Good day. Thank you for standing by. Welcome to the Vor Bio VBP101 clinical data update conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will hear an automated message advising your hand is raised. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Dr. Robert Ang, President and CEO of Vor Bio. Please go ahead.
Thank you for joining our presentation, which we are proud to present the first clinical data from our clinical trial treating patients with acute myeloid leukemia. I will point you to our disclaimer slide that you'll be able to read at your leisure on our website. We will kick off with our founder, Siddhartha Mukherjee, who will be telling you a bit about how Vor was founded. We'll then be joined by Eyal Attar, who is our Chief Medical Officer, who will provide an overview of the VBP101 clinical trial. The results will be presented by an investigator, Brenda Cooper, who will be talking through results of our very first patient treated with VOR33, also known as trem-cel. We will then hear from our Chief Scientific Officer, Tirtha Chakraborty, who'll be going through our Vor platform, and then taking questions.
With that, I'll hand over to our founder, Siddhartha Mukherjee.
Thank you, Robert. Let me talk through how Vor was conceived, the moment of its birth. I was engaged in trying to find a cure for acute myeloid leukemia and potentially other cancers for more than a decade. The conception of Vor is particularly fascinating to me. I was on the beach in Mexico with my daughters, and we were making, for fun, what I call inverted drawings. These are drawings in which, you know, rather than making a figure of with a pencil on a paper, you invert it, and it's a figure that you make an inverted figure, so in this case, a bird with by just using a stencil, all of a sudden, what's white becomes black and what's black becomes white.
This idea of inverting the paradigm inspired, that very same day in Mexico, inspired a diagram in my brain, which was, what if, you know, for decades, for generations, literally a generation, we've tried to target cancer cells with some therapy or the other. The problem is that, you know, those therapies inevitably have been toxic to normal cells, and they kill normal cells as well. I thought to myself, what if we inverted the paradigm, just like this inverted drawing? Rather than making a cancer cell, killing a cancer cell, what if we made the normal cells resistant or immune to a particular drug or therapy? Now we would essentially have the cancer cell's Achilles heel exposed.
It would be like creating or engineering a uniqueness in the cancer cell, a unique vulnerability of a cancer cell that was not present in the normal cells because you made the normal cells immune. You've inverted the paradigm. You've made black white and white black. That very night on this in this beach house in Mexico, I sketched out a possibility for a, what I think would be a potential cure for a curative therapy for AML and potentially other cancers as well. I almost imagine it as a platform. I came back from that vacation extraordinarily excited about it to my lab at Columbia, and that's where we performed the first series of experiments, and they worked incredibly well.
You could basically take a normal bone marrow and make it resistant to a drug, exposing a cancer cell, but in this case, leukemic cells, to that drug and making the leukemic cells remain vulnerable while you altered the bone marrow using gene-editing technology so that it would become resistant to the drug. Again, back to this idea of the inverted paradigm. My lab at Columbia did some of the fundamental preclinical work and established. We published a paper in PNAS and established this idea and patented this idea of using this powerful platform of inverting the paradigm for cancer. As you very well know, I mean, a discovery in the laboratory has to become a human therapy.
In order to become human therapy, we need an entire team, a clinical team, a research team, a team that will make this into a human reality, a medicine. That's when Vor was founded. It was founded with a mission of taking this very, I would say, radical and interesting idea in cancer therapy into the clinic, into human clinical trials. I'm proud to announce that, you know, Vor has been, to my mind, an absolute success. We have an incredible clinical team, an incredible team of people who have developed the platform and really realized the dream that I had from that very simple drawing made on a beach in Mexico several years ago.
We'll be presenting some of that, some of that data and the platform today, and I cannot be more excited about, as I said, this dream coming true, this diagram sketched out on a piece of paper coming through and becoming a human medicine as Vor continues its journey. Thank you so much.
Thank you so much, Sid. As Sid mentioned, Vor was really built to try to protect healthy cells, and therefore, make cancer cells all the more vulnerable and address the fundamental issue of on-target toxicity that has really plagued the whole cancer field for many decades. What we're generating at Vor is something we call engineered HSCs or eHSCs. These are cells that we want to graft into patients that are inherently protected from targeted therapies, and therefore making targeted therapies much more useful, even opening new treatment opportunities in the post-transplant space and enabling much more cancer-specific cell killing. On the next slide, we see what is generally accepted as a standard of care for acute myeloid leukemia and other similar blood cancers.
Following diagnosis, typically, chemotherapy is used to induce a remission with consolidation chemotherapy to really deepen that remission and prepare the patients for transplant. The standard of care today is simple watchful waiting. You're literally not treating the patient to prevent that relapse really because the transplant itself is very vulnerable immediately following the transplant procedure. Once a relapse occurs, the patient really has very few treatment options, and as you see, the 2-year survival is less than 20%. We wanna improve those outcomes by opening a new treatment opportunity to treat the patient in this immediate post-transplant period. We think that is a key opportunity to prevent a relapse and maybe even aim for cures in this post-transplant period.
We believe that will be enabled by these treatment-resistant eHSCs. The next slide shows you the platform that we need to build in order to enable these eHSC treatments. Firstly, we ask fundamental questions about these targets, such that if we modify or remove expression of these targets, can we do so in a safe manner and preserve the function of these cells? Can we actually do this at scale to make GMP-grade product that can be delivered in time and fit into the standard of care for patients? Lastly, of course, can we execute this in the clinic and observe that these cells are grafting normally and that we can potentially dose therapies that are typically very toxic, but potentially in a safer way? With that, I'll hand over to our Chief Medical Officer, Eyal Attar.
Hello, my name is Eyal Attar, and I'm Chief Medical Officer at Vor Bio. On slide 12, you can see the outline of the VBP101 study. VOR33 is a CD33 deleted allogeneic donor stem cell product and is now referred to as trem-cel. This figure shows the VBP101 clinical trial, which is a trial for patients with high risk acute myeloid leukemia who are positive for minimal residual disease or even have frank disease up to 10% bone marrow blasts. Patients are referred for transplantation based on their high-risk disease and consented for the protocol. As they continue to receive treatment for AML, a fully matched related or unrelated donor is identified. The trem-cel product is manufactured from donor cells and infused to the patient after they undergo conditioning for transplantation.
Following engraftment of trem-cel, the patient is eligible to receive Mylotarg after day 60 in the phase 1 dose escalation portion of this study. The key endpoints are trem-cel engraftment, protection from the myelosuppressive effects of Mylotarg, and clinical endpoints for AML, including relapse-free survival. Today, we will be talking through the data related to the patient treated on study. Despite prior delays in sites opening related to COVID, the trial is open and active at 9 sites. The initial patients are enrolled in compliance with a stagger assessing the safety of trem-cel engraftment. Based on the encouraging data you are about to see, there are multiple additional patients consented for the study. Slide 13 shows the goals for our first engineered hematopoietic stem cells in patients with acute myeloid leukemia.
We were anticipating a streamlined process of manufacturing with a high level of CD33 editing efficiency. We were anticipating successful, timely neutrophil engraftment and platelet recovery. We were hoping that the trem-cel product would repopulate the blood system with fully functional cells, and that the disease status and adverse events would be consistent with traditional hematopoietic stem cell transplants with unedited grafts. Finally, we were hoping to observe that trem-cel would reduce the on-target heme toxicities, which are common across doses with Mylotarg. Slide 14 demonstrates the trem-cel manufacturing process as well as specifications for patient 1. Keeping in mind that this manufacturing process takes place while the patient is receiving treatment for their acute myeloid leukemia, the donor cells are collected through a process of apheresis. The cells are then selected and undergo a process of genome engineering where CD33 is deleted.
Cells are harvested, release testing takes place to coordinate with the patient undergoing conditioning for their transplant. At the bottom of the screen, you can see the characteristics of the trem-cel product. The release criteria include characteristics for product dose, gene editing efficiency, and CD34%. Importantly, all of the release criteria were achieved for patient 1. Specifically, as you'll hear from Dr. Cooper, there were 7.6 x 10^6 CD34 positive cells per kilo. CD33 was edited at a high level of efficiency at 88%, there were 97% CD34 positive cells. I'd now like to introduce Dr. Brenda Cooper, Professor of Medicine and investigator on the VBP101 study, to take us through the clinical trial results.
I'm very excited to share with you the results of the first patient on the VOR33 clinical study. By way of background, AML is often a fatal disease with poor outcomes. As you can see on the graph on the right side, patients with high-risk disease are referred for allogeneic hematopoietic stem cell transplantation. In fact, about 40%-50% of AML patients have minimal residual disease at the time of hematopoietic stem cell transplantation when you use sophisticated testing to determine minimal residual disease. The outcomes for these patients are particularly poor. Moreover, many patients that do not have MRD, the relapse rate is considerable, and strategies to give post-transplant treatments are desired. This slide shows transplant outcomes for patients with AML according to minimal residual disease or no residual disease.
As you can see, the cumulative incidence of relapse for patients with minimal residual disease approaches 60%. At this point, there are no approved post-hematopoietic stem cell maintenance strategies, and targeted treatments are generally confined to small subgroups of patients, such as patients who express FLT3-ITD. For patients who relapse after hematopoietic stem cell transplantation, therefore, treatments are limited and poorly tolerated due in large part to myelosuppression. Post-transplant treatments that address the majority of patients with AML are desperately needed. Next slide. CD33 is expressed on most AML cells, but unfortunately, this is also expressed on normal hematopoietic stem cells. Mylotarg is an anti-CD33 antibody-drug conjugate approved in front-line AML alone or in combination with chemotherapy for favorable risk patients and for relapsed refractory AML.
This drug, therefore, could potentially be used after a hematopoietic stem cell transplant to prevent or treat relapse in the post-stem cell transplant setting. Unfortunately, its use is limited in large part due to myelosuppression. trem-cel is an allogeneic donor stem cell graft where CD33 is deleted using CRISPR gene editing technology, as shown in the previous slide. CD33 has been shown in animal models to be dispensable for normal hematopoiesis. trem-cel, therefore, is hypothesized to enable the use of CD33-directed therapies such as Mylotarg or even perhaps in the future, CD33 CAR-T cells that target AML cells while sparing normal blood cells. I want to share with you the information for the first patient enrolled on this trial. This is a 64-year-old female with complex karyotype AML with myelodysplastic-related changes.
As you can see on the table on the right, she has pretty much all the high-risk AML features you could imagine. Her age is greater than 60. She had primary induction failure to frontline therapy and was in relapse. She had myelodysplastic-related phenotypic changes as well as karyotypic changes on her AML, these included a large number of adverse cytogenetics, as you can see, 4 lines of them. Most importantly, she also had deletion of TP53, which is a tumor suppressor gene. After a salvage therapy, she had an incomplete remission with MRD positive disease by flow at a level of 1.8%. The patient required 2 courses of cytarabine and daunorubicin to achieve a clinical complete remission but remained MRD positive. She went on to receive 3 cycles of high-dose cytarabine consolidation.
After which, she had progressive disease as evidenced by 5%-10% blasts. She was at time referred for an allogeneic hematopoietic stem cell transplant due to high-risk factors. She was offered the VOR33 study and was eager to participate. While undergoing evaluation, she received 2 cycles of venetoclax and hypomethylating agents, achieving a complete remission, again, with MRD-positive disease, as mentioned before, and a 10 out of 10 matched unrelated donor was identified. This slide shows the protocol treatment and her early post-hematopoietic stem cell clinical course. The patient was enrolled on VBP101 to receive trem-cel. Sufficient peripheral blood samples were obtained from the donor utilizing G-CSF and plerixafor mobilization for trem-cel manufacturing and backup graft.
As you can see on the table on the right, her trem-cel CD34 dose was 7.6 times 10th to the 6th CD34 cells per kg. The total CD34 cells in the drug product were 544.5 times 10th t o the 6th cells. Total CD3 in the drug product was less than 0.6 times 10 to the fifth cells per kilogram, as these cells are CD34 selected, and CD33 gene editing efficiency was 88%. From days -9 to -1, the patient received an intensive preparative regimen consisting of busulfan, fludarabine, melphalan, rabbit ATG. Due to the nature of the preparative regimen as well as CD34 selection, no GVHD prophylaxis was required or used with this type of transplant. On day 0, trem-cel was infused. There were no related infusion reactions or AEs.
She received standard supportive care with prophylactic antimicrobials and blood product support. On day 10, she achieved neutrophil engraftment, as defined by the 1st of 3 consecutive days with an absolute neutrophil count greater than 500 per microliter. On day 15, her last platelet transfusion was administered. The next slide shows the peripheral blood neutrophil engraftment. As you can see on the left, her neutrophils engrafted on day 10. In comparison, the dashed line shows the median engraftment on a BMT CTN 1301 trial, which utilized a CD34-selected graft. The right chart shows the platelet transfusions. The last platelet transfusion was on day 15. In this case, the patient received platelets perhaps a few days longer than normal. Due to a prior history of subdural hematoma, she was being transfused at 30,000 rather than the 10,000 is, which is generally used.
By definition, the last plate, the date of platelet recovery would be 7 days after her last platelet transfusion, or day 22. This chart shows selected adverse events reported after trem-cel infusion. Serious adverse events included renal colic, which required hospitalization, as well as a deep venous thrombosis. These both occurred on day 50. The renal colic was attributed to a past kidney stone. The DVT is being treated and is resolving. She had some minor skin infections. There was a CMV reactivation on day T + 31. Of note, of note, the patient was unable to receive letermovir, and this will be administered ongoing on patients subsequently enrolled. She also had BK viruria, which was asymptomatic.
Hepatic AEs, and again, this was before Mylotarg infusion, included grade 2 AST, ALT, which were both attributed to antifungal therapy and not Graft-versus-Host Disease and resolved after this antifungal therapy was discontinued. Thus, no trem-cel-related events were reported. Slide 23 shows CD33 expression count and chimerism at day 28 and 60 assessments on our first patient. As you can see on the upper left, there was a high percentage of C-CD34 negative cells in the peripheral blood, in the neutrophil monocyte lineage, as well as in the bone marrow on days 28 and day 60 at 95%. Similarly, the CD34 positive bone marrow percentage was 94 and 91% on these data points as expected. Blood counts were sustained at days 28 and day 60.
Similarly, percentage donor chimerism was extremely high at 100% on days 28 and days 60 in whole blood myeloid NK cell fraction. As discussed, one of the main objectives of this strategy with trem-cel was to determine whether this product allows use of single-dose Mylotarg without sustaining significant myelosuppression. The first dose on our trial is 0.5 milligram per meter squared. The chart on the left shows CD33 saturation following Mylotarg single dose, and this is from the Mylotarg ODAC 2017 publication. As you can see, CD33 saturation occurs at a very high level, even at low doses of Mylotarg, starting at 0.5 milligrams per meter squared, which was our initial phase I post-transplant dosing.
The right chart shows data from the phase 1 Mylotarg study published by Sievers and colleagues in 1999, in which Mylotarg was given to patients with relapsed AML, ranging in doses from 0.25- 9 milligrams per meter squared. As you can see, even at the lowest doses, - 9 patients had grade 4 neutropenia. In contrast, this slide shows the blood counts following Mylotarg administration in our first patient with Mylotarg given at a dose of 0.5 milligrams per meter squared. Then, as then you can see, Mylotarg was started on day 68 of transplant, and we have follow-up during the first cycle from day 68 to days 87. These data are also depicted on the right graph, where you can see that platelets and neutrophils remain steady throughout this 27-day period.
In conclusion, this is the first hematopoietic stem cell transplant of a patient with high risk relapsed acute leukemia using trem-cel, a CD33-deleted allogeneic donor graft. The patient had an uneventful post hematopoietic stem cell course. Engraftment occurred rapidly and appears to be comparable to unedited cells. There were no unexpected post-transplant adverse events. There was a high percentage, greater than 90%, of sustained CD33 negative hematopoiesis at the 2 points evaluated to date, day 30 and 60 post-transplant. No cytopenias were observed during cycle 1, date, up to day 20 following Mylotarg dosing. These data suggest that trem-cel may enable post hematopoietic stem cell Mylotarg and potentially other CD33-directed therapies moving forward.
Thank you for sharing this exciting data, Dr. Cooper. We're pleased this patient is doing so well, that they've successfully received an engrafted trem-cel, and that they tolerated Mylotarg therapy well. We'd like to thank this patient for their courage and your team for your care of this patient. I'd now like to introduce my colleague, Dr. Tirtha Chakraborty, who is Vor's chief scientific officer, to discuss our exciting platform.
Thanks, Eyal. As you know, Vor Biopharma's oncology treatment system has two main pillars, HSCs and CAR-T. To be able to surge ahead with a meaningful and long-term solution for the patients, we need to be the very best on both fronts. These are not just therapeutic pillars, but also we have significant platform development going on for both of these. For HSC, we need to create the next generation transplants by deleting biologically dispensable targets. Whereas for CAR-T, we are creating allogeneic single or multi-targeted therapy to complement the engineered HSC transplant. I want to highlight that the central technology pillar that holds the two biology platforms together is genome engineering. In the next three slides, I'll give you a snapshot of progress on each one of these platforms. On to the next slide.
When HSC engineering is your central thesis, it is really important to understand the cells and their biology very well. Hematopoietic stem cells are somewhat mythologic. We all know that they are there, but we don't know how they look. They're extremely small proportion of the CD34 positive cells that we work with, and their markers are not well defined. We have come up with a marker panel combination internally at Vor that allows us to detect them during our process with unprecedented accuracy, as described on the left. On the right, we show how these panels translate into primary and secondary xenotransplant preclinical model systems, thereby lending tremendous validity to this new diagnostic hematopoietic stem cell detection panel. It happens from both cord blood as well as from peripheral blood-derived CD34 cells. In the next slide, we talk about our advancement in the genome engineering front.
While CD33 is absolutely the dominant molecule on the AML cells, it still does not cover 100% of the patients or 100% of cells in a given AML patient. To add to that, while there is no known evidence of CD33 antigen escape in AML, we still don't want to be caught off guard like the B-cells did. To prepare ourselves, we are planning a multi-pronged CAR-T assault on AML, and to keep the patients safe, we need to complement that approach with a multi-deleted HSC transplant. On the left side of this slide, we show how successfully we can delete out CD33 and another molecule, CLL1, at nearly 80% efficiency from our hematopoietic stem and progenitor cells using two independent technologies. Whether by CRISPR-Cas9 or by base editing, the efficiency stays extremely high. Now, CRISPR creates double-strand DNA break. We all know that.
Having 2 or more of these breaks at the same time inside the same nuclei will create translocations. As you can see on the right, we have addressed that too. They are there, the translocations, to begin with, but improving delivery and dose of the enzyme system by using inhibitors and by using base editors, we can now make multi edits without translocation and thereby keep our patients safe. Now, on the last slide, I'll talk about our advancements on the CAR T side of things. This is an example of our progress of the CAR T platform. As I mentioned in the previous slide, what if, and only what if, CD33 targeting alone is not enough? We created 1 T-cell with 2 CAR molecules expressed on the surface, 1 against CD33 and the other against CLL1. We took an AML cell line, HL60, that expresses both molecules.
In cell culture, we exposed this line to the dual CAR. We see significant cell death if we do so, the left side red bar. We knocked out CD33 and CLL1 individually from this line, not at the same time. As you can see in the blue and green bars, the single engineered cells still get killed by the dual CAR T. At the very right in gray, we have the dual knockout cell line, where we have knocked out CD33 and CLL1 at the same time. As you can see, these cells are completely protected against the dual CAR T. That is exactly what we expect to see when we launch our multiplex treatment system. Dual CAR T kills the tumor but spares the allogeneic nascent graft. On the right side of this slide is a snippet of our CAR T progress in process development.
Most CAR-T products are imperfect gametes of transduced and untransduced cells. As a result, what we put in the body of the patient is a highly uncontrolled product with rather unpredictable efficacy. We have started a process improvement where we have been able to improve the quality and the purity of drug products through a selection process that leads to an increased proportion of transduced cells from mid 20%-mid 90%. This improved process will give us a great degree of control over our CAR-T product quality and dose. These are still early days. Stay tuned for the rest. Now, I will hand this back to Robert.
Thank you, Tirtha. I think what you've seen today is the first example from the first patient where we've observed that we can manufacture product, fit it into the standard of care. The cells have been grafted normally per previous benchmark with complete chimerism. These cells are reconstituting the blood system with a CD33 negative cells. No untoward safety events to date with some degree of protection following the first dose of Mylotarg, where now we see maintenance and in fact, improvements of their blood cell counts. What we're looking forward to next is confirming the result with additional patients to make sure that the phenomenon is not isolated. Also we'll be dosing patients with multiple repeat Mylotarg dosing, as well as potentially with higher doses of Mylotarg. We're also looking to potentially broaden eligibility beyond the patient population described in the study to date.
There are interesting related conditions, such as MDS, that could be very interesting to explore, as well as other patient populations to really assess how the Vor platform could really broaden impact to patients in need. I'll also point to the fact that we have a CAR-T program, VCAR33ALLO, that will be entering the clinic soon with an IND in the first half of 2023. Of course, we're all looking forward to developing the treatment system where we can dose trem-cel as a substitute of their regular stem cell transplant and follow it with a VCAR33 CAR-T therapy. I just want to thank the care team as well as the patient who showed unbelievable bravery being this first patient in our clinical trial. We can't be pleased enough in regards to the clinical course for this patient.
We hope this is the start of great things to come. With that, we'd like to open up for questions.
Thank you, Dr. Ang. We will now begin the Q&A session. As a reminder, to ask a question, you'll need to press star one one on your telephone. Please stand by while we compile our Q&A roster. Our first question comes from Sylvain Turcan with JMP Securities. Your line is open.
Yes, good morning. Congratulations on this milestone data set. Great presentation. I just have a question, obviously about what comes next. For this one patient, how do we measure early impact on relapse rates? How do you envision that going forward? How about MRD negativity, to comment on that? Thank you.
Hi, Sylvain. This is Eyal Attar. Thank you very much for the question. We are really excited to discuss this data that you just heard from Dr. Cooper. Your question is important. This patient will go on to receive additional cycles of Mylotarg in the dose phase 1 dose escalation portion of this study. You've already seen the exciting data from cycle 1. No impact on neutrophils from this patient at all through day 20 of cycle 1 of Mylotarg. It's anticipated that this patient would then go on to get cycles 2, 3, and 4, with each cycle being 28 days in duration. We are going to be measuring the minimal residual disease. The patient will be getting sequential bone marrow biopsies, and we have important efficacy endpoints for acute myeloid leukemia built into the study.
For a patient like this that starts Mylotarg in the MRD negative state, of course, we're looking at relapse parameters, time to relapse-free survival, and overall survival.
Great. Thank you very much. Obviously, the side effect profile looked excellent here post the transplant. Just have 1 question about the deep venous thrombosis at day 50. That was pre-Mylotarg, right? That's most likely related to the preconditioning.
That's exactly right. That deep venous thrombus occurred before the patient began administration with Mylotarg. It's believed by the treatment care team that that may have actually even occurred before the patient entered transplantation. Recall that this patient, like many AML patients, this patient had 6- 8 months of treatment for their AML before even being enrolled in to our study. That's an incidental finding that is in a state of resolution right now.
Great. Thank you very much. Thanks for taking my questions, and congrats.
Thank you, Sylvain.
Our next question comes from Stephen Willey with Stifel. Your line is open.
Yeah, good morning. Thanks for taking the questions, and congrats on the update. I think the patient vignette is pretty thorough. Maybe for the company, you can just kind of speak as to what the next update's gonna look like, just in terms of timing, and patient numbers. I guess for Dr. Cooper, I know the required stagger has been kind of a key rate-limiting step in terms of your ability to enroll patients, but have there been any other eligibility criteria or protocol requirements which has impacted your ability to enroll patients beyond the stagger? I just have a quick follow-up.
Right. At this moment in time, we are complying with the protocol mandated stagger that we agreed on with the health authority, and that's simply to ensure that the initial patients are engrafting accordingly, considering that this is the first time that allogeneic donor cells have been deleted for CD33 and are being engrafted in patients. The eligibility criteria set forth in the protocol really applies to a broad range of AML patients, considering that approximately 40% or 50% or more AML patients remain positive for minimal residual disease. The eligibility is really set to apply to a broad range of patients with AML. We are working through the enrollment of patients.
We actually have more demand that we can meet at the present time, but we are working with patients through, again, in accordance with the FDA mandated stagger part protocol. We would anticipate having additional data in 2023, not only for this patient, but for additional patients that we would enroll and treat onto the protocol. We would anticipate presenting that at major medical meetings and hope to have more information in 2023.
Okay, that's helpful. Now, Robert, you talked about perhaps expanding the eligibility criteria to include other disorders such as MDS. I guess in your ability to expand out the protocol, how does this work from a regulatory perspective, including the patient stagger as well? I guess, is there a threshold number of patients that FDA has suggested they wanna see successfully engraft before they allow a continuous flow of patients into the study? Is this just something whereby you're gonna get a sufficient amount of data in hand, approach the agency, and then just have a conversation around whether or not you can eliminate the stagger?
Yeah, thanks for the question. The staggered enrollment was dictated to us by the FDA during the IND submission and review process. The language was clear and applied to the trial design that was submitted. What we want to do is have further dialogue with FDA and clarify with them what we can do after additional data that we see here, and we'll provide further updates soon.
All right. Thanks for taking the questions. Congrats again.
Our next question comes from Jonathan Miller with Evercore ISI. Your line is open.
Thanks so much for taking my question. Congrats on some really good initial data here. One thing that I noticed going through the deck, it seems like the release criteria were pretty conservative, only 50% editing efficiency, 3/10 into the 6 cells. Do you anticipate those criteria being stable moving forward, or will they tighten up as you get to later trials? Then, maybe relatedly, but then post-transplant, I might have expected that CD33 negative cell percentages would go straight to 100 after Mylotarg treatment if the, if Mylotarg is indeed ablating CD33 positive cells that are remaining in the graft. Does that suggest that there's not enough Mylotarg for this patient to have seen cytopenias, even with a normal transplant? Just could you put that into context for me?
Why wouldn't CD33 minus cell percentage go to 100% at day 28 or day 60 after Mylotarg treatment?
Jonathan, we appreciate the question, very, very much. I'll address them sequentially. Indeed, the release criteria is conservative. We have discussed it extensively and agreed upon it with the agency at the time of the IND submission. We're confident that we can, you know, manufacture, you know, in excess of the release criteria on a consistent basis. They're really there to specify the minimal requirements that we would want in a suitable manufactured trem-cel graft. Recall that the CD33 editing efficiency with 88% is presented by Dr. Cooper in the presentation. Indeed, you've touched on a very important point. The data on slide 23 demonstrates that at least 90% of the cells in the bone marrow peripheral blood are deleted for CD33. That, of course, is by design.
We have not presented additional data at this point in time regarding the CD33 negative to positive fraction, because those kinds of assessments are going to take place after the Mylotarg administration. Indeed, you've keyed in on the fact that it is, it is possible that we may see the CD33 positive fraction diminish with time as the patient continues to get Mylotarg. That's something that we will be studying in detail.
Okay, maybe one follow-up. Can you comment on the neutrophil level spiking before it stabilizes at about 2,000 per microliter? I'm just wondering what's causing that and how that's reacting to follow-up treatment.
The neutrophils spike immediately following the transplantation because the patient is receiving myeloid growth-stimulating factors, which is part of the standard of care following allogeneic stem cell transplantation. All patients will have a spike. The GCSF at that point is discontinued, and the neutrophils then equilibrate. That equilibration process continues to take place within the patient's body, even through day 100 and beyond. For example, if you look at the first dose of Mylotarg administration, you can see that the neutrophils continue to increase. That's not only a favorable sign because, you know, on the one hand, we were expecting the neutrophil count to decrease in response to the Mylotarg, which again is something that is seen across doses.
Not only did we not see a decrease in the Mylotarg, in the neutrophil count following administration of the Mylotarg, we saw the neutrophil counts continue to increase, and that's really just demonstrating that the donor graft continues to equilibrate and thrive within the patient's body.
Thank you. One moment for our next question. Our next question comes from Carter Gould with Barclays. Your line is open.
Great. Good morning, guys. Robert and team, congrats on the early data here. Very, you know, very cool. I guess a couple from our end. First, Robert, can you maybe or a team, can you maybe just expand and kind of, you know, some of those commentary you made around potentially broadening the eligibility? You mentioned MDS, but should we be thinking about sort of, adjacent indications relative to AML versus more kind of tweaking or relaxing some of the inclusion/exclusion criteria within the AML population?
As we think about additional data presentations that you'll be making over 2023, should we be thinking about it taking sort of like a similar format to this where we'll get sort of the post-Mylotarg follow-up versus, maybe, you know, more data just on the enrichment in greater number of patients? Thank you.
Thanks, Carter. Let me answer the first part of that question, then I'll hand over to Eyal for seconds. Look, we're really excited with this data. This is first of its kind. It is 1 patient's worth of data, and so we'd like to confirm this finding. We also have a dose escalation to address here as well as what happens with subsequent Mylotarg doses, where we want to see maintenance of this kind of development. I think we've still got a little bit of homework here to do. That being said, we also want to really accelerate the way that we think broader patient populations can benefit from this, which might include MDS. We're also looking at other strategies and different types of transplants, we'll provide more updates instead this week, too.
I'll hand over to Eyal for the second part.
Carter, can you just repeat the second part of your question for me?
I think it was more related to, as we think about sort of the presentations that come over the course of 2023, should we expect, you'll continue to wait until those patients kind of amass and you can, you know, give that portrayal across both, the engraftment and the Mylotarg? Or could we see that kind of split up and maybe... Obviously, you'd have patients, you'd have, potentially a greater number of patients with engraftment and maybe you could share that data. Just trying to understand kind of how those presentations might flow over the course of 2023.
You know, we want to make certain that we have the most fulsome, you know, datasets, available, that put forth important concepts in these patients' care and not just necessarily dribble out small amounts of information. You can anticipate for this in all patients, we would like to be able to present safety data regarding multiple doses of administration of Mylotarg. Patients in this study get 4 planned monthly cycles of Mylotarg. We'd like to be able to present some of that data commensurate with an understanding of the CD33 positive to negative ratio, as your colleague mentioned earlier. We also would like to be able to establish tolerability of Mylotarg at higher doses in the higher cohorts, in cohorts 2 and 3.
Our plans are to, you know, present this data as we arrive at fulsome increments to be able to make important scientific statements, and that's why we are planning for medical and scientific meetings for 2020 and 2023.
Thank you. One moment for our next question. We have a question from Jack Allen with Baird. Your line is open.
Hi. Thank you so much, and congratulations on the great data. I was hoping we could touch a little bit on the liver-related adverse events surrounding Mylotarg. You provided a lot of data on the neutropenia and the time course of that, but I was wondering if you could provide some context around time of onset of liver-related adverse events with Mylotarg, and maybe the early confidence you could derive from the LFT data that you presented from the first patient here as well.
Certainly. Veno-occlusive disease is one of the types of adverse events that have been reported in patients that receive Mylotarg, particularly in the allogeneic stem cell transplantation setting. LFT increases are other types of adverse events. Again, they've been reported. They are in addition to the hematologic adverse events that we discussed throughout the protocol. We've taken great care in this protocol to ensure that the patient is in the safest position possible, and that includes not only waiting until at least 60 days after the transplant to administer the Mylotarg, but starting at a very, very small dose of Mylotarg in our dose escalation design. We've taken great care to really maximize the safety for the patient. I'd like to turn our attention to the liver function test abnormalities.
You'll notice that following administration of the Mylotarg, there are absolutely no LFT perturbations reported for this patient. There are 2 episodes of LFT abnormalities reported for this patient that occurred before the administration of the Mylotarg. These LFT increases are absolutely a consequence of the prophylactic antifungal medications that this and all patients receive in the post-transplant setting. These antifungals are known to cause increases in ALT and AST, that's exactly what was observed in the 2 instances reported for this patient. The reason we know they were related to the antifungal medications is that they, in both instances, promptly resolved and completely normalized once the treating team switched to a different class of prophylactic antifungal medications.
Great. Thank you so much. Just briefly as a follow-up, I was hoping we could talk a little bit about the recruitment to the study. Any color you can provide as it relates to the time course of this patient being recruited in the study and how many patients maybe are enrolled to date or the backlog of patients that are looking to get into the trial? Thank you so much.
Right. While we can't unfortunately comment on the specifics of enrollment and numbers, what I do want to state is that the great success thus far demonstrated by this patient has dramatically ramped up the enthusiasm for this study. You know, as Robert was alluding to earlier, you know, we really applaud the bravery and courage of this first patient to undergo a first in the history of medicine type of treatment. As a consequence, we have more demand than we can meet right now for the study. There are additional patients consented, and there are additional patients enrolled, and we're looking forward to a very exciting 2023.
Great. Thank you so much. Congratulations again on the data.
Thank you.
Our next question comes from David Nierengarten with Wedbush. Your line is open.
Hey, thanks for taking the question. Most of mine have been asked, but I was just curious on the patient. This patient clearly had a very unfortunate, you know, prognosis, right, with the set of mutations and everything. I was just wondering, I know it's an N of 1, but if there were any, you know, with a patient of this type, you know, kind of the typical relapse timing for a patient post-transplant. You know, is it still, you know, kind of in the 50% at 6 months or, you know, is it a little bit higher sooner? Just if there are any comments on that. I know it's hard with an N of 1.
One of the reasons I appreciate this type of question, I think is that it really underscores why the data for this patient is so exciting. You've keyed into the fact that for patients who are MRD positive or have frank AML disease going into a transplant, their 3-year relapse rate is 65%, and the median time for those patients to relapse is around 6 months. Those numbers are even worse for patients with mutations in P53, for patients that are in first, second, and third relapse. Dr. Cooper on slide 19 outlined all the adverse characteristics that this patient brings to the table. It can be anticipated as a combination of these adverse characteristics that a patient like this would have a time to relapse after the transplant that could be in the 3- 6-month range.
For this patient, the fact that they've tolerated the transplant well, the fact that they've engrafted with the trem-cel drug product, they've established a CD33 negative hematopoiesis to a large extent and tolerated the Mylotarg, I think bodes very, very well and lends to the excitement for the data that we're seeing.
You know, maybe one quick follow-up on Mylotarg. Yeah, I know it's, again, it's early days, but is there a maximum dose that you're targeting for future patients? I mean, you would think you would want the lowest dose, you know, with the highest saturation, right? So I'm just curious if there's a ceiling that you're looking to hit, and, you know, still be safe or if you're planning to, you know, dose as high as you can and see, you know, until you hit that maximum tolerated dose in these patients. I'm just curious if you have a, you know, an idea for what dosing you might end up at.
Indeed. Dosing is guided by the adverse event profile at each cohort, the pharmacokinetics, and, finally signs of activity against the disease in patients who might be MRD positive after the transplant or those that have frank disease after the transplant. Our ceiling dose in the protocol is at 2 milligrams per meter squared, which is taken directly from the Mylotarg product label as the continuation dose of Mylotarg in patients who are receiving long-term Mylotarg therapy and have relapsed refractory AML.
Got it. Okay. There's no desire to stop early or anything to, you know, just to, maybe have a better tolerability, maybe along, you know, more potential repeat doses or anything like that. The goal is still to hit, the labeled dose.
The goal is to advance in a way that makes scientific sense and for what's clinically reasonable for those patients. We're in a constant evaluation of the safety, efficacy, and PK data and would make any dose escalation decisions accordingly.
Okay. Thanks.
Thank you. Our next question comes from Swaya mpakula Ramakanth from HCW. Your line is open.
Thank you. This is RK from H.C. Wainwright. Most of my questions have been answered. I just want to have an understanding of the adverse event profile that we could expect from these patients who have been treated with VOR33 and Mylotarg.
When would we get a, you know, a deeper panel on the adverse events, you know, for this patient? Also when I was looking at the infection rate that was seen in this patient, is this typical for Mylotarg or is this better than what you would have expected if the patient was just treated with Mylotarg without the VOR33? I'm just trying to understand that part piece as well.
Thank you for your question, RK. You know, patients that undergo ablative allogeneic stem cell transplantation have a very, very high rate of adverse events, typically, centered around the risk of infection. We're pleased that on slide 22, the adverse events reported for this patient in the post-trem-cel setting are completely in line with what would be expected for patients receiving a standard type of transplant. You can see that even focusing on the infections, they're all of low grade and at various stages of resolution for this patient. According to the care team, there are no unusual adverse events for the post in the post-transplant setting experienced for this trem-cel-treated patient. I'd also like to point out that the adverse event data that we're providing is full through the end of the data cut.
The data cut is day 87 following trem-cel infusion, which coincides with day 20 of cycle one of Mylotarg. I would just like to emphasize that there are no reported adverse events as related neither to the trem-cel nor to the Mylotarg.
Thank you. Thank you for taking that question.
Thank you. That's all the time we have for questions. I would now like to turn the call conference back to Mr. Robert Ang for closing remarks.
I wanna thank you all for joining the call today and hearing about data from this first patient. We do think this is very interesting data and really potentially a launching point for us to study this with even more vigor as we expand into different indications, different patient populations, and really take the whole platform to its true potential. Thanks very much. We look forward to speaking to you again soon.
This concludes today's conference call. Thank you for participating. You may now disconnect.