Hey, good afternoon, everyone. Thanks for joining us this afternoon at the Oppenheimer Virtual Conference. Pleased to introduce our next fireside, which is with Vor Bio. And we've pretty much got the full team here, with Han, Tirtha, John, and Eyal. Thanks, guys, for joining. You know, this is like kind of one of the funnest companies that I cover, and the technology's pretty far out of left field, but it kind of makes sense. The biggest issue I think I have with investors is explaining in a coherent way that makes sense what you're actually doing. Han, do you want to just maybe start with your generalist pitch on what the approach is and how revolutionary it could be?
Sure. Sounds good. First of all, thank you as well for having us. We're very happy to be able to speak with investors at your conference. Also, before we get started, I need to say that we'll be making some forward-looking statements and obviously refer you to the disclaimers and disclosures and the relevant SEC documents. What we're trying to do with Vor is to create a system, a solution for certain blood cancers, AML in particular, acute myelogenous leukemia, that shields stem cell transplants, which are a mainstay way of treating AML, but at the same time attack and allow other therapies to go after the cancer cells itself. The way we do that is by our lead product, which is called trem-cel. It's a gene-edited stem cell transplant that has a specific antigen called CD33 deleted out.
CD33 has been found to be a unique antigen in that it is disposable. There are people walking around without CD33 being expressed on their myeloid, their bone marrow blood cells, and they do fine. They had perfectly normal lives. By editing out the CD33 in our stem cell transplant, what that enables us to do is to marry it with an antineoplastic agent such as an antibody-drug conjugate like Mylotarg or potentially with a CAR-T so that those therapeutic modalities can more specifically attack the cancer cells while preserving and shielding the healthy and the donor-derived stem cells that we are transplanting in. What the ultimate outcome or goal is, is to allow these patients to not have relapses of their cancer because the biggest problem with having stem cell transplants is that these patients often experience relapses in their cancer.
By enabling antineoplastic agents like Mylotarg or CAR-T to attack those cancer cells while shielding the stem cells that we're transplanting in, we think those patients will have better clinical outcomes.
This is not an autologous therapy. Most people think of cell therapies as, you know, CAR-Ts, oh, you need to have this huge manufacturing workup where you apherese the patient and then you do the gene editing and you re-infuse. I mean, this is, you're basically just taking the tried and true stem cell transplant method, Be The Match, you find a donor, you do your thing to the graft, and then you're, that's really what it is. I mean, you're following the standard of care here. You're just adding the genetic modification step. That's right?
Yeah. That's well said. I'll just say, you know, with AML, the most common leukemia out there, unfortunately, also the one with the highest death rate. We exactly like you said, our process that Eyal will go through and can talk to that we use for VBP101, our first Phase 1 study, we follow the exact same process. You know, thousands of transplants go through every year. All we're doing is making that CD33 edit to those donor cells. It's nice. It's easy for us to kind of tap into that tried and true transplant process that's been used now for many decades.
The first iteration is with Mylotarg, which is CD33 -targeting ADC. That's always been limited by its therapeutic window, right? I mean, there's a lot of toxicity associated with it. The idea is that if you edit out CD33 on the graft, when you then infuse Mylotarg, it'll have a much higher therapeutic window. It seems like we're seeing that already.
That's right. That's right, Matt. You pointed out exactly right, which is Mylotarg, the first ADC developed, has suffered in the standard AML setting because while there are responses, it also induces on-target toxicity. Unfortunately, patients do suffer from neutropenia and thrombocytopenia. Physicians would have loved to use it in the maintenance setting after a transplant, for example. The problem there has been even worse on-target toxicity in the setting of these fragile grafts. What we have found in our VBP101 study with our CD33 -deleted allograft is that Mylotarg has a broadened, a greater therapeutic window when administered after trem-cel. Moreover, Mylotarg can for the first time be administered as a maintenance therapy across multiple cycles with stability of the platelet and neutrophil counts, indicating that in fact, our shielded graft is doing its job.
How has that translated to clinical benefit, albeit early so far?
Yeah. We were very, very pleased where in collaboration with our investigators, we were able to escalate the dose of Mylotarg in our clinical protocol to our target dose of 2 mg per meter squared. An important milestone for the program, Matt, was in November, our dose escalation committee team met. They reviewed the data from at that point, six patients who had received 2 mg per meter squared of Mylotarg. They reviewed the safety, the PK data, and the outcomes of these patients in entirety. They declared 2 mg per meter squared of Mylotarg given once a month for eight cycles to be the recommended Phase 2 dose. We have continued enrolling into the protocol.
Now, even before achieving the recommended Phase 2 dose of Mylotarg, we were already starting to see a very interesting and encouraging trend in the relapse-free survival curve for these patients because indeed, that is the most important clinical outcome for patients with high-risk AML who are enrolled to our VBP101 study. We want to improve the relapse-free survival for these patients. When we presented at ASH the updated data, we were able to show that with a median duration of follow-up of 7.4 months, the median RFS for the patients in our study had not yet even been reached.
That compared very positively with two published controls that we were comparing against, the MRD positive population that has a median RFS of about three and a half months, as well as a high-risk genetic group of patients who have undergone a standard of care transplant who have a median RFS of about six months. To not even have our median RFS reached is something that we were very enthusiastic about, and it timed very nicely with our FDA meeting at that point.
How does the recommended Phase 2 dose of Mylotarg, 2 mg per meter squared, compare to kind of what the labeling of Mylotarg is? I mean, it's a little bit less, but isn't that because you're seeing much higher exposures because you don't have that CD33 antigen sink?
That's exactly right. Due to the paucity of CD33, which we've intentionally created by having these patients receive a CD33-deleted graft, a dose of 2 mg per meter squared of Mylotarg in a trem-cel patient looks like a dose of 9 milligrams per meter squared of Mylotarg in the standard AML patient. That's something that we're quite pleased in. We were able to see that in the parameter of the area under the curve. That's the efficacy parameter of Mylotarg. At the same time that we're seeing that encouraging area under the curve, what we're not seeing is an increase in the Cmax to dangerous levels. The Cmax is the toxicity parameter for Mylotarg. We sought to stay below a level of 2,000 nanograms per mL. That's also where the approved dose of 6 mg per meter squared is.
The Cmax in our patients at our recommended Phase 2 dose is only 1,000. So we're steering well clear of that safety margin.
From an exposure perspective, you're getting 33% higher exposures than what's really tolerated in a typical patient?
We're getting a much higher exposure. At 2 mg per meter squared, we're getting an AUC of 90,000, which looks like 9 mg per meter squared of Mylotarg.
Interesting. What are the next steps for the program? Are you planning to have maybe like an end of Phase 2 meeting with the FDA? When is that? What is the strategy for the Phase 3 pivotal trial?
For this protocol, what we're doing is we, on the heels of an FDA meeting that we were very pleased in, that took place in December, in fact, that was our first clinical Type C meeting for this particular program. It brought home two very important points. The first is that we were able to gain agreement regarding the safety of the trem-cel graft, the engraftment, the adverse event profile. In fact, a view with the agency that the adverse event profile looks very much like an unedited CD34 -positive graft. That's something that we were very pleased with. The second point is that we brought forward a comprehensive plan for pivotal study.
That pivotal study is a one-to-one randomized study of trem-cel followed by eight cycles of Mylotarg at the recommended Phase 2 dose of 2 mg per meter squared administered monthly for eight cycles compared to a standard of care transplant T -replete. There are no maintenance therapies approved in AML. We were able to gain agreement with that pivotal study as it relates to patient eligibility, study design, the statistical plan, stratification, as well as relapse-free survival as the primary endpoint for the study. In order to make sure that we can design that pivotal study in the most thoughtful way forward, we plan in the second half of 2025 to be able to bring forward data from a more robust cohort of patients.
We plan at that point to have approximately 20 patients on our study who have received Mylotarg at the go forward dose of 2 mg per meter squared with a median duration of follow-up of about 12 months. We think that will really help us to fully understand the relapse-free survival curve so that we can appropriately power the pivotal study.
Makes sense. One of the changes I think you want to implement as you look to a Phase 3 is expediting the time that patients can receive Mylotarg because right now it's something like 60 or 90 days. I think it's really important to bring that forward. Can you maybe just start with give us the history of why you needed to have that window like the FDA required you to have that window and then maybe how important it is as you think about preventing further relapses from tightening that window to really soon after the transplant?
That's right. You know the 60 days for administration of Mylotarg after the transplant is something that we, out of an abundance of caution, had built into the original study. It is on the heels of data that was generated a decade ago that showed that for patients who got Mylotarg before a transplant, there was an increased risk of veno-occlusive disease when they had an ablative allogeneic transplant. Again, in an abundance of caution, we wanted to make sure that the patients had enough distance from the transplant before they started Mylotarg. We also wanted to give time to make sure that this CD33-deleted allograft had the ability to engraft neutrophils and platelets fully.
Fortunately now with 25 patients that we presented at ASH and obviously we've continued to make progress, more progress since then, you know we have a lot of confidence in the neutrophil engraftment and platelet recovery, the ability of our edited graft to sustain hematopoiesis long term. We are also able to gain additional safety regarding the feasibility of giving Mylotarg in the post-trem-cel setting. Considering the safety that we're seeing giving Mylotarg after transplantation, we feel much more reassured bringing the Mylotarg administration from 60 days after the trem-cel graft to 30 days after the trem-cel graft. That's something we've discussed with the investigators. It's a potential benefit they'd like to offer their patients so the patients don't have to wait too long to start Mylotarg.
Yeah. Really, it was only in the last few months, maybe around ASH when we started to see kind of like the design of this Phase 3 start to come forward. Version 1.0 of this platform was always with Mylotarg, but that was often seen as like low hanging fruit. I think the dream was version 2.0, which was the CAR-T. For many people, the story was all about the combination of trem-cel with a CAR-T given just how well CAR-Ts tend to work and the need for it given what we've seen from just CD33 and other CD123 CAR-Ts on their own. I think seeing how well the Mylotarg combination is working really has put the emphasis again back on version 1.0. My question to you is, where does version 2.0 stand right now?
What are your thoughts on potentially future combining with that you have your own CD33 CAR-T with a trem-cel or what's the status of just the CD33 on its own?
You know, to your point, it's incumbent on us to understand the Mylotarg data as well as we can. We were really, really intrigued, pleasantly so, when we saw that relapse-free survival data develop as 2024 moved along. That is what led us to generate this pivotal study design and to have the FDA meeting. We are also encouraged by our CD33 CAR-T program. I want to emphasize that what's unique about our CAR-T and different from, for example, the commercially available CAR-Ts is that our CAR-T is generated from healthy donor cells that are fully matched to the patient. Commercially available CAR-Ts are generated from autologous lymphocytes from a patient who unfortunately, like the patient, have been exposed to chemotherapy and have grown up in a milieu of cancer that could potentially impair their ability to expand and provide anti-cancer activity.
What the team here did was really think carefully about this problem. From the beginning, our CAR-T, it is generated from healthy matched donor cells to the patient. We believe that that's going to provide improved expansion, persistence, and anti-leukemia activity. In fact, we presented the expansion data from the first three patients in September to our website where we were very encouraged by the levels and the pattern of expansion we're seeing from VCAR33. This is an area of intense unmet medical need, and we've continued enrolling that program further. We are expecting in the first half of 2025 to be able to release data on the update of this VCAR33 program that will give a better sense regarding the safety and efficacy of VCAR33.
Ultimately, what we want to do is provide the best modality or modalities for these high-risk leukemia patients who receive trem-cel and to improve their relapse-free survival.
That makes sense. Maybe we'll talk a little bit about the pipeline. I want to get Tirtha involved as kind of one of the scientific founders here. AML is a very heterogeneous disease. When we think again about version 1.0, version 2.0, version 3.0 is really starting to think about targeting the multiple resistance mechanisms of AML and just the heterogeneity of the tumor itself. It might be naive to think that knocking out CD33 alone is going to give us the best bang for the buck. Can we knock out multiple targets and generate multiple kind of therapies for this?
You're absolutely right, Matt. There are two kinds of heterogeneities that we need to worry about for AML. One is interpatient heterogeneity that is, given any two individuals, there may be a significant difference in the surface antigen that's presented, and that's well known already. The other that we talk less about is intrapatient heterogeneity. That is, even within one individual, the level of targetable antigen for a particular antigen may not be enough. Though we have had no concern so far regarding another issue, that is antigen escape in case of AML, AML antigens also have not been hit very hard. There is a possibility. Right now, it's a theoretical possibility that if you hit something like CD33 really, really hard using a very successful potent CAR-T, it may have a way to downregulate it. Not only heterogeneity, but a biological response is also concerned.
What we have done here is to think of a multi-headed CAR-T where we are using CD33 and CLL-1 on two sides of the same CAR-T and thereby targeting the AML cells in a multi-pronged way. The way you set up the question makes a lot of sense because if we have to do that, we also need to protect the nascent hematopoietic graft from this multi-pronged attack. That is a shielding concept that Han spoke about. We are also working really hard towards creating a transplant where we would have deleted both CD33 and CLL-1 from the graft. Multi-headed CAR-T has gone very far. We have practically come very close to choosing what would be our lead candidate. The multi-pronged HSC engineering project is also quite far along the line.
You mentioned CD33 and.
CLL-1 .
CLL-1 , but not CD45. That's interesting because you recently licensed a CD45 -directed ADC. What's the purpose of that program?
Correct. CD45 is a remarkably powerful antigen to miss. We don't want to miss CD45. CD45 is a pan-hematopoietic antigen. It's expressed on all hematopoietic cells, good, bad, ugly, all types, except for mature RBCs. Now, as I said, it is expressed really high on both normal compartments as well as on AML blasts. The level of CD45 is even higher than CD33 or CLL-1 alone by nearly an order of magnitude in both AML blasts as well as normal cells. The issue is you cannot knock out CD45 straight up because then these cells will collapse and some of them will not even develop because CD45 has many isoforms and most of them play a very, very critical role in the hematopoietic development.
Now, what we are planning to do by having this asset that you are familiar with, which is the CD45 -directed ADC, what we are doing is to try and figure out is there a way to epitope engineer these cells where a CD45 epitope would be hidden from the CD45 -directed immunotherapy. That is to talk about the shielding transplant kind of concept. Even otherwise, in a more conventional way, a CD45 -directed ADC, which is an asset we already have, can be used in relapse refractory transplant, I mean, relapse refractory AML because the CD45 antigen load is just so high. This is something that we can take advantage of. There are multiple other things we can do for this.
We can think of using CD45 as a myeloablative conditioning agent for AML, for other cancers if need be, as well as setting up the hematopoietic recipient using the CD45 ADC for conditioning or even gene therapy for rare disease. I would like Eyal to pitch in here in case he wants to add something.
No, I think you've summarized it perfectly, Tirtha. I would say that from the clinical perspective, having a CD45 -directed antibody-drug conjugate, I think offers a lot of potential therapeutic arenas in which to benefit patients. One is to do cytoreduction in the setting of AML. We already know there are some other agents that have used CD45 linked to a radionuclide to try and accomplish that. As Tirtha is mentioning, the ability to condition patients in rare genetic disease settings using a more targeted approach that perhaps preserves fertility in the recipients, for example, in a young population is an approach that's appealing. Looking at treatment of autoimmune diseases represents another possible therapeutic avenue in which to pursue this agent. Finally, using epitope modification techniques. It is obviously very exciting, particularly what Tirtha and his team are moving us toward.
Yeah, I agree. Maybe just in the remaining time here, we could talk a little bit about catalysts for this year and next. I know we focused on a few of them, but it'd just be helpful to get a rundown again.
Sure. The main catalyst for this year is in first half, we'll be presenting and disclosing data from our VBP301 trial, which is of our CAR-T, our CD33 directed CAR-T. In the second half of this year, we'll be giving an update from our VBP101 trial of trem-cel Mylotarg. At that point, we should have a robust number of patients with a longer follow-up time, obviously, for which to measure the RFS curves.
Makes sense. Han, maybe just finish up. You joined as CFO a few months ago. What was it about the company that attracted you?
Many features. I think, first of all, the company has a very unique approach to AML and to potentially broadly all cancers. It's also in a space where there's really nothing available to patients. The unmet need is very clear. I think there's been a disconnect with regard to valuation and the tremendous potential that this company has.
I agree. Looking forward to seeing more of it. It's been fun to watch over the last three years progress. Really, the cadence of data is picking up now, I think, as more transplanters get familiar with the procedure. It's really exciting to see. Thank you guys so much for joining us today. I look forward to talking to you later this year.
Thanks for the opportunity.
Thank you.
Thank you.