Good day. Thank you for standing by w elcome to the Vor Bio analyst call. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. After the speaker's presentation, there will be a question-and-answer session. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. I would now like to hand the conference over to your speaker today, Robert Ang, President and CEO. Thanks very much. I really appreciate your time in going through this new data. We think it is very exciting and an interesting time for Vor as we've continued to recruit patients and now able to look at other outcomes, including overall relapse-free survival. If we go through what we're going through today, I'm happy that Eyal Attar will be providing a clinical update. We'll also talk about a new update on our CAR-T program, VCAR33, and introduce a new asset, which is called VADC45. We also have the privilege of having one of our key investigators, Guenther Koehne, on the phone, who will be able to provide some remarks and answer questions. And so, just as a reminder, our clinical strategy has really been to create a therapeutic platform for Trem-cel, which is a shielded transplant upon which you can then layer around different therapies, including ADCs or CAR-Ts. As we have gone into the clinic, initially with Trem-cel, with Mylotarg, we've demonstrated some early proof of concept, but now have the ability to look at additional data, including outcomes data in our patients. And in addition, we are studying VCAR33 independently, which allows us to look at the efficacy of this first in human CAR-T program. As a reminder, it's very difficult to treat patients in maintenance setting after a transplant, T he transplant is still fragile as the patient's blood system is still recovering, and anything that is used to treat the cancer can be very toxic for the patient. However, the relapse rate can be really quite profound, and this is something that we want to address. So the question is Can shielding? actually lead to improved outcomes? By using a shielded transplant, can we actually change the way that these patients are treated and potentially how they may or may not relapse after the transplant? So there's four key outcomes that we're looking for that we'll be going through. Engraftment, again, that we've seen a consistent trend in the first eight patients that we released around ASH last year, but does that trend continue? Shielding, we last saw data at 0.5 mg of Mylotarg per square meter, and we now have data even at 2 mg dose. Looking at the therapeutic index of Mylotarg, we've studied the pharmacokinetics of different doses, which we're very interested to showcase for you and looking at patient benefit. As a reminder, Trem-cel is manufactured from standard apheresis material from healthy donors, where we select stem cells and then CRISPR engineer CD33 from these cells. We freeze down this product and that becomes Trem-cel, and we're very proud of the genome engineering and the success that we've seen in manufacturing of this product. With that, I will hand over to our Chief Medical Officer, Eyal Attar. Great. Thank you very much, Robert. I'd now like to begin by discussing the VBP-101 study, which is a Trem-cel study with, followed by Mylotarg in a phase 1, 2 setting. This trial is for patients with high-risk acute myeloid leukemia, who, based on adverse genetic factors, the presence of minimal residual disease or even active disease, are proceeding to allogeneic transplant. Patients with one or more of these risk factors historically have a 60% or 70% chance of relapsing and/or dying from their disease after transplant, as Robert has just alluded to. In this clinical trial, once a patient is identified and recommended for transplant, they're consented to the protocol, and an eight out of eight matched, related or unrelated donor is identified in standard fashion. While the patient receives consolidation or salvage chemotherapy to prepare for the transplant, the donor undergoes peripheral blood mobilization, and the apheresis product is taken to our manufacturing facility. Here, Trem-cel is prepared from isolated CD34-positive cells using CRISPR to delete CD33. An unmodified backup graft is also prepared for each patient. Importantly, after receiving transplant conditioning, the patient is infused with the Trem-cel drug product, and here we monitor first and foremost for neutrophil engraftment and platelet recovery. The patient is able then to receive maintenance Mylotarg once they reach day 60 following transplant. As Mylotarg, a CD33-directed antibody-drug conjugate, causes low blood counts when used in standard settings, we monitor for stable platelets and neutrophils as a measure of shielding provided by the CD33-deleted Trem-cel graft. In addition, we measure the Mylotarg PK to determine the therapeutic index of this ADC in this setting and the relapse-free survival to determine the potential impact of this treatment modality on the patient's relapse and survival. The Trem-cel drug product was generated for all 18 patients in this data cut successfully, and with a high degree of CD33 editing efficiency, the median being 89%. Importantly, we observed that the median time to neutrophil engraftment for these nine, for these patients was nine days, and that exceeds the benchmark median of 11 days for unedited CD34 positive grafts. The median time to platelet recovery for these patients was 16 and a half days, which compares with the benchmark median of 17 days for unedited CD34 positive grafts f inally, as anticipated, all of these patients had full donor myeloid chimerism when measured at day 28 and beyond. Now, in standard use for patients with AML, Mylotarg is associated with profound cytopenias. Patients are subject to low neutrophil and platelet counts, and in fact, several studies have documented that using Mylotarg after a standard transplant is associated with deep reductions in blood counts, and that's why it's never used in that setting. This figure provides the platelet counts in the top line and the neutrophils in the bottom line for patients in the VBP101 study who received post-transplant Mylotarg, with the day one corresponding to the first administration of Mylotarg, which is typically sixty to seventy-five days after the transplant. In this figure, each large icon represents a Mylotarg administration, and the individual lines represent the three Mylotarg dose cohorts of point five, one, and two mg per meter squared, assessed in this phase one dose escalation trial. These data, which represent forty cycles of Mylotarg administration across these patients, show stable platelet and neutrophil counts, consistent with successful shielding provided by the Trem-cel graft. Now, we then explored the Mylotarg exposure in the setting of Trem-cel, anticipating that the exposure would be unique, given Trem-cel patients have far less CD33 than standard AML patients and considering that Mylotarg, like other antibody-drug conjugates, is cleared upon binding to the corresponding antigen. The left panel here represents the AUC or area under the curve t his is the Mylotarg exposure parameter, which has been linked with response. The right panel represents the Cmax, which is the Mylotarg exposure parameter related to liver toxicity and the risk of veno-occlusive disease. Across these figures, the gray bars represent the population PK data presented in the 2017 FDA ODAC minutes, and the blue bars are from data in the VBP 101 study. Now, on the left, consider that the FDA-approved doses of Mylotarg are 6, 3, and 2 mg/m², depending on the indication. Here in the VBP 101 study, the area under the curve of Mylotarg at the 2 mg/m² dose is 90,000 nanograms per mL hour, and this actually corresponds to a Mylotarg dose of 9 mg/m² in the standard AML setting. Considering that the AUC is related to efficacy, these data are viewed favorably. On the right, the Cmax at the approved dose of six mg per meter squared is slightly over 2,000, and it's preferable in general for the Cmax to be under 2,000 because this is where the risk of VOD increases on the exposure safety curve. As you can see on the VBP-201 study, at two mg per meter squared, the Cmax is 1,000 nanogram per ml and well below the 2,000 safety threshold s o taken together, the increased area under the curve, coupled with the Cmax in the safe range, corresponds with a favorable broadening of the therapeutic index of Mylotarg in patients who have received Trem-cel. Now, we then sought to understand the outcomes for patients treated on this study. This demographic table provides information regarding the percentage of patients enrolled to the study who have these well-defined high-risk characteristics associated with increased risk of relapse after transplant i would just note that patients may have had more than one high-risk feature on this study. Note that 17% of the patients had active disease, which is defined as having 5% or more blasts. 11% of the patients had MRD disease, 61% had adverse cytogenetics, 44% secondary AML, and a quarter of the patients had P53 mutation. One recurring theme is that investigators have referred patients to this study who might not typically undergo standard allogeneic transplant at their institutions, just due to the overwhelmingly high-risk adverse features that some of these patients have, specifically active disease and P53 mutation status. The VBP101 as treated column reflects the group of patients who received maintenance Mylotarg therapy on this study, and their demographic features reflect the study population at large. Now, to place the outcome for patients on this study in context, we reviewed the literature for post-transplant outcomes for patients with high-risk AML, and you see that reflected in the last two columns. The data from Araki represents the MRD positive population of patients at the Fred Hutchinson Cancer Center in Seattle, who underwent allogeneic transplant and who all had MRD positive AML. The rightmost column represents data from one of the German groups, and this is data from patients who all had adverse risk by ELN criteria t hat's adverse risk genetics by ELN criteria. On the next slide, you can see the relapse-free survival curves for these different groups of patients t he blue line represents the RFS data for the 18 patient. R epresenting the ITT group on the VBP one zero one study, with a median duration of follow-up of approximately six months. The Iraqi data, represented by the red line, we're calling this is the MRD positives, published population, has a median RFS of 3.8 months, and the Genge data, again, that's the group of patients with adverse risk genetics by ELN criteria. It's represented by the green line and has a median RFS of 6.2 months. Although continuing to mature, the VBP101 RFS data appears favorable to these comparative studies, as the median RFS for the 101 study patients has not yet been reached. This is particularly intriguing considering only three of the patients at this point received the 2 mg per meter squared maintenance Mylotarg dose, as of this data cut. As patients are entering the study now are receiving 2 mg/m² Mylotarg, this data will continue to be followed very, very carefully. This swim plot provides the course for patients on the Trem-cel study, all 18 patients engrafted in a timely fashion, as represented by the yellow symbols. The red triangles represent the 40 cycles of Mylotarg, segregated according to the 0.5, 1, and 2 mg/m² Mylotarg dose cohorts. Please note that only two out of 10 patients who received Mylotarg experienced relapse, as indicated by the black circles. One patient was in the 0.5, and one was in the 1.0 Mylotarg dose cohorts. Both of these patients had TP53 mutations, and this is important because the TP53 genotype is associated with increased multidrug resistance and P-gp expression on the surface of leukemia cells, a known mechanism for Mylotarg resistance due to efflux of the calicheamicin chemotherapy payload. At the bottom of the swim plot, you see several patients who are recently transplanted and have not yet had the ability to receive Mylotarg, as they had not reached day 60. Two patients, both with high risk and active disease, relapsed prior to Mylotarg therapy, and you'll notice also that, among some of the earliest patients on the study, there was one instance of graft failure that occurred after an atypical coronavirus infection. Although this patient responded extremely well to the backup graft, the second patient with a blue box had an autoimmune platelet condition, which was treated with corticosteroids and ultimately a stem cell boost from the backup graft, to which the patient responded well. As these backup grafts are not edited for CD33, Mylotarg was not administered in either setting, as Mylotarg is simply too toxic to administer post-transplant outside of the Trem-cel setting. The first two rows here reflect the data from patients who relapsed prior to Mylotarg administration, and note that both of these patients had very high risk disease, as measured by the fact that they had 16% and 8% blasts, respectively, going into the transplant. The second two rows reflect the patients who relapsed after receiving Mylotarg. Note that while one of these patients had MRD with 1.8% blasts going into the transplant, the other had 78% blasts, really profoundly active disease going into the transplant. Both of these patients had P53 mutations, and both of these patients received the lower doses of Mylotarg on study, maintenance Mylotarg on study, 0.5 and 1 mg/m². Thus, it's hoped that at the exposures that are being observed on the study at 2 mg/m² that we could potentially overcome some of these Mylotarg resistance mechanisms i n summary, Trem-cel was successfully manufactured for these first 18 patients and grafted quickly. You know, the data it provided shows that immunologic protection and shielding was afforded across multiple cycles of the Mylotarg doses tested. The Mylotarg exposure here resulted in a favorable therapeutic broadening of the therapeutic index, but only two patients relapsing after Mylotarg, and the evolving RFS data appears favorable compared to published outcomes in high-risk AML. We'll now turn our attention to our next plans, which have to do with our development of a pivotal study. This potential registrational study will seek to enroll adult patients with high-risk AML, and in the experimental arm, treat these patients with a Trem-cel transplant to be followed with eight cycles of maintenance Mylotarg, much like you've seen in the VBP-101 study. A control arm would consist of either an observational matched control group or an active standard of care transplant, a prospective control group, randomized in one-to-one fashion with the Trem-cel Mylotarg arm. The primary point of the study would be the relapse-free survival, and of course, the overall survival of the median time to relapse, as well as the immunologic protection afforded by the Trem-cel graft from Mylotarg. Hematox would be studied very, very closely, and it's anticipated that this study would enroll approximately 60- 80 patients across the two arms o ur go-forward dose for Mylotarg is two mg/m² based on the ongoing VBP one zero one study, which is the dose to which the study is currently enrolling patients. Our second program in clinic is the VCAR33 allo drug product t his is a transplant donor-derived CD33-directed CAR- T, and what makes this drug product unique is that it is generated from healthy donor cells, which are fully matched to the patient, and this has the potential for improved expansion, persistence, and anti-tumor activity, compared to autologous products n ow, VCAR33 allo utilizes the same CAR construct, which is reported in a study from the National Cancer Institute in patients with AML, though in that study, the CAR-Tcells were generated from autologous patient cells. Importantly, in the NCI study, among five patients who were dosed at the highest dose, one times ten to the seven CAR-Tcells per kilo of patient. Among these five patients for whom responses could be assessed, two had complete remissions, as reported by the study group at the American Society of Hematology meeting in 2023. The VBP301 study design, in brief, is as follows. Here, patients who have relapsed after either a standard of care transplant or even a Trem-cel transplant are eligible for this study. The prior transplant donor is approached for collection of donor lymphocytes, and from this apheresis collection, the VCAR33 allo is generated. For the patient, following a period of lymphodepletion, patients receive VCAR33 allo and are then monitored for safety and response. Two dose cohorts, one for MRD-positive patients and the other for patients with morphologic relapses of 5% or more blasts, are enrolled in parallel. Among the three patients who have been dosed on study, who all received one times ten to the six CAR-Tcells per kilo, which is the initial dose on the study, CAR expansion was measured and detected by digital droplet PCR. The peak was experienced at day seven. These in vivo expansions in these patients are encouraging. The investigators continue enrolling patients, referring patients to this study, given the lack of available treatments for their patients, and we continue to generate more data for this study moving forward. Thank you very much, Eyal. So, just a quick update on a new asset called VADC45. This is a CD45 antibody drug conjugate. Now, CD45 is expressed ubiquitously throughout the blood system, and so this is an approach that could be potentially applicable to a number of different cancers. And in addition, this asset uses a linker payload that was licensed from ImmunoGen. It is the same linker payload from one of their assets, and so has actually been in several hundred patients. We think there's several potential applications for this, including heme malignancies, but also it was really purpose-built to be an asset, interestingly, in non-chemo-based conditioning. As we know, sickle cell and other genetic diseases require transplants, and it's difficult to use chemotherapy like busulfan, which can be oncogenic as well as cause sterility issues. So something like this could be very interesting in that space. In addition, immune reset approaches have been increasingly used in autoimmune conditions. Unlike, say, standard B-cell approaches, such as in CD19, this asset could provide a more holistic reset for the immune system, thereby could be applicable to a broader range of diseases. And lastly, we're exploring use of this asset using the Vor approach. So unlike CD33 and Trem-cel, CD33 appears to be biologically dispensable. CD45 is unlikely to be. However, we've undertaken an approach to epitope-modify CD45 that would allow preservation of this protein's function while altering the binding of this particular antibody. So a couple of data slides. This shows an engraftment model in non-human primates, where the stem cells have been genetically modified for the BCL11A therapeutic edit that is used in sickle cell today. What you see here is that there's very nice preservation persistence of gene-edited cells over a 52 week period in these non-human primates. Secondly, this slide shows that this CD45 can deplete multiple different immune cell populations. Certainly B cells on the top right, but also T cells, monocytes, and granulocytes t hat could be an interesting approach as a more holistic immune reset indication. Just in summary, Vor Bio, we really have a unique way that we've been approaching cancer cures. Trem-cel has now shown to have robust data across multiple doses and very interesting pharmacokinetics with Mylotarg, alongside early outcomes that look intriguing. We look forward to following these trends and potentially engaging with regulators soon to discuss a pivotal trial. Our VCAR33 program shows encouraging signs of in vivo expansion, and we look forward to pursuing that approach further along, as well as this new asset, VADC45. I will now invite one of our investigators, Guenther Koehne, to provide his perspectives on the VBP101 trial. ... Thank you. Thank you for allowing me to be part of it c an I be heard okay? Yes. Thank you, Guenther. Thank you. Okay. So thank you, everyone, and not to reiterate the exciting results that were just presented, but for me, as a physician scientist that deals with transplants and with patients with acute myeloid leukemia, these are exciting new steps t hat's crystal clear for me from my perspective, for many reasons, n umber one, as you heard, high risk AML, characterized by certain mutations such as TP53 mutation. Another one is a FLT3 mutation. These patients relapse after transplant, despite transplant, I should say, at a very high percentage. So we need to do something for this particular patient population. A limitation for all of these patients is to control the relapse. Now, as in other malignancies such as multiple myeloma or lymphoma, the targeting or maintenance treatment that is being administered in these patients has been limited for patients with high-risk AML, simply because the markers expressed on the leukemia cells are shared with the expression on the healthy hematopoietic stem cell. So therefore, these initial results, downregulating CD33 expression on the healthy hematopoietic stem cell by gene editing, as you just heard, allows therefore, the administration of maintenance treatments such as Mylotarg or specific targeting of donor-derived CAR-Tcells, targeting CD33, that is then expressed primarily by the leukemic cell population s o this is a real important step to control the relapse rate in patients with high risk AML. Another aspect that may not be so clear because it's more from my perspective or transplant physician, is that the platform of a Trem-cel or BP-101 transplant contains a chemotherapy-only regimen because three drugs, BuMelFlu, busulfan, melphalan, fludarabine, are combined to induce a platform for the transplant. That is other than it has been before, because total body irradiation was part of all the conditioning regimens. But I was one of the pioneers at my place at Memorial Sloan Kettering Cancer Center that introduced the chemotherapy-only conditioning regimen for this transplant, and with that, the tolerance of transplant is improved without affecting outcome i n fact, the quality of life is much better. In fact, the development of acute and chronic graft versus host disease is significantly reduced, which also then affects the quality of life t his platform for this BBP 101 trial is chemotherapy only, with limited risk of inducing graft-versus-host disease, and have to treat the graft-versus-host disease, and therefore have an ideal platform for post-transplantation immunotherapies or a targeting as this is the case with Mylotarg or the CAR-Tcells. These, I think, are additional aspects, and the results shown now are encouraging with respect to the safety of this approach, because as mentioned many times, I also published on BuMelFlu conditioning and engraftment, so the time to engraftment of the neutrophils and platelets is consistent with the data that we developed at Memorial Sloan Kettering Cancer Center i n other words, the gene-edited product does not inhibit or prolong engraftment data and therefore provides a platform for post-transplantation targeting. All in all, together, I think from my perspective, this is a really important and critical step forward. If there are any other questions to me, I'm ready to answer them, but I don't want to waste too much time. I hope I added to the information. Thank you. Thank you very much, Dr. Koehne, for your perspective. With that, we'd like to open it up for questions. Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. One moment for questions. Our first question comes from Matt Biegler with Oppenheimer & Co. You may proceed. Hey, guys. Thanks for the update today, and congrats on this engraftment data. First, Rob, maybe if you could just put the Mylotarg results into context, you know, as you think about a future Trem-cel plus VCAR33 combo, if that's still, you know, even the plan or maybe now, given the strength of the Mylotarg data, if you think, you know, you mentioned possible phase 2 design randomized. So if you think that maybe that's the better way forward. But also kind of as it relates to VCAR33, maybe serving in a more maintenance setting, you know, could we maybe make that leap based on the data that you have today? And my second question was for Dr. Koehne on, you know, whether these data would make him more amenable to prescribing Mylotarg, given, you know, as discussed, a lot of its shortcomings. Thank you. Thank you, Matt, for the question. We believe Trem-cel could be a therapeutic platform for patients, and that's ideally what we'd love to do, that it could enable multiple different therapies as indicated for these patients, that could have clinical utility in different settings. What we're seeing with Mylotarg, we think justifies at least initial planning and exploration into a pivotal design. We certainly want to continue to see this trend going forward, but we just find it very encouraging, which is why we'd want to start really planning these next steps. We certainly would love to do the same thing with VADC45. So the treatment system, as we had envisaged, could be both Trem-cel with Mylotarg and Trem-cel with VADC45 in a maintenance setting. Now, we still have homework to do. We would like to see efficacy with Trem-cel in the monotherapy setting prior to us moving into that maintenance setting trial, but that's something we still think has a lot of promise. And with that, I'll hand over to Dr. Koehne. Yes, thank you. So though the short-term answer, the short answer is I'm not concerned to administer post-transplant Mylotarg in this setting. As you know, and I think that's why you were asking, Mylotarg induced significant percentages of VOD in the treatment of acute leukemia and the combination, while it was then reduced to lower doses and was reestablished. But this exciting data presented by Eyal also indicates that two mg dose is totally well tolerated. And the question which I will not be able to answer, but whether or not it needs to be escalated further is one, as it has been tolerated s o from this perspective, I have no hesitation to enroll patients onto this trial with the administration of post-transplantation Mylotarg. Understood. Thank you very much. Thank you. Our next question comes from Carter Gould with Barclays. You may proceed. Good afternoon. Thanks for taking the question, and congrats on the data r eally exciting to see some of that RFS data today i guess, first, when you think about sort of the amount of data you'd like to see before you go to FDA, it sounded like you're gonna continue to enroll. Is there sort of like a certain number of patients at that two mg/m² dose of Mylotarg you'd like to be able to, you know, get out to, where those patients actually got Mylotarg and some level of follow-up? You know, I guess looking at the slides, it looks like only three there, and you had sort of a mismatch of you know, random occurrences that kind of sort of complicate things there s o is there a specific number? And then it sounds like you've sort of locked on to what you think your sort of Mylotarg optimization kind of looks like. Is that a fair characterization, and if you-- any additional work on that front? Thank you. Carter, this is Eyal. Thanks very much for that question. You know, we feel that we are in a very good position from the perspective of the Mylotarg exposure data. Because while you saw the data from three patients treated at two mg/m² as of that July 19th data cut, the trial continues to enroll at a very brisk pace, and even just several weeks after that, as you may know, we released that we had dosed the 21st patient on study. So the study continues to enroll at two mg/m², as our study team here, along with Dr. Koehne and the other investigators, seek to understand the Mylotarg exposure very well and understand the safety and the relapse-free survival for these patients on the study. We feel that we have enough to approach regulators with these preliminary trial results, and gain input regarding study design, and all the other elements of the potential pivotal study, that we would like to conduct. Thank you. Our next question comes from David Nierengarten with Wedbush. You may proceed. Hey, thanks for taking my questions i have a couple. Just first off, on the demographics, it seems, you know, important to remember, you know, the demographics of these patients, the baseline demographics a nd so I was wondering if you could maybe put into context the expected kind of relapse rate in the patients treated here in the study. And then, for the CD45 program, if I could have a second question. We've seen, you know, kind of selective conditioning approaches in CD45, you know, be attempted, I think, in investigator-sponsored studies before. And I was just wondering, you know, what the differences were with this construct with maybe some of the other academic efforts. Thanks. Yeah, David, thanks very much for the question. And what I'd like to do is address a couple of these key factors and then also have Dr. Koehne comment on the kinds of outcomes that would be expected for patients with this demographic profile on the clinical trial. You know, David, just reviewing, we segregated the data according to the active disease MRD, the adverse genetic risk, secondary AML, and P53 mutations. These are well-documented, high-risk features for patients with AML. And as you know, many of the patients had more than one adverse risk feature. Comparing them to publications, which will often focus on the outcomes of any one particular factor, is really the opportunity that the literature provides a nd so that's why we selected what we thought. Where the highest risk factor, that is the MRD positive group of patients, and there the benchmark is the Iraqi data with the median RFS of slightly under four months, as well as this gent data, which is from patients with the adverse risk genetic groups by the ELN criteria, where the median time to relapse is about six months. Our best estimate for groups of patients that have this demographic profile is that the median time to relapse is in the four- to six-month range, maybe the four- to seven-month range after a standard transplant. It is that data compared to the experience of the VBP-101 patients at this point in time that makes us enthusiastic about the outcome for the patients on this study m aybe I can ask Dr. Koehne Can you comment on expected time to relapse for patients with some of these high-risk features as you see in the 101 study? Yeah, Eyal, thank you. I agree with the numbers you just mentioned i think, unfortunately, most studies have not really differentiated the high-risk diseases from the not so high-risk disease or intermediate risk diseases to assess these outcomes separately, but TP53 mutated and FLT3 mutated AMLs, regardless of the transplant approach, have a very short progression-free survival. And therefore, like you mentioned, four- five months, I would concur with this, and unfortunately, on this study, as you mentioned, there were two patients with TP53 mutated AML that relapsed prior to the Mylotarg, that is within, you know, transplant prior to day 60, so this basically gives us an idea how high risk of this disease is and how quick the disease may recur. Therefore, as you mentioned also, the MRD monitoring is really critical t hat will allow to interfere earlier, if need be, and therefore, the day 60 of Mylotarg may not really be, you know, the earliest time point that can be administered. But I'm also looking forward for more results with the administration of the donor-derived CAR -T-cells that will certainly be administered to patients at early relapse and will hopefully extend the progression-free survival and therefore also overall survival. Thank you for that context, Dr. Koehne. And, David, let me just address your question on the VADC45, if that's okay. And, you know, I think that this is potentially a very, very important asset for the four indications that Robert had discussed earlier in this presentation, owing to the fact that this antibody can, in fact, bind to all of the isoforms of CD45, which, as you know, is expressed across leukocytes. The payload and linker here, which are from ImmunoGen, have been used in the antibody drug conjugate bound to CD123, which is in development for patients with a BPDCN. And thus, it really gives us confidence in the safety and tolerability of this linker payload. Furthermore, the non-human primate data that you saw, which really shows comparable engraftment of edited grafts compared to busulfan in non-human primates, really provides a lot of very strong evidence. That this could be used certainly in conditioning strategies with the hope that it could preserve fertility, that it would have less toxicity, and there is preliminary evidence that really it does go in that favor a nd finally, the payload here is not a radionuclide, and I think that the chemotherapy payload really is favored here just for ease of use in the clinic and in the hospital setting. David, and this is Robert. Let me just add to say that this is an asset that is the very same asset that Cynthia Dunbar, John Tisdale, and Lisa Olson have published on previously. It was developed at Magenta Therapeutics, from which we adopted the asset and have further developed this. It has been... The chemistry has been such that to design it with a short half-life, which really speaks towards its application in as a conditioning agent, where you don't want any of that drug around as the new graft is engrafting. And then we have pushed further the preclinical experiments and have all the more confidence over and above the datasets from the academics and from Magenta that this is an asset definitely worth developing. Great. Thank you. Thank you. Our next question comes from John Miller with Evercore. You may proceed. Hi, guys. Thanks for taking my question, and congrats on the updated results here. I've got a couple myself l et's start with this. If you do decide to pursue a Mylotarg-based registrational study, can you give us some context around timeline there? And how much could that accelerate Trem-cel's time to market, relative to waiting for the CAR-Tto proceed? And then relatedly to that, to that potentially registrational design, you've spoken in the past about shortening the delay after Trem-cel before giving Mylotarg, and obviously, that's important given the early relapses some of these very poor prognosis patients are having, even visible in the data that you presented today, but I noticed the proposed registrational trial also cites a 60-day delay before giving Mylotarg after Trem-cel, so what are the pushes and pulls around that number? Are there other ways that you could avoid early relapses in a potential registrational trial, whether it's Mylotarg follow-up or CAR -T, changes to inclusion criteria or endpoints that prospectively look only at the dosing window for the follow-up therapy, something like that? Thank you, Jonathan. So, let me tackle the first question, then I'll hand over to Eyal for the second. So, potentially being able to start a phase three trial or registrational trial with Mylotarg, it would be a dramatically accelerated timeframe compared to waiting for the CAR -T. As you know, we've dosed three patients with the CAR -T. We think the kinetics of the expansion are encouraging, but we get to see CRs. As such, we certainly have some homework to do to escalate the dose of the CAR-Tand see evidence of that, as well as really verify its safety before we then justify putting that into a maintenance-setting trial, Trem-cel, followed by VCAR33. And so I think but however, we now have in hand some encouraging data with Mylotarg that we think can justify this potentially pivotal design. Let me hand over to Eyal to talk about the 60-day timing. Yeah, absolutely. And what I'll do is make a few comments and then also ask Dr. Koehne to comment on that. But you know, John, this is a very important question a nd in fact, the study lead, Dr. Raffel and I, and Dr. Koehne, were just discussing this yesterday, in that we are you know, potentially enthusiastic about bringing the Mylotarg on sooner than day 60, provided that this can be conducted safely for the patients s o far, it looks like you know, the starting point of day 60 is extremely safe? for these patients. We are continuing to enroll to the study, as you know. We're continuing to enroll to the two mg per meter squared maintenance Mylotarg dose and plan to work with Dr. Koehne and the other investigators to carefully review the data. And determine what is the safest path forward to administer the Mylotarg early, while still avoid any potential, you know, toxicity to the graft. So far, we're absolutely not seeing that, and so we're optimistic that we'll be able to make a modification like that, provided it's in the patient's best interest b ut Dr. Koehne, do you have some comments about the potential to move Mylotarg sooner? I'm looking forward to the study to perform this, but to administer it at an earlier time point to prevent early relapse, in addition, but we need to study it, of course, as you just mentioned. In addition, there is not necessarily a strong push to start at necessarily, I say, at two mg from a two-mg dosing at an earlier time point i f tolerated, fine, but it can also be a dose escalation, starting with a lower dose and then gear up to two mg at day 60, for example. Those are all ideas that I have right now and that can be discussed and tested. But what didn't really come through today, that is, I think is a really critical observation in two or three patients, that the neutrophils and the engraftment, the cells engrafted after the transplant, had certain percentages of CD33 positive cells still a nd after the introduction of the Mylotarg, these cells disappeared, and the CD33 negative population rose up to close to 100% which indicates that Mylotarg does something to the residual CD33 positive cells. And that provides me with the hope that it also does something to residual leukemia cells that we cannot measure at an early time point post-transplantation, that will likely prevent the relapse, as we have seen in patients that tolerated it well starting at day 60. But all of that taken together really prompts me to think about and to suggest to consider moving the Mylotarg at an earlier time point, be it at a lower dose or if tolerated, at the two-mg dosing. Thank you, Dr. Koehne. Great, thank you a nd if I could squeeze in one more follow-up. I noticed there's no VCAR33 patients at this point o f those three patients that you presented today, none of them are post-Trem-cel, at this point. So how are you approaching making sure that those patients are available for the VCAR33 study, which I know that they're part of the protocol, but what limits the availability, the ability to get those post-Trem-cel relapses that you do see onto VCAR33 and onto that study? I'll go ahead and take that question. And John, it's a very good question. Of those four patients who relapsed after Trem-cel, one of them relapsed before the VCAR study was even open. Certainly, we have tried to maximize the ability of any patient who relapses after Trem-cel to go on to VCAR, and we've done that by having near complete overlap of clinical trial sites that offer both the Trem-cel protocol a s well as the VCAR33 protocol s o that's what we've done. A nd the investigators overlap in their entirety, so they're intimately familiar with both protocols and can work with us to shuttle the patients across, and make VCAR immediately available for them o ne of the components here that's really important to note is that when patients relapse after an allogeneic transplant. In many instances, and particularly for an early relapse, that's a relapse that's occurring within the first 100 days. Unfortunately, the lifespan for those patients can be measured in days or weeks, and there's often not time to put them on any kind of clinical protocol, including a protocol where we go back to the donor to obtain healthy cells in order to generate the CAR-Tfor them. So, we are keenly following the Trem-cel patients alongside their investigators and making VCAR33 available for them wherever possible. If I may just add, these patients will come, unfortunately, unless this new approach really has a cure rate of 100%, which is unlikely to be expected, but the relapses of these high-risk population patients will occur, and that would provide then the administration of the CAR-Tcells to these patients. Alternatively, there would be a limited approach, as Eyal just mentioned, the lifespan is really very short, and they are post-transplant i t's difficult to give them more chemotherapy at this time point, so the platform, and as you likely all know, the development of therapies are all focused on immunotherapeutic approaches away from additional chemotherapy. Yeah, and John, well, I'll just add one more point, which is to say that, we, in conjunction with the investigators like Dr. Koehne, have worked on a strategy to develop the VCAR33 Allo, at risk and save it for the highest of, the Trem-cel patients, in case, they do relapse down the line t hat is to prophylactically manufacture it and have it available. So that's a strategy that we don't have in motion at this moment in time, but it's something that, we have, strongly considered, and taken steps toward. Okay, thank you very much. Thank you. Our next question comes from Jack Allen with Baird. You may proceed. All right, thank you so much for taking the questions, and congratulations on the data. Maybe I'll start with a question for Dr. Koehne. Thanks so much for your providing the context around the data. I guess my question is around your experience with Trem-cel and how it fits into the treatment paradigm. I'd love to hear about how the product is procured and any kind of major differences you see as it relates to the ease of use of this graft as compared to a non-engineered stem cell transplant. Then in that context, what kind of clinical benefit you'd look to see from this program in order to adopt a therapy like Trem-cel? Yes, thank you for this complex question b ut, my experience is very extended through the establishment of CD34 selected allografts, which I pioneered at Memorial Sloan Kettering Cancer Center. As I mentioned before, introducing the chemotherapy-only conditioning regimen that in combination leads to the platform that we have here. My experience with the modified product is based on patients that I treated here at my center in Miami now for high-risk AML and, in fact, high-risk myelodysplastic syndrome. The encouraging data that I experienced is that the patients tolerate this gene-edited transplant equally well as compared to the non-gene-edited product s o there are really no differences in terms of tolerance or outcome in terms of the engraftment, which is really very, very encouraging s o that obviously leads to the safety that I mentioned, that, that I wanted to see first. And, with no limitations or no changes and, engraftment of neutrophils at day 9-11 and platelets at day 14-16 is, equal to what we saw with the non-gene-edited, product. I'm not sure this answers your question, but... No, no, it's very helpful. I guess, just in the context of such strong safety, what sort of clinical benefit would you be looking for from this product to see strong adoption of Trem-cel and Mylotarg regimens? Well, the benefit is now the option of having a maintenance treatment possibility that you would not have without the gene-edited product. So for me, the first most important information is that it's very safe to administer these products to patients with leukemia, with high-risk AML, and therefore provide a new platform to specifically target or maintain the patients in remission with Mylotarg, or the option of having the v CAR-Tcells as an alternative for treatment of early relapse or relapse. Or maybe at some point, even once we know the CAR-Tcells are effective and safe, which I believe they will be, to administer those VCAR cells for minimal residual disease positivity, that is, very often the case in these high-risk AMLs coming after transplantation. Got it. Got it. Thank you so much, and thanks so much for all the context on the data. Maybe just one last brief one for the company as well. When do we expect to see additional data from the Trem-cel program? And then also, just a logistical question on the CD45 ADC program, how close is that to entering the clinic as well? ... Yeah, thanks, Jack. So, we haven't provided a guidance of the next data update yet, but we aim to do so soon. And the VADC45 program is finishing IND-enabling experiments. Got it. Thanks so much. Congratulations again on the data. Thank you. Thank you. Our next question comes from Stephen Willey with Stifel. You may proceed. Yeah, good afternoon. Thanks for taking the questions, and congrats on the update. Not sure if you can speculate, and I appreciate the color around potential registrational trial design, but not sure if you can speculate just how receptive regulators might be to the use of an observational control group in the proposed trial design. And whether you think a randomized trial using a more traditional standard of care control arm would provide you perhaps with more traction just on the utilization and commercialization front. And not sure if Dr. Koehne has anything to add there. I'll go ahead and take that question, Stephen t hanks for bringing that up. You know, we would like to explore the opportunity to have a observational, perhaps a, database cohort, of which there are several important databases that have outcomes for patients who have undergone transplantation within the country. We would like to explore the possibility of that serving as the control arm for this study because of speed and cost. But we're also well aware that there are some trials, registrational trials in progress with other products that do in fact use a standard of care, active, prospective, control arm. And so we are aware that that is an option, and it does in fact have several advantages from the perspective of generating contemporary data against a standard of care, against which we can benchmark ourselves for both regulatory and commercial purposes s o these are all important topics that we plan to discuss with regulators. Okay, and I guess just to follow up, in the utilization of a standard of care control arm, and I'm not sure about how those other trials that you referenced have been designed, but would those trials or this trial also allow for the utilization of post-transplant maintenance of off-label targeted therapy? At this point, our current thinking is that in order to best simulate the real world setting, against which we hope Trem-cel and Mylotarg would indeed provide benefit, you know, we're aware that while there are no FDA-approved post-transplant maintenance therapies for AML, we're aware that some off-label use does occur, and it tends to occur in certain high-risk genetic groups like P53 mutant, or in groups such as IDH1 mutant patients or FLT3 mutant patients, where there are addressable, targetable lesions. So to best simulate the real-world situation, we imagine that a small portion of patients on the standard of care arm could potentially receive maintenance therapies at the investigator discretion. And of course, we would power the study appropriately to account for that. Okay, that's helpful. And then, maybe just on the patient enrollment front, I think you pointed out that an additional three patients have been dosed since you last made a disclosure, regarding the progress made in the trial, at least relative to the cutoff date that's in the presentation a nd just wondering if we think about that rate, which I guess appears to be maybe about a patient per week, how extrapolatable? is that through the year, through the end of the year? Specifically, I guess, in the context of whatever the manufacturing capacity of the company is right now. Hi, Steve. So we have a theoretical manufacturing capacity of one per week. However, that is ideal in terms of not counting any process development runs or engineering runs that need to happen or planned shutdowns at our manufacturing facility. Our investigators and our medical team here do a phenomenal job of air traffic controlling all the interest coming into our study. And as you can anticipate, sometimes patients may not be able to stay enrolled on the basis of, you know, their disease or other factors regarding transplant eligibility. So I think what we'd like to communicate is very strong enrollment and very high interest in the study as we continue this year and move into next year. All right. Thanks for taking the questions, and congrats. Thank you. Our next question comes from Silvan Tuerkcan with Citizens JMP. You may proceed. Thank you. Congrats on the data, and thank you very much for taking my question. Maybe one question for Dr. Koehne. Can you please, you know, in light of the fact that there may have been some patients enrolled here that may not have otherwise received a transplant. And also the fact that the preconditioning may be slightly different, can you comment on the magnitude of difference in the survival rates that we see at this early time point? I I mean, to me, it seems like we're moving to the direction of probably a survival of like different risk groups here. If you could just talk to that, that'd be great. Thank you. I'm not sure I'm able to answer. So can I refer this question to Eyal? He has the breakdown on the patients. Sure. And so, you know, Silvan, this is a really good question. We are not at a point now of being able to disclose the outcomes for the specific groups of patients. I'm recognizing that these are small numbers of patients. And certainly, as we continue to enroll more patients to the study, we hope in the future to be able to provide outcomes according to the specific risk groups, so that we can better understand responses and potential benefit, patient benefit in these specific groups b ut we don't have data on that to report right now. Great. And then regarding the relapse patient, you know, we've talked about the 64-year-old female before, but the new 51-year-old female patient, taken together, you know, they still have CD33 expression. What do you attribute the relapse to, with Mylotarg? Is it the fact that they're just TP 53 mutations or just the high-risk nature of these patients? Yeah, Silvan, it's a good question. These, all of the patients who relapsed continued to express CD33 within their AML blast a nd so it does not appear that loss of CD33 is a resistance mechanism in this paradigm, that is, Mylotarg after Trem-cel. It's known that Mylotarg is susceptible to extrusion, particularly the colchicine payload to extrusion by multidrug resistance channels and P-gp. These are more highly expressed t hey tend to be more highly expressed on the surface of leukemia cells that have complex karyotype and bear P53 mutations. So we hypothesized that, particularly for these genotypes, that it is multidrug resistance activity extruding colchicine that's responsible for the relapse. We also hope, however, that at the two mg per meter squared maintenance cohort of Mylotarg, we would be able to overcome extrusion by those pumps. We don't know that to be the case. We still have TP53 mutant patients on study at this time receiving Mylotarg, and so this is data we hope to generate in the future. Great, and lastly, just quickly, did you observe any Veno-Occlusive Disease? No, not at all. Great. Well, thank you so much, and congrats, and thanks for taking my questions. Thanks. Thank you. Our next question comes from Justin Walsh with Jones Trading. You may proceed. Hi, congrats, and thanks for taking the question. You'd mentioned that the VADC45 is the agent that Magenta had tried to bring forward. Can you confirm? I believe that they had had their main issue with the CD117 targeted agent and not this agent. Can you confirm that? And maybe just give us some clarity on either takeaways that you guys have from the experience that company had, and how you maybe plan to avoid some of the safety issues that they had observed. Yeah. Thanks, Justin. So yes, we were privileged to take over this asset, and some employees from Magenta into Vor. This asset is totally different to the CD117 asset, that used a different toxin, obviously a very different target. That toxin was extremely potent. In addition, as you probably know, CD117 has been described to have expression in the lung, and they did see a number of grade four and five safety events, with lung involvement that may have been on target or may have also been related to the novel potent toxin that they were using. This asset is very different in terms of the clinically validated linker payload as well as the target that we think is really quite ideal for a number of indications. Great. Thank you for the clarification. Thank you. Our next question comes from Andrea Tan with Goldman Sachs. You may proceed. Good afternoon. Thanks for taking our questions. Maybe just a follow-up here. Just in the context of the results you've now seen with Trem-cel and Mylotarg, just curious on what efficacy profile you would look for from the VCAR33 monotherapy cohort to advance that asset within the transplant system? So, Andrea, thanks very much for the question. You know, CAR-Ts and AML have not, across a variety of different antigens, have not documented potent responses. However, we're very encouraged by the data from the NCI that utilizes the exact same CAR construct. That we utilize, and considering that in that study, at the highest dose they tested, two out of the five evaluable patients for response had complete remissions, as they presented at ASH. We are looking for a similar or improved profile for the VCAR33 allo asset to continue to move it along further. ... Okay, thanks so much. And then maybe very quickly on the ADC asset here, just wondering if you could speak to the strategic decision to explore this now, just in the context of your other pipeline efforts. I think you had some other gene-edited multiplexed assets that were early in development. Thanks, Andrea. So, we're absolutely still moving forward with our multiplex engineering efforts with stem cells, as well as our multispecific CAR-Tprograms. This ADC asset was purchased because of its synergy in the transplant space. We certainly need also more therapies that allow patients to become transplant eligible, as its utility may be interesting in relapsed/refractory disease, alongside, you know, other indications that we mentioned. And so, we believe this provides optionality for us, potential licensing opportunities, and that synergy across our portfolio. Thanks so much. Thank you. Our next question comes from Jack Allen with Baird. You may proceed. Thanks again for taking all the questions i just have one brief follow-up. Looking through the data, I realize the cutoff was in mid-July 2024. I'd love to hear any comments you're willing to make as it relates to the continued progress of some of these patients that had not had the opportunity to receive Mylotarg on to, potentially, Mylotarg. So Jack, you know, we were quite deliberate about this predefined data cutoff, and but of course, as Eyal mentioned, we have been strongly enrolling since. We'll be providing additional data later on. But what I would say is, as patients have continued on in this study, the trends that we observed in these first 18 patients absolutely continue. Got it. Thanks so much i 'll have to look forward to the additional data updates. Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.