll let the data sort of lead the way in terms of that strategy.
I think that'll be the first step. In terms of the tumor reduction or incomplete reduction, that's a function of complete metabolic response and residual tumor and just an artifact of PET scan versus CT.
Yeah. Thank you.
Our next question comes from Dane Leone with Raymond James. You may now unmute your line.
Hi. Thanks for taking the questions. Congratulations on the progress. Two for me, just, I see a lot of hands raised here. Could you maybe take us through patient 5, which was the 1 billion times 3, large B-cell lymphoma patient that has a complete remission post month 10? The question there is relates to the treatments that they received. If you could just disclose how many cycles of treatment have they received and whether they got any consolidation treatment and maybe when they received that. I think people are just trying to understand time course of response and remission as a function of treatment intensity for some of these patients that are seemingly having durable responses. Second for me, a simple one.
In terms of, the expansion cohorts of the study, should we expect, additional, clinical sites to be opened, heading into 2023 here to maybe help with the cadence of enrollment, you know, versus the sites you're using right now? Thank you.
Yeah, thanks. First, patient 5, the patient with large B-cell lymphoma. Both patients with large B-cell lymphoma achieved complete response after a single cycle, and both were consolidated immediately thereafter. On the swim lanes, those circles represent disease response evaluations, not additional treatment. Both, in terms of that patient 5, patient 5 was reported and detailed in our previous update, and one of our case studies. In terms of the additional site and enrollment cadence, we feel pretty good about the sites that we have. Some of the enrollment has been related to, you know, stagger or dose escalation or evaluation between. We're obviously always looking at enrollment cadence, number of sites, et cetera.
We feel that interest in the study has been pretty good. I think we'll obviously do what we need to do to keep enrollment in the study going. We're encouraged what we've seen so far.
Dane, not having the stagger is the main driver of not needing additional sites right now.
Okay. Just one point of clarity, so I got that right on patient number 5. You're basically saying that post the presentation of that patient, in April of this year, they have not received additional therapy or additional cycles...
Correct.
of therapy?
Correct.
Okay.
One cycle of treatment and one cycle of consolidation only.
Okay, great. Thank you.
Thanks, Dane.
Our next question comes from Stephen Willey with Stifel. Steve, you may unmute your line.
Yeah, thanks for taking the questions. Congrats on the data. Maybe just a couple for me. On the PK side, is there anything that you can say about the.
PK or the Cmax of cells that you're seeing administered in cycle 2 and beyond for those patients that are getting retreated. I don't know if you collect that information. I know that you're lumping together the 1 billion and the 1.5 billion doses, but do you see a meaningful difference between those two doses in terms of Cmax?
Thanks. The, you know, PK is inherently challenging, you know, and these are relatively small numbers. In terms of additional cycles, we haven't sort of broken that down, but I think what I'll say is, you know, I think we're encouraged by the clinical activity and, you know, PK generally follows that. Remind me your second question. I'm sorry.
it was whether or not you actually see a meaningful difference in Cmax between the 1 billion and the 1.5 billion doses.
Yeah. Again, small numbers, which is why we put them together. You know, I think PK, you know, we saw at least one complete response without detectable PK. I think we're understanding, trying to build our experience. We're including it for transparency's sake. You can see the trends here, but I think that difference between one, you know, 1 billion and 1.5 will, you know, the difference is small in terms of dose. You know, I think it's too early to tell. As we build more experience with the 1.5, I think we'll be able to tell that more effectively.
Right. Okay. I guess I asked the question because I think as of the April update, you had indicated that there was one patient with a grade one infusion reaction and a transient fever. It looks like the higher proportion of fever and maybe infusion-related reactions is occurring at the, at the 1.5 billion dose. Is that a safe assumption?
It's an assumption in the fact that those are the numbers. You know, there's a couple patients in there with CLL. I think, as I said, those patients were particularly challenging. I don't think it's a dose issue.
Just lastly, I know the tolerability profile here looks good. You're not seeing any real significant signs of grade limiting CRS or CRS at all. But in your discussion with, I guess, the agency around the protocol, have they communicated to you some proportion of either grade two or grade three CRS that would preclude outpatient administration?
Yeah. Again, we haven't yet got the granularity, that kind of granularity. I think as the safety profile becomes a bit more robust, we'll be able to talk about that. In terms of what we're seeing clinically so far, which is why we show the details of these presentations, we don't think there's anything that'll be restricting for outpatient administration.
Yeah. We also think that it's gonna emerge what this particular syndrome actually is, because it's clearly not classical CRS. I think with more time and more patients, we'll have a better handle on what that profile looks like, and we'll have obviously interactions with the FDA about that. We're not overly concerned that this looks like classical CRS with the same kind of worries that goes along with it so far in terms of treating these patients as outpatients has had no impact on this.
I have to go Steve Willey next, yeah.
Very good. Thanks. Taking questions.
Yeah. Thanks, Steve.
Our next question comes from Daina Graybosch with Leerink Partners. Daina, you may now unmute your line.
Hi. Thank you, guys. Thanks for the presentation. 2 questions from me. The first one is, could you help us by going through the 1.5 and 1 billion patients one by one and telling us what their prior therapies were? In particular, how many of these had received a prior CD19 CAR T or other CD19 therapy? The second question, following up on the nice PK discussion. It's interesting that you have a correlation with CR with your peak Cmax. I'm a little surprised by that. You have a high variability. Could you maybe discuss, you know, why you think you're seeing lower PK in some patients versus other patients and why that's correlated with the clinical benefit? Thank you.
In terms of the CD19 question, everybody in dose finding were intentionally CAR naive. All the patients you've seen so far will be CAR naive. The expansion cohorts will include CAR experienced patients, but everyone here is CD19 CAR naive. In terms of the PK, yeah, it's, you know, PK, this is early. We're gathering these data and letting the data lead the way. In terms of the Cmax peak and the correlation, we continue to think that the depth of response is really what drives durability and impact rather than sort of a slow persistence over time. If we're asked to sort of make hypotheses on that, I think that's probably it.
If we can drive the availability of active cells against the tumor, that's probably most meaningful than having them stick around for a long time.
Got it. Sorry. Back on the treatment question. I sort of meant broadly the treatment history, so if the patients are also naive. What should we know about these patients that they're enrolling, that they're CAR T naive in terms of their past treatment history?
These are, you know, this is a CAR T available environment. If patients are, you know, eligible or, and can, and access commercial CAR T, then they're, they can. Those that are CAR naive, you know, we know that only 20%-30% of patients that can receive or benefit from CAR T ultimately receive it, and there's challenges in terms of whether or not patients can be bridged or other factors that make CAR T appropriate. All the patients here, again, have seen at least two prior lines of therapy. Yeah, I think mirror a CAR T eligible population, certainly in the large, you know, among the large B-cell patients.
W e broke down a little bit in terms of the high-risk disease and follicular lymphoma and others. We feel like this is a pretty representative population.
Great. Thank you.
Our next question comes from Bennett Greasley with Mizuho. You may now unmute your line.
Hey, guys. Congrats on the data, thanks for taking our questions. I guess if you could comment a bit more about these non-classical CRS cases. How was their progression exactly? You know, was there any patient characteristics that may be associated with it? Also, is there any particular Hodgkin's lymphoma subset that may be responding better or worse to treatment? I'm not talking here about lymphoma type, but like subtypes like ABC, the LBCLs or GCB. Thank you.
Sorry. Bennett, let me just be clear there. Nobody here.
Sure.
what we consider classical CRS but we l et you know what we think we saw here. Dave?
Yeah. In terms of those patients with, you know, fever after infusion, you know, we're obviously trusting investigators and you know that in terms of their assessment. They're very familiar with cell-cellular therapy. When patients develop fever, I think, you know, it's sort of what they're accustomed to calling these things. I think as Paul mentioned, this is clearly not classical CRS. In terms of their course, the reason we put the such detailed description is to understand this as a clinical entity. These are all patients that actually appear pretty similarly, which is fever within the first few hours of infusion that responded pretty promptly.
By the time, you know, 24 hours came and went, you know, these patients were more or less back to their clinical baseline. That's the, you know, There's a fair amount of granularity in that those descriptions, and we did that intentionally so that you can see how these patients progressed.
Okay. About the any lymphoma subset?
Oh, yeah. Yeah. I mean, what we've seen is, you know, it. For one, they're small numbers, right? We're in. We intentionally enrolled a broad group of B-cell malignancies and different histologies, and we're encouraged that we could see activities across different subtypes. You know, we've seen responses in follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma now. Importantly, you know, of the patients that we've treated with large cell lymphoma, they seem to, you know, we're encouraged that both of the CRS came after a single cycle. Yeah. It would be too early to say that one over the other or in terms of sub. You know, once we start slicing subtypes of subtypes, then I think it gets even less meaningful.
We're certainly encouraged that the activity in large cell lymphoma, and some of the other, more difficult to treat diseases.
Okay. Thank you, and congrats again on the data.
Our next question comes from Yaron Werber with Cowen. Please unmute your line.
Great. Thanks for taking my question. I've maybe just a few just to understand. In the consolidation, I'm sorry if I did miss this. You can only get 1 more consolidation regimen, or can you get more than 1? Secondly, it sounds like you've treated 6 new patients, right? It sounds like 4 of them responded and the 2 that didn't respond, I'm referring to slide 13, were they CLL and ALL patients? Finally, on slide 17, can you talk about on the bottom right side, when you talk about the isotype there, related to toxicity, what do you mean by that specifically? What exactly are you expecting in combination with Rituximab? Do you expect better activity in CAR T naive or in CAR T experienced, and how does that relate to CD20 loss? I know it's a lot of questions. Thank you.
We wrote them down, so we're good. Let me try and knock these out. In terms of consolidation, it's one additional treatment cycle beyond complete metabolic response. It's whatever X number of cycles it takes to get to no residual disease, it's one more than that. One consolidation cycle beyond, and that includes lymphodepletion. In terms of the 6 new patients, you're right. The 2 that did not respond were CLL. The 3 patients with ALL were in the last data update, treated at either 300 million or 1 billion, and we've disclosed those previously. The 2 patients included here that did not respond did have CLL.
In terms of the figure from our SITC presentation, in that bottom right corner of slide 17, the iCEP is meant to be an antibody control versus adding a CD20 monoclonal antibody with rituximab. The activity there, you know, whether or not it's more beneficial in CAR T naive or CAR experienced, we think potentially both, right? So long as a, you know, obviously rituximab will target CD20. Our NKX019 will target CD19, so we have potential there for dual antigen targeting. We know that rituximab, or NKX019 drives ADCC through rituximab, and we presented those data. It's just sort of a summary there in that combination results in an enhanced tumor killing.
That cohort is open to both CAR naive and CAR experienced. We have a reason to believe that even in monotherapy we'll have activity in the CAR experienced. The rituximab combination, we're gonna see its effect on both safety and efficacy because that will be open at the same 1.5 billion cell dose and we won't have to repeat dose expansion.
Okay. maybe another way to also ask the question. you've seen an ORR of 83%, right? in patients who are treating at $1 billion plus and $1.5 billion plus, it was essentially 3 out of 4. you only had 2 patients so far did not have any response, and I guess it's, you know, kind of 3 patients out of 10 didn't have CR. What do you know about the CD19 or the CD20 at baseline in those patients that didn't respond? Thank you.
We're evaluating the, you know, strength of staining, et cetera, and pattern of staining as a part of exploratory analyses. Patients are required to have CD19 expression at study entry, and, you know, We have a CD19 targeted product. We wanna make sure that that target is still there. The same with the combination cohort. Patients' tumors will still need to express CD20 to be eligible. In terms of that, you know, I think what you're asking is, you're already at a higher CR rate, what can we add with rituximab?
I think the idea is, one, we wanna make sure that, you know, some of it may not become available immediately or the benefit may not be available immediately, say in, you know, maybe in durability that it has a potential impact by driving deeper responses. It may have an impact on safety. I think that's why we wanna make sure we explore it. It's... Rituximab has been incorporated into the landscape of NHL therapy so broadly that we felt it was our responsibility to see that combination impact.
As we develop this drug, if it continues to hold this kind of CR rate at monotherapy, we will pursue both monotherapy and combination therapy registration-wise.
Do you need to be CD20 positive also for the Rituxan regimens at baseline? Thank you so much.
Yes. Yes. CD19 for everybody. CD20 for the combination cohort. CD20 loss, as you know, can occur and CD20 expression is not required for the CD19 only monotherapy cohorts.
Our next question comes from Matthew Biegler with Oppenheimer. You may now unmute your line.
Hey, guys. Thanks for the question. I was curious about the use of Tocilizumab because it looks like it was only used in 2 patients if I saw the numbers correctly. Maybe if I could just squeeze in one for Dr. Dickinson. I realize it's small numbers, but is that less Tocilizumab use than you would expect? Thanks.
Michael?
Sure. You know, I don't think, as you've heard, I don't think the syndrome that we're seeing is typical for cytokine release syndrome. Where I've seen it in my patients, it's been a very, very short-lived simple fever that has occurred. It's been associated in time with the infusion, in that the infusion occurred first and the fever occurred some hours down the track, but it was largely self-resolving, and didn't require really any intervention. I think if I recall correctly, my patient that stands out had paracetamol on 1 occasion. It really did not feel like cytokine release syndrome to manage. I think...
I can't comment really on the use of Tocilizumab in the particular case that's being asked, but certainly where I've seen this in my own hands, we've not needed to use it. I suspect what happens is that people see cellular therapy, see a fever, and reach for Tocilizumab pretty easily, probably as a surrogate for whether this is cytokine release syndrome. The use of Tocilizumab even in that individual case is not really a good indicator because this doesn't have other features of the cytokine release syndrome to my mind.
I guess dovetailing on that, Paul, do you think that the safety is the main competitive advantage that we're seeing here? Obviously CD19 CAR NK, it's very competitive. We're not hearing anything from KLS about supply constraints right now, particularly in large B-cell lymphoma. I mean, what's kind of the pitch here for you guys? Is it the safety maybe allowing use in the community setting?
I think it's as we've been saying all along, Matt, if we have similar efficacy and the safety that Dr. Dickinson just explained to you he's seeing with his patients, that means these patients have access to therapy. That means they have access to multiple rounds of therapy. It means they have access to repeat therapy even if they relapse six months or later after they've received therapy. Absolutely, there's a great safety advantage, but the bottom line is patients need access to these cells, and NK cells are exquisitely available for more than one use and for use over long periods of time.
Yeah. Got it. Okay, thanks.
Our next question comes from Sami Corwin with William Blair. You may now unmute your line.
Hey, guys. Congrats on the data, and thank you for taking my questions. I have a couple of quick questions, and then one about the, you know, interesting safety signal you're seeing. What was the average time from enrollment to treatment? What is kinda the timing of the consolidation dosing relative to the time that the CR was achieved? With regard to the safety signal you guys are seeing, I mean, any hypotheses on what's causing that? Do you think it's dose-related or something intrinsic about the NK cell biology? Did all of them occur on the first cycle of treatment? Thanks.
Okay. Did you get those? Yep.
I think so. Thanks, Sami. In terms of the cadence of enrollment to dosing, that when our investigators want to treat, they can. Sometimes a patient will a investigator will say, "Hey, I've got a patient with really aggressive disease. I'm gonna do this scan in a couple of weeks, but I don't think they're gonna respond. I wanna be ready with NK one-seven-nine." There isn't that delay. Sometimes we're approached earlier and patients will sign consents or something like that. The availability is essentially instantaneous. If the physicians want to use it's, you know, we can get them on. In terms of the timing of multiple cycles.
I think I said the median is 8 days. That's pretty consistent across cycles. You asked about the timing consolidation, that would apply. In that sort of 1-week timeframe is the median, but it's as short as 0 days. In those cases, investigators have gotten so familiar that, you know, patients will receive cycle 2 almost regardless. If you have a complete response after cycle 1, cycle 2 will be consolidation. If you have a very good partial response, cycle 2 will be to deepen. We can have that plan ready to have T minus 5 of cycle 2 be the same as the response day of cycle 1. It's pretty seamless.
In terms of the disease, this fevers around the time of infusion, we're still learning on that in terms of what that is. It's clearly in terms of is it the disease biology? It's clearly not T-cell biology, because that's that sort of delayed onset, delayed extended duration, which we're just not seeing. I think it would be hard to posit too much on what's going on there, but I think it's related to the infusion of the product. I think it's reasonable to assume that it's part of the infusion. Beyond that, I would...
The numbers are so small, only happened in a few patients, and again, including them for the sake of transparency, but has not really been a major clinical entity for us.
Again, if this kind of efficacy holds, Sammy, with this kind of safety profile, it tells us that we're in the sweet spot between $1 billion and $1.5 billion in terms of phase 2 dose.
Great.
Dave you wanna add something?
Yeah. I mean, I think infusion-related reactions are common. You know, I mean, even rituximab has a black box warning for infusion-related reactions. I think that this... You know, having something around the time of infusion is, I think to be expected, occasionally. Again, even then, the numbers are small. I don't expect it to be limiting.
Great. Thanks, guys.
Our next question comes from Gil Blum with Needham. You may now unmute your line.
Good morning, everyone, thanks for taking our questions as well. Maybe a clarification. We talked about approximately 5 potential cycles of treatment. How many times can you give conditioning?
The protocol allows up to five. I think we, you know, we haven't gone into the granularity of who's got how many cycles, but I think you can follow some of that with the swim line in terms of deepening of response or not. I, we have not found lymphodepletion at these doses to be limiting. W e importantly stay within a realm of lymphodepletion that considered to be standard, and have intentionally not elevated that because once we get into the higher doses of cyclophosphamide, additional days of cyclophosphamide or fludarabine, I think toxicity does become a real concern.
We wanted to stay within a range of lymphodepletion doses that have been demonstrated to be safe by the autologous CAR T-cell therapies and other past experience. I mean, we feel in terms of our safety profile, that this is a patient population that was pretty heavily pre-treated beforehand, you know, including intensive chemotherapy and other sort of new age therapies. Although they're CAR T-naive, we had some patients that had seen a, you know, more recent agents. We really have been able to deliver multiple cycles of lymphodepletion effectively. I think the answer is how many can they get? 5 according to the protocol, but as many as they need to get the deep durable responses we're seeing.
It might make sense to ask Dr. Dickinson to give us a little bit of his perspective on the importance of lymphodepletion and the relative risk and reward of giving it with these patients, given these multiple cycles, given that you've had these kind of patients.
I mean, at the doses that are currently being given, the best analogy would be the use of FC or FCR as a treatment regimen in low-grade lymphoma, where there's a long-standing history of giving multiple cycles at very, very similar doses. In that situation, traditionally we would give 6 cycles. That's, that's falling out of favor in routine care, particularly in the US these days, but, you know is where I practice still a standard of care.
Now in the cellular therapy setting, what I don't think we're seeing with this agent is the sort of CAR T associated cytopenia that you see after standard of care CAR T treatments, where you may have very sustained cytopenia lasting after giving products like axi-cel or tisi-cel, that would then preclude a further lymphodepleting cycle of treatment or cytotoxic chemotherapy for patients who aren't in a complete remission. Here, the kinetics after giving lymphodepletion are not really dissimilar from giving that particular combination outside of a cellular therapy context. Count recovery is fairly reliable and as has been articulated in a center that's got its logistics sorted out, you can deliver a second cycle or a third cycle generally on time.
There will be inter-patient variability, so patients who are very heavily treated before going onto the trial may tolerate repeated cycles of FC less well. It's a very different context from sustained cytopenias that you might see after a single cycle of FC followed by CAR T-cells. Here it's much more reminiscent of a typical, you know, short-lived cytopenia that you see after conventional cytotoxic chemotherapy in routine use.
Yeah. Gil, let me just add that what you just heard from Dr. Dickinson is what we've heard from all of our investigators. There seems to be a trend for people to say we should do away with lymphodepletion. I think anyone would say the least amount of toxicity to deliver a patient would be the best. When we talk to our investigators, we and they believe that lymphodepletion is absolutely essential for cell therapy and for cycles of cell therapy. That's our position, and we're gonna stick to it.
All right. That was actually very, very helpful. Thank you. Maybe an additional question. Was there any relationship between kind of that fever, AE that you guys saw and a response in patients?
No. No, it doesn't seem like. It seems it's more idiosyncratic. Again, very small numbers and it's, you know, small numbers of small numbers. No, it does not appear that any kind of toxicity is required for a response, which we were certainly encouraged by or cytokine elevation itself.
Okay. That's helpful. Kind of a last one. You mentioned pivotal studies probably in 2024, but is there no option for accelerated approval off of your expansion cohorts given you're looking at some, you know, CAR T experienced patients? Thank you.
Yeah. Gil, we're gonna look at all the options we have in front of us as the data emerge. We won't leave a stone unturned. I think with that, we're at the time we have, and we really appreciate everybody's. Did you wanna add? Yeah. We really appreciate everybody's attention this morning. We're very excited about the data. We're looking forward to updating you on these data in 2023. Really, really thanks for the questions. Dr. Dickinson, thanks for calling in from Australia and answering those questions. Really appreciate it. Take care, everybody.