Nektar Therapeutics (NKTR) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Nektar Therapeutics Investor and Analyst Event. [Operator Instructions]. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Vivian Wu. Please go ahead.

Thank you, Crystal. Good morning, everyone, and thank you for joining us on today's analyst call to discuss the potential role of IL-15 within the cell therapy landscape to review data presented for the NKTR-255 program at the 2022 American Society of Hematology Annual Meeting. Before we start, I'll remind you that this presentation includes forward-looking statements regarding Nektar's drug candidate, NKTR-255 and other potential drug candidates, clinical trial results, the timing of the startup and plans for ongoing or planned clinical trials with partners, the therapeutic potential of our drug candidates, the timing and outcome of regulatory decisions and future availability of clinical trial data. Because these statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict and many of which are outside of our control. Actual results could differ materially, and these statements are subject to important risks and uncertainties set forth in the Form 10-Q that we filed on November 4, 2022, which is available at sec.gov. We undertake no obligation to update any of these statements, whether as a result of new information, future developments or otherwise. A webcast of this call will be available on our IR page at Nektar's website at nektar.com. On our call today are Nektar's team members, Dr. Mary Tagliaferri, our Chief Development Officer; and Dr. Mario Marcondes, our Head of Clinical Development at Nektar Therapeutics. In addition, we are privileged to have here with us today our guest speaker, Dr. Cameron Turtle, who is the Chair of Cancer Immunotherapy at the University of Sydney, an affiliate of the Fred Hutchinson Cancer Center. Dr. Turtle spent 16 years at the Fred Hutchinson Cancer Research Center serving as Professor of Medicine and attending physician specializing in treating blood diseases with cellular immunotherapies. He is a leader in the field of immuno-oncology and novel T cell therapies and has led many clinical trials evaluating CAR-T cell therapies. Dr. Turtle designed the investigator-sponsored Phase I trial of NKTR-255 at Fred Hutchinson Cancer Research Center, and we are very pleased to have him with us here today. So here's our agenda for today. To start off, Mary will review the NKTR-255 data being presented at ASH 2022. Dr. Turtle will provide an overview of the cell therapy development landscape and rationale for combining NKTR-255 with CAR-T cell therapies. Finally, Mary will review the ongoing planned studies of NKTR-255 in combination with CAR-T cell therapies. Then we'll open event to any questions from the audience. And with that, I will hand the call over to Mary.

Thank you, Vivian and thank you everybody for joining us early this morning. We appreciate it. There are 3 pillars to our strategic development plan with NKTR-255. And today, we'll cover the data supporting the ability of NKTR-255 to augment antibody-dependent cell-mediated cytotoxicity or ADCC of monoclonal antibodies. In addition, Dr. Turtle will discuss the strong biological rationale for combining NKTR-255 with cellular therapies. And finally, our third pillar is combining NKTR-255 with checkpoint inhibitors to enhance the immunological response in the maintenance setting of advanced bladder cancer in combination with avelumab and in stage 3 non-small cell lung cancer post chemoradiation in combination with durvalumab. Next slide. IL-15 is a potent immunostimulatory compound. This is because IL-15 is a growth factor for lymphocytes and leads to development, proliferation, activation and survival of NK cells, cytotoxic T cells, memory T cells, and it does all of this without affecting T-regulatory cells. The problem with recombinant IL-15 is that has a very short half-life of roughly 2 hours. Our approach in the design of NKTR-255 was to leverage our deep expertise in polymer chemistry to change naturally occurring IL-15 into a molecule that can access the full biology of native IL-15. Here, you can see NKTR-255 is a stable mono-PEGylated conjugate consisting of IL-15 covalently bound to a single linear 40-kilodalton PEG. The design has a few key features. First, the PEG chain enlarges the hydrodynamic volume of the drug and is designed to result in a longer effective half-life and reduce clearance. This leads to improved PK and sustained receptor engagement and superior pharmacodynamics. Second, the polymer conjugation is covalently bound to the native IL-15 amino acid sequence with no immunogenesis and therefore, we avoid the risk for unwanted immunogenicity. Third, unlike engineered IL-15 agents, NKTR-255 preserves the binding to IL-15 receptor alpha as well as the common IL-2, IL-15 beta gamma subunits, maintaining the alpha dependency allows for trans-presentation and cross talk between antigen-presenting cells and immune-effector cells. Next slide. There continues to be an unmet need for novel agents that can boost natural killer cell population and function with the aim of augmenting efficacy of ADCC agents. At the top of the slide, you can see the mechanism for NKTR-255 to enhance ADCC in combination with antibody therapies used in both liquid and solid tumors and on the bottom of the slide, NKTR-255 can expand CD8+ T cells to improve CAR-T cell therapy. Next slide. Last year at SITC, we presented data from patients in the monotherapy portion of the ongoing Phase I study of NKTR-255 and heme malignancies. Today at ASH, we're presenting an update of preliminary safety, efficacy and biomarker results from the ongoing dose escalation part of the Phase I study of NKTR-255 in late-line heme malignancies as well as preliminary data from patients who are treated with NKTR-255 in combination with daratumumab. NKTR-255 monotherapy was evaluated at doses ranging from 1.5 to 12 micrograms per kilogram. We also evaluated NKTR-255 plus subcutaneous dara in patients with relapsed or refractory multiple myeloma who have progressed on multiple prior lines of treatment. Our new monotherapy data set includes a total of 22 relapsed or refractory patients, including 14 patients with multiple myeloma and 8 with non-Hodgkin lymphoma. In addition, we'll show the biomarker data from the first cohort of patients with relapsed or refractory multiple myeloma treated with NKTR-255 at 4.5 micrograms per kilogram plus DARZALEX. The study is enrolling a heavily pretreated patient population with a median of 4 prior lines in the NHL cohort and 6 prior lines in the multiple myeloma cohorts. Enrollment is currently ongoing for the combination cohort of NKTR-255, 9 micrograms per kilogram plus dara for patients with late-stage multiple myeloma. As you can see on this slide, NKTR-255 was well tolerated at doses studied ranging between 1.5 and 12 micrograms per kilogram as monotherapy and up to 9 micrograms per kilogram in combination with dara. Most of the treatment-related adverse events were transient and low grade. These short-lived AEs tend to resolve either spontaneously or with antipyretics or antihistamines. To fully characterize the safety profile of NKTR-255, patients were not permitted to receive concomitant premedication during the first cycle. That said, no dose-limiting toxicities were observed, no patients required dose reductions and no patients discontinued NKTR-255 due to a related adverse event. Serious AEs are shown a no high-grade cytokine release syndrome or infusion-related reactions have been observed to date. You can see with the ability to administer premedications such as Tylenol or Benadryl and that was allowed in the combination cohort in cycle 1. No patient treated with dara followed by NKTR-255 experienced a grade 3 or higher treatment-related adverse events. Now I want to highlight the important data on this slide. Consistent with the design and therapeutic benefit of an IL-15 targeted agent, NKTR-255 monotherapy resulted in a notable expansion and proliferation of both natural killer cells and CD8+ T cells. At 9 micrograms per kilogram, NKTR-255 monotherapy achieved a 17-fold increase in the absolute number of NK cells and twofold increase in CD8+ T cells in the first 2 cycles of treatment. Sustained proliferative activity of NK and CD8+ T cells was seen across multiple cycles, indicating no evidence of tachyphylaxis or exhaustion. Here, we show treatment with NKTR-255 monotherapy resulted in a substantial increase in 2 different markers of NK cell activation across multiple cycles with single-agent NKTR-255. Now transitioning to our combination data shown on this slide is an analysis of 3 patients treated with NKTR-255, 4.5 micrograms per kilogram one day after the administration of daratumumab. As expected, daratumumab caused a substantial contraction of NK cells including the CD16+ NK cells that play a vital role in ADCC mediated cytotoxicity. NKTR-255 administered one day following resulted in a fourfold expansion of the NK cells, including the CD165 positive NK cells. Hence, NKTR-255 was able to fully rescue dara's depletion of NK cells. Now looking across multiple cycles of NKTR-255 following dara you see the NK cell expansion is maintained in this heavily pretreated patient population. All patients had 3 or more prior lines of treatment and all show disease stabilization. So in summary, the combination data provides proof-of-concept data for the mechanism of action for NKTR-255 because of the unique consequence of DARZALEX to deplete NK cells. This occurred since dara as the CD38-targeting antibody also depletes CD38-positive NK cells in addition to the pathogenic tumor cells in multiple myeloma. Since NK cells are the critical immune effector cells that execute the ADCC mechanism, restoring NK cell levels during dara treatment may be important to enhance efficacy. Now returning to the monotherapy data. This graph was presented at ASH last year. The patient data shown was generated by Dr. Turtle and his colleagues at the Fred Hutch Cancer Center. The figure shows patients enrolled to the monotherapy dose escalation study who also had CAR-T therapy as one of their prior treatments. Three of the patients received the CAR-T cell therapy well over a year before enrolling in the NKTR-255 study and all the patients had minimal -- next slide -- sorry. Thank you. I appreciate that. 3 of the patients received CAR-T cell therapy well over a year before enrolling in the NKTR-255 study and all the patients had minimal detectable levels of CAR-T cell cells at baseline. And remarkably, all 4 patients with detectable CAR-T at baseline experienced a substantial increase in their transgene cells after treatment with NKTR-255 monotherapy. These compelling data reinforce our conviction that there is an important role for NKTR-255 as a CAR-T cell potentiator. Now in our study, we were also able to see the effects of NKTR-255 in patients who had previously received off-the-shelf allogeneic CAR-T cells. And these data were generated by Dr. Larry Fong at UCSF and indicate that investigational allo CAR-T cells administered 5 to 7 months prior to NKTR-255 monotherapy were also expanded by NKTR-255. Importantly, these biomarker data suggests there is no allo reactivity to the off-the-shelf allo CAR-T cells undergoing clinical investigation. Interestingly, you will also see NKTR-255's ability to expand the allo CAR-T cells was maintained in subsequent cycles in 2 of the patients with available data. So in closing, the new data we are presenting today at ASH are consistent with the preliminary results from our solid tumor study. In our dose escalation trial in solid tumors, we have observed a consistent increase in natural killer cells as well as CD8+ T cell across patients with late-stage colorectal cancer and head and neck cancer. Across tumor types, we also see that the PK profile is favorable and highly predictable allowing us to dose NKTR-255 every 3 or 4 weeks. These summarized results highlight NKTR-255, optimal profile that supports our 3-pronged development plan. Today, we're extremely fortunate to have one of the world's foremost experts with us to discuss why NKTR-255 has the potential to potentiate cellular therapies, our biological rationale to pursue this path is based upon our early clinical observations as well as a number of preclinical findings from Dr. Turtle's lab, and with that introduction, I will turn it over to Dr. Turtle, to provide an overview of the cellular therapy space as well as a review of the preclinical data combining NKTR-255 with CAR-T cell therapies. Dr. Cameron?

Thanks Mary. Vivian, do you have the microphone? The mic, yes. Okay. So I'm going to talk to you today a little bit about my field, which is adoptive T-cell therapy and how NKTR-255 maybe an asset for this field. So adoptive T-cell therapy really refers to taking immune system T cells from a patient or other sources. And then in vitro generating a population of tumor reactive T cells that can be reinfused back into the recipient. This is not a new idea. It's been around for decades using this approach at the top, in which polyclonal cells would be repeatedly stimulated with antigen often over the course of 2 to 3 months and then reinfused back into the recipient. And there were some spectacular responses with this approach, but they are sporadic in few and far between, not really a mainstream option for further care. But more recently, we've had these advances in genetic modification of T cells that allow us to really very rapidly introduce the tumor antigen receptor, either a CAR or a T-cell receptor or other types of receptors and rapidly generate this tumor reactive population within a couple of weeks that can be reinfused into the recipient without that need for repetitive antigen stimulation and exhaustion. So we're going to focus on chimeric antigen receptors here. So these are synthetic receptors. And you can see the structure on the right-hand side of a CAR compared to the much more complex structure of a native T-cell receptor. So a native T-cell receptor is a highly polymorphic structure that can only result in T-cell activation when you have the right peptide presented in the context of the right MHC molecule. So this is basically a patient-specific situation. You can't develop a generic product using TCR-based activation that will be suitable for an entire population. Chimeric antigen receptors on the other hand, essentially, the majority of them use an antibody-based ligand binding domain, either a heavy chain only or a single chain variable fragment as shown here. So this is an MHC independent binding. So these products can be used in any patient without looking at their HLA type or the TCR clonality. So this ligand binding domain is fused to one or more intercellular T cell signaling domain such that when you get ligation of the ScFv with a tumor antigen in the case of large cell lymphoma, we're going to talk about CD19. You end up with full activation of the T cell and then killing of the target cell. So this is a new strategy despite ASH. I'm sure you've seen being swamped with discussions about CAR-T cell therapies. It's really only about 10 years old that these therapies have been developed. And what we're looking at here is progression-free survival data from 3 pivotal trials of 3 commercially FDA-approved products for patients with large B-cell lymphoma. And the key point here is that the sort of patients that were eligible for these studies were examined in a previous publication in a SCHOLAR-1 study, which was a meter analysis that showed that with conventional approaches, chemotherapy, transplant, [ and these sorts ] of strategies -- these patients only had a 7% CR rate with the standard of care. And those CRs were not durable. So really bad population of patients. When these patients were treated with CD19 CAR-T cells, you can see from the PFS curves, that there's a plateau. So again, this is a really a stunning result at the time to see that you could actually induce durable survival with these products. Despite the paradigm-changing outcomes of CAR-T cell products, there is still about 60% of patients who failed to achieve a durable CR after CD19 CAR-T cell products. So there's a lot of room that we have to try and improve on these strategies, and we need novel approaches to try and increase the CR rates and enhance the duration of response of CAR-T cell therapies. So what are the CAR-T cells doing? What we're looking at here is a figure that's just showing a number of days after CAR-T cell infusion. And then on the Y axis, we're showing the percentage of CAR-T cells in blood. And -- what you see is the sort of crescendo -- decrescendo response of the number of CAR-T cells in blood after infusion. And this is really mimicking what we would see with antiviral response. If you get a viral infection, T cell specific for epitopes and the virus are going to go up. They're going to kill -- eliminate the virus and then they're going to contract. So we're seeing the same sort of approach here. So what happens when the cells are transferred in vivo is that they [ hom ] to sites of antigen, you get CAR signaling, binding of the antigen to the ScFv and the CAR. That induces T cell activation with proliferation, cytokine secretion, you get elimination of the tumor. If you're going to get some side effects. This is generally when it will occur, 3, 4, 5, 6 days afterwards. And the idea is that after you get tumor elimination, you're left with this long-term surveillance population that prevents relapse. So the term living drug has been coined for CAR-T cells. And the in vivo dose, so the sort of area under the curve here, it really depends on a whole bunch of things. The cell dose that you infuse, how much tumor antigen is around, how much tumor is around, what type of lymphodepletion you use before you give CAR-T cells, essentially chemotherapy to make space for the T cells and other characteristics of the patient. So what I'm going to talk about now is the relationship of IL-15 to CAR-T cells and clinical responses, and the data that I'm going to present comes from a clinical trial that we did at Fred Hutchinson Cancer Research Center using an in-house manufactured CD19 CAR-T cell product. We use a CAR construct that's shown here that comprised an anti-CD19, FMC-63, ScFv, 4-1BB costimulatory domain CD3-zeta signaling sequence. So this CAR construct is the same one that's used in liso-cel. The CAR construct was separated by a ribosomal skip sequence from a truncated human EGFR. This is a marker of transgene expression that lets us follow the numbers of CAR-T cells in the patients. So the patients underwent a leukapheresis. Leukapheresis is split into 2 aliquots, CD4 and CD8 T cells that were separately transduced with the CAR expanded over 15 days, and then they were formulated in a defined composition 1:1 CD4 CAR-T cells to CD8 CAR-T cells and then infused back into the patient 2 to 4 days after lymphodepleting chemotherapy. I won't go into detail about the eligibility criteria, but these are patients with relapsed/refractory B-cell malignancies with no curative options. All adults, you can see that the response rates that we had here in line with what you would expect from a good quality CD19 CAR-T cell product. And if you need some late-night reading, there are plenty of references down there to keep you amused. So one of the critical things here is that the CAR-T cell counts that we see in the patient after infusion are closely associated with response. So this is work that [ Kevin ] how you did in my lab a few years ago. And these are logistic regression curves. And what we're looking at here on the Y axis is the estimated probability of any of these outcomes in the color-coated curves for any given peak of CD8 CAR-T cell expansion in blood on the left, CD4 CAR-T cell expansion in blood on the right. And I'll draw your attention to the very dark blue curve. This is the complete response by Lugano criteria in patients with non-Hodgkin's lymphoma in the study. And the main point here is that this is really a linear relationship between the probability of achieving a complete response and increasing number of CAR-T cells in the blood. So as you shift across to the right-hand side on the X axis, your probability of response is going up. So intimate association of CAR-T cell counts in blood and response. One of the things that we looked at was IL-15 and factors that might be associated with high CD19 CAR-T cell count. So this slide is showing a number of days after CAR-T cell infusion on the X axis. And then CAR transgene copy number on the Y axis. So essentially a number of CAR-T cells in the blood on the Y axis. And the color coded curves refer to tertiles of peak IL-15 concentration. So in essence, patients in the blue curve had the highest IL-15 concentrations in blood after infusion. Those in the red curve had the lowest IL-15 concentrations in blood. And you can see that the ones with the highest concentrations had much higher area under the curve of CAR-T cells compared to those in red. So really sort of a massive difference here in CAR-T cell numbers in the patients who had a more robust IL-15 concentration. And this is not the only data set that's showing this. There's a group at the NCI who showed an association between IL-15 peak concentrations and CAR-T cell counts, and similar finding with the area under the curve being high in patients who achieved a response, another group from looking at axi-cel also showed that patients who responded had higher IL-15 levels on day 0. So this association has been shown by a number of different groups. To close the loop, the next part of this is, well, how does the IL-15 concentration in humans actually relate to response at different levels of disease. The challenging part of CAR-T cell therapy is how do we fix the patients who've got high-risk disease. And LDH here on the Y axis is one of the strongest markets that we found that associates with poor response to patients who go into CAR-T cell therapy with high LDH levels don't do well, those who go in with normal LDH levels do much better. So these are contour plots in 3 different diseases, acute lymphoblastic leukemia on the left, chronic lymphocytic leukemia in the middle and non-Hodgkin's lymphoma on the right. The color-coded contours show the probability of achieving a response in each of these different diseases. So yellow here is a high probability of response, dark blue is a lower probability of response. On the X axis, we have the peak serum IL-15 concentration. And so you can see as you shift along the X axis, you're going from the dark color coding across to the lighter color coding. And the important thing is that not only at these lower levels of disease risk, so low pre-lymphodepletion LDH, you see this transition from dark to light. But you also see it up at these very high levels of LDH. So the association of IL-15 response is not just present in those with low-risk disease, but critically, it's also present in those with high-risk disease. So just to summarize the rationale of combining NKTR-255 with CAR-T cell therapy and other adoptive therapies, about 60% of the large B-cell lymphomas treated with CAR-T cells failed to achieve durable CR. That's with the current FDA-approved products. Poor in vivo CAR-T cell counts are a key reason for failure of CAR-T cell therapies in these patients showing high IL-15 levels promote higher in vivo accounts in a higher area under the curve of CAR-T cells, and also high IL-15 levels associated with better response rates in both high- and low-risk disease. So the conclusion here is that exogenous IL-15 supplementation is a logical way forward. So on the left-hand side, we have that same figure that I showed before that just shows the tertiles of IL-15 concentration being associated with CAR-T cell counts in blood. On the right hand is really a theoretical illustration of what we would be trying to achieve by using NKTR-255 supplementation. So in the black curve, we have the CAR-T cell counts. So CAR-T cells would be infused here on day 0, up against the Y axis. You see CAR-T cells would go up and then they would come down as we saw in the previous figures, with NKTR supplementation shown in the pink arrow, the intent is that you would actually dramatically increase this area under the cure here. So this pink shaded area is really the added benefit that you would get with NKTR-255 increasing the area under the curve of CAR-T cells. So the question is, how are you going to give IL-15. There's a lots of different ways you can do this. This is a study that we did in non-human primates. And what it shows is a comparison of the PK, the IL-15 concentration of the Y-axis time after infusion on the X axis in monkeys that were treated with recombinant human IL-15 or with NKTR-255. You'll notice that there are different dose levels here. This is essentially because the PEGylation in NKTR-255 increases the molecular weight. So this is designed to be an equivalent IL-15 dose. And you can see there's a really marked difference here with a much longer half-life of NKTR-255, 30.5 hours versus the 1.2 hours with recombinant human IL-15. So if you're using recombinant human IL-15 and you're trying to get area under the curve to support your CAR-T cells, you're going to have multiple Cmax spikes over and over noted here, as you repeatedly dosing at very short intervals, not really feasible in a clinical setting. So with that in mind, we then went to look at in vitro at how would CAR-T cells -- human CAR-T cells respond to NKTR-255. So this is a slide showing CD19 CAR-T cells stimulated with K562 cells transduced to express CD19, the target antigen. It's a bit of a complicated slide, but we'll walk through. We're looking at CD8 CAR-T cells at the top, CD4 CAR-T cells down the bottom. On the left-hand side, we're looking at BCL-2 expression. So BCL-2 is an anti-apoptotic molecule. So effectively, it's associated with better survival T cells, limited death of T cells. On the right-hand side, we're looking at fold expansion in vitro at the CAR-T cell, so essentially accumulation of live CAR-T cells in vitro. The pink versus gray refers to different antigen burdens. So this affected target ratio at the top, the pink basically refers to a lower antigen burden, the gray refers to a higher antigen burden. We also looked at multiple different effective target ratios. The message here is that as you go along the X axis from left to right with increasing concentrations of NKTR-255, you see dramatically increased BCL-2 expression in both CD8 CAR-T cells and CD4 CAR-T cells, and you also see markedly increased fold expansion, particularly the CD8 CAR-T cells, but also CD4 CAR-T cells with increasing concentrations of NKTR-255. The next question is that if we can get CAR-T cells to proliferate and survive in response to incubation with NKTR-255 in vitro, do that translate to increased antitumor efficacy in vivo? So we used this endogenic model here. And this is a sub-therapeutically treated model. So these immunodeficient mice were inoculated with CD19 expressing Raji tumor line up in the top left here. This was luciferase expressing tumor line. So we were able to take images of it and the color coding here is essentially the amount of tumor in those mice. We then treated the mice with a subtherapeutic dose of CD19 CAR-T cell. So this is a really, really low dose. Normally to induce clearance of these mice we'd use about 3 million to 5 million CAR-T cells per mouse. This is 800,000 CAR-T cells here. And then on day 6, we gave the first injection of NKTR-255 at 2 different doses, and then at weekly intervals with imaging to look at the tumor response. So on the right-hand side, you can see that the mice that received just PBS [ vehicle line ] basically had very rapid progression of the tumor and all the mice died. The mice that received the subtherapeutic dose of CAR-T cells did a little better at day 7. They had some evidence of clearance of tumors, but very rapidly, the tumor progression got away from and they all died. In contrast, the mice that received the subtherapeutic dose of CAR-T cells and NKTR-255 supplementation as described in the model, had really quite a dramatic improvement in tumor clearance. And it was a dose-dependent improvement. So you can see that supplementing NKTR-255 really dramatically enhance the efficacy of the subtherapeutic dose of CAR-T cells and both the mice -- both the cohorts of mice that received NKTR-255 had 100% survival in the experiment. So what are the CAR-T cells doing in these mice that received NKTR-255? Again, there's a lot of data on this slide. At the top, we're looking at CD8 CAR-T cells, at the bottom CD4 CAR-T cells left-hand side, we're looking at Ki67 as a marker of proliferation of those cells. On the right-hand side, we're looking at BCL-2, again, a pro survival molecule, and the X axis is the number of days after CAR-T cell infusion. This is a sacrifice experiment. So we're looking at cells in the bone marrow of sacrificed mice at these time points. And what you can see in pink here is that the mice that received CAR-T cells with NKTR-255 had higher proliferation of both CD8 and CD4 CAR-T cells at multiple time points after infusion, and they also had quite dramatically elevated expression of this pro-survival molecule BCL-2 when they received NKTR-255, that increase in proliferation and increase in the pro-survival molecule translated to accumulation -- increased accumulation of CAR-T cells. So here, we're looking at CD8 CAR-T cells, and we're looking at an increased absolute number and much better numbers of CAR-T cells in the NKTR-treated mice in pink versus those in black who just had CAR-T cells alone. And when you look on the right-hand side of the area under the curve, again, you see quite a marked increase. One thing to point out here is that these X axis are all logged and [indiscernible]. So we're talking about -- at these time points, we're talking about a hundredfold roughly increase, at this point about a tenfold increase at that point. So a very potent effect. And the last bit of data I'm going to show is just to demonstrate that the CAR-T cells after clearance of tumor actually still functional in the NKTR-treated mice. So this is the same model we talked about before. Mice who received tumor cells alone -- mice who received on the left column; in the middle column mice that received the subtherapeutic dose of CAR-T cells alone and in the right column mice that received the subtherapeutic dose of CAR-T cells and NKTR-255, and what we did was after day 35, we selected the mice that received CAR-T cells and NKTR-255 who had actually eliminated tumor. We then took those from -- that sort of that right-hand column down the bottom there, day 35. We then took those mice into a second tumor challenge. So on the right-hand side of the slide here, so these are the 4 disease-free mice who have been treated with CAR-T cells and NKTR-255. Both cohorts of mice here were then rechallenged with Raji cells. So the mice on the left-hand side we're naive mice treated with Raji cells. So you can see the Raji cells are still growing, and the outlook is as bad as it was at first with rapid progression and death of those mice. The ones that had previously received NKTR-255 had no evidence of tumor progression. You will note on the slide that there is drop out of 2 of the mice. These experiments -- rechallenge experiments are difficult to do because they take the mice out to quite a long age out from their initial CAR-T cell dose and they can develop xenogeneic GVHD, but the main point is that even with this sort of tiny residual population of memory T cells after the initial clearance of tumor, they were able to re-expand and eliminate a tumor rechallenge. So I'm going to wrap it up there. The main points are that although CD19 CAR-T cells are a paradigm-changing cancer treatment. There are still 60% of large B-cell lymphoma patients who don't get a durable CR and ultimately most of those are going to die of their disease. In large B-cell lymphoma patients, IL-15 is associated with high accounts in both -- a better efficacy in both high- and low-risk disease. As we've talked about, NKTR-255 is a novel IL-15 agonist that demonstrates favorable pharmacokinetics compared to native IL-15 in non-human primates. NKTR-255 enhanced proliferation and survival of competent human CD19 CAR-T cells and enabled better antitumor efficacy and immunodeficient mice bearing human lymphoma and treated with human CAR-T cells. So the ramp-up is really that the preclinical data provides strong rationale to support studies of NKTR-255 supplementation, not just in CD19 CAR-T cell therapy, but I think we really need to think of a lot of the newly developed adoptive immune cell therapies that are being studied at the moment. Thank you.

Thank you, Cameron, for a wonderful overview of the CAR-T cell therapy space. And as Cameron alluded to, there's a strong rationale for continuing to explore NKTR-255 with CAR-T cell therapies. And based on this body of research, Nektar has worked with its collaborators to initiate a number of studies in combination with CAR-T cell therapies. We currently have 2 studies underway with external collaborators to evaluate NKTR-255 in combination with CAR-T cell therapies. The first study is sponsored by Dr. Crystal Mackall, who is the Founding Director of the Stanford Center for Cancer Cell Therapy and is combining Stanford's Proprietary CD19/CD22 bispecific CAR-T cell therapy with NKTR-255 in patients with relapsed or refractory acute lymphoblastic leukemia. The second study is being conducted by Dr. Turtle's lab at Fred Hutch and is combining NKTR-255 with BREYANZI in relapsed or refractory large B-cell lymphoma patients. The goal of these 2 studies is to demonstrate the safety, PK and PD of NKTR-255 following CAR-T cell therapy in patients. Specifically, our objective is to demonstrate that NKTR-255 can increase the expansion and the persistence of CAR-T cells with repeated treatment. Additionally, the studies will assess the full safety profile of NKTR-255 when beginning treatment shortly after the start of CAR-T cell therapy. We expect to have the results from the first several patients in these 2 studies in 2023. Yesterday at ASH, Dr. Miguel Perales, the Chief of Adult Bone Marrow Transplantation at Memorial Sloan Kettering unveiled the trial design of our new Phase II/Phase III study in patients with relapsed or refractory large B-cell lymphoma. The studies of randomized, double-blind, placebo-controlled, multicenter trial of NKTR-255 versus placebo following commercial CD19-directed CAR-T cell therapy. During the Phase II dose selection component of the study, approximately 56 eligible patients with relapsed or refractory large B-cell lymphoma will be randomized following CAR-T therapy to 1 of 3 different NKTR-255 dose regimen or placebo, with approximately 14 patients in each cohort. The primary efficacy endpoint will be the complete response rate at 6 months. Key secondary endpoints include safety and tolerability, duration of response, the CR rate of 3 months event-free survival, progression-free survival, overall survival, PK and PD effects of NKTR-255 versus placebo. Autologous CAR-T cell therapy has transformed management of patients with large B-cell lymphoma. As Dr. Turtle pointed out here, despite this major advancement clinical responses with CAR-T cell therapies are not always durable and over half the patients receiving these therapies for large B-cell lymphoma will eventually progress. Hence, strategies to further improve the long-term efficacy of CAR-T cell products are urgently needed. Dr. Turtle also highlighted that high serum IL-15 levels are correlated with CAR-T kinetics and have been associated with the effectiveness of these treatments. Based on the preclinical and clinical data we've reviewed today, we postulate that NKTR-255 administration following CAR-T therapy cancer as a cellular therapy potentiator by enhancing both the Cmax and the AUC metrics for CAR-T cells. During the Phase III registrational component of the study, patients with relapsed or refractory large B-cell lymphoma following treatment with a commercial CD19-directed CAR-T cell will be randomized in a 3:2 ratio to receive either the selective NKTR-255 dose regimen from Stage 1 or placebo. All eligible patients will be treated with study medication starting 14 days after commercial CAR-T cell therapy and will receive up to 7 additional cycles of treatment administered every 3 weeks. The precise sample size and primary efficacy endpoint for the registrational part of the trial will be defined after the Phase II part of the study is unblinded, and of course in alignment with the regulatory authorities. The Phase II portion of the study will be conducted in the United States, and then we will expand ex-U.S. for the Phase III part of the trial. Our target is to start enrollment by the end of this year, and as stated in our Q3 earnings call, we are expecting initial data in the second half of 2024. And with that, I will open it up to questions from the room here in New Orleans and from the dialed in line, and let's start in the room. And I know that there's no chance for you to follow a fleet because it's freezing in this room.

That's true.

And I'm going to let Vivian be the moderator, the decision maker.

Greg Harrison from Bank of America. Thanks for the presentation and for taking the question. So is there a way to predict in advance which patients could be more likely to benefit from higher IL-15 levels? Is there a threshold or maybe having more IL-15 does or does not add incremental benefit? Or is this something that would ideally be given to all CAR-T patients?

Great. Thanks, Greg. Since Dr. Turtle has spent his large part of his career studying this, I'm going to turn this question over to Dr. Turtle.

Yes. I think it's a really good question. Short answer is we don't have the data. I think the data that we do have suggests that there's a strong association across all patients with IL-15 and response. So the initial studies we would look at supplementing in all [ corners ]. But part of the analysis of that would be to try and identify whether or not there were patients who may have had lower IL-15 at a certain time point who had a better increment with supplementation, see what their outcome would be. When you think about the outcome of supplementation, it's really to boost those CAR-T cell numbers in the area under the curve. And it's to me, quite plausible. I think why there's so much enthusiasm about these studies that all patients will hopefully be able to increase the area under the curve and benefit. I think what we need to do a little bit more work about is to look at whether different types of T cell dysfunction may respond better than others and whether we can sort of honing down a little bit on how the patients are going to go at that point. But that's something that once we've done these studies, we'll get additional information, hopefully, I'll be able to answer those questions.

Mara Goldstein from Mizuho. I just wanted to ask, given the short activity of IL-15 in its native form and the study design where you're giving cumulative doses. I wanted to ask a question about cumulative toxicity and what you might anticipate with that. And if within the context of the trial, you have the ability then to delay or dose down patients?

Yes. Thank you for the question. As you know, I mentioned that we have 2 ISTs underway evaluating NKTR-255 in combination with CAR-T cells. And so we were very fortunate at Stanford, they have gone and those patients at 2 different doses of NKTR-255 in combination with their proprietary CD19/CD22 CAR-T cell therapy. And I think both the FDA and we were very pleased to see that these doses were well tolerated in patients so far and nobody needed to stop treatment, delay treatment or decrease the dose. So while that is a possibility built in the protocol, given this early emerging data that we have out of our Stanford IST with Dr. McCall, we don't believe that there will be a problem with toxicity. Likewise, in our protocol in the eligibility criteria, patients do have to clear grade 3 toxicities at the time of dosing.

If you allow me to add, Mary, we haven't seen any toxicities as part of the dose escalation portion of the trial. So I think it's encouraging early results from the Phase I -- and I think, as Mary indicated, Dr. McCall is continuing to dose patients, no concerns. And actually, it was very helpful as part of the FDA negotiation for the Phase II/Phase III.

Great. Great presentation. This is Andy Hsieh of William Blair. Three questions, if you -- if I may. So first one for Mary. I'm just curious for the dara NK cell depletion. I'm curious if there is data that suggests that those patients who have been treated with dara and you see NK cell depletion actually have worse outcome compared to those who see a lesser extent. That's question number one. Question number 2 for Professor, Turtle. I'm just curious, is there a threshold that you can really delineate between patients in terms of the cell count, these patients will have very better outcome, and this is kind of the goal for 255 to achieve? And then lastly, maybe this is kind of a forward-thinking question. For those who had manufacturing failures that do not have the proper [ spec ] for infusion. Would this be a good rescue potentially in the future?

Thank you, Andy. I'll take the first one and Dr. Turtle can answer #2 and #3. So the short answer is yes. There are, and we can provide you with those publications. And then for 2 and 3, I'll turn it to you.

Yes. I mean -- so the second question about the -- is there a cell count threshold above which you've got a very high probability of CR and below which a low probability of CR. Short answer is there's not a single threshold, it's a continuum. And so that's why, in answer to your question earlier on, it was really that there is potential for all patients, hopefully, to benefit by shifting them along the higher cell count end of that curve. The other question about manufacturing issues. I think this is a really important point because we do know that there are failures in manufacturing their [ phases ] in products that pass release and says everything looks good, but the T cells don't function. And so I think that's one of the intents here is that we may be able to get some of these suboptimal T cells to actually enhance their function with supplementation, stimulation with IL-15. So I think that's a really good point. That's what we're after.

And Andy, in fact, over dinner Cameron proposed that clinical trial to us.

It is also separate proposal for -- we talked about lymphodepletion chemotherapy being given -- can we talk about that?

Yes. Yes.

So in the CAR-T cell therapy, you need lymphodepletion chemotherapy part of what lymphodepletion does is actually to increase the available cytokines to support the incoming CAR-T cells, one of which is IL-15. But chemotherapy is chemotherapy. No one wants to have that. So the question is, can we actually back off on lymphodepletion intensity or maybe even omit it completely and use NKTR-255 as the cytokine support, which would be a game changer with patients going through this sort of treatment. So that's a study that we're hoping to develop down the track.

Jess Fye from JPMorgan. With respect to the association between patients peak IL-15 levels in the CAR-T cell area under the curve, is it understood why some patients have lower versus higher peak IL-15 than others? Is that a function of other factors that could contribute to CAR-T cell numbers? Or has that been ruled out? And then second question, how do the NKTR-255 doses being studied in the clinic relate to the NKTR-255 concentrations that were associated with a more robust CAR-T cell expansion from Slide 33.

Okay. So the first question, you want me to take this Mary. So the first question was about whether or not we know who has high IL-15 levels versus lower IL-15 and what the cause may be. And the short answer is, we don't. We do know that we have some other interesting data when we look at different intensities of lymphodepletion chemotherapy. We get really high-intensity lymphodepletion chemo versus low-intensity lymphodepletion chemo. We actually see better responses in the patients who get high-intensity lymphodepletion chemo. And as a population, they have higher cytokine levels. The interesting thing is if you actually split that high-intensity lymphodepletion group into the ones who had a good cytokine response versus a bad cytokine response, the ones who do well are the ones who had a good cytokine response. The ones who do badly who have a poor cytokine response do badly. So the improvement in outcome that you see with high-intensity lymphodepletion is not the chemo. It's not the cytotoxic effect on the tumor. It's actually cytokine support that's available for the incoming T cells. So to answer your question, we don't know specifically what is causing some patients to have a poor IL-15 response versus a good IL-15 response. But the association of IL-15 and accounts and the response I think is strong enough to be able to test this hypothesis and the preclinical data that adding IL-15 exogenously will support those patients who aren't doing well. I've talked so long that I've forgotten your second question.

Great. Second question was just about how the NKTR-255 doses in the clinic relate to or drive comparable or different concentrations of 255 that were shown to have the most robust CAR-T cell expansion in the n Hirayama paper?

I think you're asking about equivalent dose in the preclinical model versus the human -- do you wanna take it?

Please go ahead.

So this is an immunocompetent model. It's not immunocompetent. It's actually immunosuppressed, NSD animal. So it's very hard to extrapolate the results that Cameron has done in the clinic because in the multimodal NK cell driven the toxicity, in humans the toxicity is driven by CD8. So -- and we push to the max. But I think the learning is actually is equivalent because we can actually make it extrapolation about the MOA, but it's very hard to answer your question, actually. Would you - to add to the sort of doses the studies that you guys already have in humans are going to inform us of the doses and the data that Mary showed about CAR-T cell expansion in those few patients who received 255 essentially at the wrong time, long after their CAR-T cells were given and you still see expansion of those CAR-T cells in patients, as I mentioned, who are getting 255 late, late, late after the CAR-T cell infusion. So I think the human studies are ultimately what's going to inform about dosing

[indiscernible] Yes. And the data that Cameron was actually referring from [indiscernible] NCI, where there is a tier about separation between the good responders versus the nonresponders. We are talking about like 120 picograms versus 40 picograms for the nonresponders. And we can do that kind of job for pretty much every single dose that we're exploring in the clinic, like 1.5, the 3, the 6 is like 10, 20 logs of magnitude higher with the correlative data.

And I think that's why we think this is a universal application that NKTR-255 could work with any CAR-T cell either any CAR, NK or any CAR-T cell to both increase and drive up the Cmax and expand persistence in the area under the curve. So we're really excited to have a compound that universally could be applied as a potentiator to cellular therapies.

And I think also what is fascinating about the role of IL-15 is actually dates back from the 90s from Steve Rosenberg data with TILs. So the first thing they were looking for patients -- melanoma patients that actually enter CRs or cytokines and chemokines. And they found that in the 90s that IL-15 correlated with durability of CRs of TILs, so -- which is also very interesting.

Jeff LaRosa, SVB. So one thing that stands out today is obviously all the optionality and directions you can go with developing 255. I guess, throw in another potential direction. I mean have you thought about T cell engager combinations. Would you get a similar potentiating effect with that activity that you would [ link ] with CAR-T? And related to that, this brings up, I know, some of the early data in expanding CAR-T cells in previously treated CAR-T patients that kind of brings up sequencing, which has talked a lot at this meeting. One thing [ distinct ] is Janssen has talked about adding their BCMA bispecifics after CAR-T to potentiate the expansion of the prior BCMA CAR-T. I mean do you see IL-15 working in that kind of related to the bispecific combination point, not just upfront, but maybe down line to what you thought about this? And just because I brought up these is -- do you see a similar rationale in multimyeloma as well as lymphoma?

Yes. Let me take this one. Actually, we work with [ Krina Patel ] that presents that KarMMA-2 trial, right? And one of the things that she observed as part of the dose escalation is that patients will receive bispecific and then they went to receive NKTR-255 in the clinic. They have a very different phenotype of T cells, and they have a very high collection yield before production of ABECMA, for example, a CAR-T cell. And why is that, we know that bispecifics when they're giving up front, they tend to exhaust CD8 and CD4 cells, CD3 as a whole. And what we are thinking here and she has this very good idea. I hope that she doesn't get mad with me, is that actually, she's thinking about resetting the lymphocyte compartment of this heavily pretended myeloma patients in order to be able to actually sequence these agents better because people avoid bispecific before CAR-T cells because you're basically messing up with the whole immune system, right? So I think 255 has shown this small data set that can actually improve the collection in yield for -- but this is just another idea where we can actually redirect the development of 255.

I'll take some phone questions now. I'll start with Chris Shibutani from Goldman Sachs, who is asking about the Phase II/III study design that utilizes a fixed dose duration for 255. And he wonders if there's room for exploring potentially longer dose durations for further potentiation, and then additionally, for the NK cell recovery data with 255 after dara were subsequent dara doses administered in that study. And how are you thinking about the ultimate scheduling of 255 treatment with respect to dara treatment?

We are actually -- there is a very good rationale why you want to actually -- once we enter CR, right, you -- if you achieve CR 6 months and this -- we are talking first about our Phase II, Phase III, right? You actually -- the durability of the CRs at 6 months are quite good. There's very few drops. So we believe that actually, if you give NKTR-255 and you maintain your CR 6 months, the likelihood of dropping that CR is very low and Cameron can speak to it. So this is one of the things why we believe that only 5 to 7 cycles of NKTR-255 [indiscernible] , but we will have the ability to actually look at this data before we open the Phase III. But I think since our primary endpoint, is also the 6 months, so it's important to keep that in mind, okay? In regards to the dara combo, we're actually giving DARZALEX FASPRO as per label. So we are keeping both agents going. So we have seen some durable responses. We're going to be presenting the data tonight. There is a poster, right, where we have some of these patients actually are 7, 8 months out in the combination of DARZALEX with 255. So I think it's exciting. I think we can maintain these [indiscernible] in the clinic. So our push in NK cells is sustainable across subsequent cycles. And I think that's very much.

We have a question from Roger Song of Jefferies. It's twofold. Mechanistically, does 255 only induce CAR-specific T cells, but not other types of T cells? And then how many fold increases of in vivo CAR-T do we think is needed to improve the response of these CAR-T therapies and their durability?

I'll start, and then I'll pass it off to Cameron. So the answer is that NKTR-255 has increased both CAR-T cells as well as endogenous T cells, and we see this as a very positive effect because when you look at the BREYANZI data, and this was presented in 2019 here at ASH, those patients who achieve with large B-cell lymphoma treated with BREYANZI, who achieved the CR, guess what, they also had elevations in their own endogenous CD8 positive T cells and those patients who didn't have increases in their own endogenous T cells didn't do well. And remind me the second part of the question, Jennifer. I know the cells. So it's interesting. I thought a lot about increase in CD8 CAR-T cells. And from Cameron's data, when you look at -- when you get to 1,000 cells per microliter, you see a very high potential for achieving a CR. And so it's interesting. It's very similar like a cholesterol test. If you can drive down your LDL, you really reduce your risk of an MI. Likewise, if you can drive up those cells to 1,000 per microliter, you saw that in Cameron's own data that he published, the probability of achieving a response is very high. So this is unlike solid tumors where you have to get those cells out of the blood through fibrotic tissue and into the tumor microenvironment. Here, the cells that you have, the CAR-T cells, in the blood are directly correlated with response. And as you can see from Cameron's data, there's a numerical value to that high probability of response. So I find this very encouraging for scientific rationale, and I'll turn it over to you, Cameron.

I don't have much to add other than that, that the association is really strong. So increasing the accounts is highly likely to increase your response rates for any individual patient to say, do you need to double it? Do you need to triple it, you need to add another 10 cells per microliter, I think it's really hard to say. But from the stimulatory data that we can -- we can see in vitro and the data from the human single-agent trials, I think it's quite achievable to increase those cell numbers to the point at which we will see increased response rates.

Our next question comes from Boris Peaker of Cowen, and he's directing it at Dr. Turtle. How do we know that the IL-15 concentrations are actually correlative to the proliferation of the CAR-T cells in a [ causeway ] and not an effective CAR-T cell proliferation, driving the higher IL-15 level.

That's a good question. I mean I think the [ Murin ] data would answer that. I think it's not known that IL-15 or the CAR-T cell proliferation alone will dramatically increase your IL-15, but it's not something that in our experimental studies we've specifically addressed, but I don't think that's the likely scenario here.

Yes. I can add something. So [ David Nicolas ] just published a paper looking at biopsies of patients actually that actually have durable CRs, and he did immunohistochemistry analysis and this was published in Nature like last month. And actually, one of the things that were interesting is that when he stained the biopsies for IL-15 receptor alpha is actually the patients who had CRs, they have more IL-15 receptor alpha and that was actually being secreted in the tumor microenvironment. So I think this provides some correlative evidence that the IL-15 is coming from the patients who have more cells that actually can produce. And -- but this, again, is a limited data set because it's only for patients who had available biopsy on the trial. But this is another hypothesis to explain the correlative work and who's making the IL-15.

The next question comes from Neil Carnahan from Stifel. Severe TRAE seem relatively infrequent and they resolved quickly. Does this mean you plan to continue to dose 255 higher in combination with dara or do you think you've achieved the maximum achievable NK cell activity with the doses that you've looked at already?

I think the 17-fold increase in NK cells was very telling for us that we were achieving the type of PD effects that we were eager to see. And so our dose exploration with dara is ongoing. And right now, we're testing 9 micrograms per kilogram. And what we'll be looking for is the type of responses that we see at this dose, and we'll continue to monitor these patients for their ability to tolerate treatment for a long, long period of time.

The final question comes from Cheng Li on behalf of Jay Olson from Oppenheimer. It's a twofold question. The first is, are there any stratification analysis for the Phase II/III study? And secondly, this goes back again to the higher IL-15 levels after receiving CAR-T, do we have a rationale for why some patients have higher levels and those who don't. I think we've answered some of that earlier with Jessica's question.

So in terms of stratification, we will stratify both by the product-type, liso-cel, versus axi-cel. And then we're also going to stratify by LDH 440 or higher LDH units per liter that is. Do we have any other questions? That's it. Great. Well, I'll turn it over to Vivian in a second, but it's really nice to see so many of you face-to-face. It's been a very long time. I think it's been pre-COVID since the last time I saw a lot of you. So we really appreciate you coming and enduring this very cold room without a winter coat. So thank you.

Thank you, Cameron for coming.

This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.