Hi, good afternoon and good morning for folks still here on the West Coast. We'll get started with our next company, Vor Biopharma, where we have with us CFO Nathan Jorgensen, CSO Tirtha Chakraborty. Great to have the whole team with us here today. For the audience, thank you for being part of this, and feel free to email me directly questions at mmomtani@brileyfin.com. Obviously, you know, the team, Nathan, Tirtha, you've had a very productive end of 2022. In the back half of the year, you had initiated manufacturing in-house in, around your Cambridge headquarters, and in December, you obviously had the first clinical data with your trem-cel Mylotarg combination.
Throughout the course of the year, I believe you have presented some updates from your multiplex projects. You know, we'll dig into all those different components one by one, but at the highest level, Nathan, could you get us started about how at the highest level, how we think about Vor and sort of going into 2023, what should be the goals that you're looking to accomplish?
Well, thanks, Mayank. Thanks for having us here at the B. Riley conference. We're excited to participate. 2022, as you mentioned, was a big year for Vor. We showed important proof of concept in one patient that we could have or could delete off CD33 and engrafts, and it protects against Mylotarg. We'll get more into that later. What I wanna start off doing is just talking about our platform and what we wanna do in terms of our approach. What we do here is we solve one of the big problems for cancer drug development, and that's finding a cancer-specific target. Our approach was founded by Siddhartha Mukherjee, and what he came up with is you take a patient that's getting a bone marrow transplant, which is standard of care for a lot of different blood cancers.
You delete off CD, an antigen, and for our lead program, it's CD33, and then you can transplant that patient with those cells. It repopulates the immune system. The immune system now doesn't express that particular protein. However, any residual cancer still does. Now you can target that cancer specifically. Our lead program, and we'll talk about it, we use an ADC Mylotarg, which was the first approved ADC. What we ultimately wanna do is combine that with a CAR-T, so we in licensed a CAR-T. It's a two-step approach where we delete off an antigen to a patient getting a bone marrow transplant, and then we follow up with a therapeutic that targets that particular antigen.
What we do by this process is create that specific cancer-specific antigen, then we can enable treatment post-transplant. We think this approach can enable a CAR T and AML, but there's a lot of other diseases we could use this approach for, such as MDS, NHL, and multiple myeloma and T-cell malignancies. Tirtha will talk about that later. It's a very exciting broad platform, and we now can say that we have the initial proof of concept of we've edited out CD33 out of one patient's transplant and grafted successfully.
Great. Thanks for that overview. With any platform, I, as you guys know, process product development becomes extremely important. Maybe we can start from there, you know, in terms of, you know, starting material, how you're thinking of manufacturing, you know, what are some of the targets for turnaround time and, you know, gene editing efficiency that you're sort of working towards, where you're at and what sort of targets you've set out as you look to have this in-house manufacturing process set up?
Our process is actually pretty simple. It's 7-10 days vein to vein time. In terms of cell therapy, it's pretty short. With the process it starts with an allogeneic transplant, at least for AML, 'cause that's standard of care. We find a matched donor. It could be related or unrelated. For our first trial, we are requiring a 10 out of 10 match. However, we can loosen that requirement as we go forward. We just didn't wanna introduce extra variables in our lead trial. The process is we take those cells, there's a prep step, but then we do a CD34 selection. That pulls out all the stem cells. Then we can delete specifically the stem cells, and we use CRISPR-Cas9 in our lead program to delete off CD33.
Then we take those cells, and we can put them back in the patient. When we can do this 7-10-day processing time in parallel as the patient is going through consolidation, induction, and myeloablation. Actually there's no impact onto the patient in terms of timing. Then we can have those cells, put them back in the patient, it can repopulate the immune system as I was just mentioning, and then we created our cancer-specific target. The cool thing about this process is when we do that CD34 selection, where we pull out the stem cells, the waste fraction is actually billions of T-cells. These are healthy allogeneic T-cells we then can use to create a CAR T.
Of course, those cells are perfectly a match to the new immune system in the patient, so it has all the benefits of like traditional autologous CAR Ts, but with the healthy cells like the allogeneic. We're gonna create that CAR T and use those post-transplant. I think that has the potential to really transform the outcomes of those patients.
You know, we will get into the clinical data that was out there last quarter, but maybe just if you could build on that sort of two-pronged strategy that you're taking. The CAR-T effort with your system is extremely important to investors. Could you sort of touch upon like how you're thinking of the CAR-T autologous effort and also sort of building capacity towards the allogeneic effort also in the back end? It looks like the CAR-T that you licensed is closer to IND. What are sort of the remaining steps there?
Hi, Mayank. The autologous CAR-T program is actually led in collaboration with NCI, National Cancer Institute. We are using the exact same construct to make our own allogeneic CAR-T program. The construct is not being changed, but the cells are different because this is not from the patient. The NIH trial is happening with pediatric to young adult patients, whereas we are going to use adults for this. The allogeneic program, we are doing a monotherapy trial. The IND is required first as far as the agency's opinion is concerned. The final aim is to do exactly what Nathan is saying, to put it as a treatment system in combination with the CD33 knockout hematopoietic stem cell transplant. We are filing the IND for the monotherapy for allogeneic CAR-T in the first half of this year.
We are all guns blazing, as you may imagine at this point. Everything looks good and the manufacturing is in-house, so everything is under control.
Got it. Next, maybe if we could dive deeper into the ongoing phase I, II trial that you have. Again, you know, you're doing this to establish and understand the proof of concept for the platform, but it does have, you know, important clinical implications. In a setting very difficult to treat AML post-transplant. Could you sort of touch upon the trial sort of design, the key objectives you set out and how far along we are and what this initial data set kind of taught us about sort of next steps to take from here?
This is ongoing phase 1/2 trial. We're enrolling AML patients with intermediate who are intermediate and high risk and who are MRD positive going into transplant. These are patients with a lot of unmet need. What the trial is, we enroll the trial patients, find a donor that's 10 out of 10, as mentioned earlier. We find, we process those cells and have them ready, so when the patient is ready for the transplant, we'll have those cells ready. The first readout is engraftment. This is just to show that we can delete off CD33 and it's safe. The first patient we reported, we gene edited 88% of the CD33. That's much higher than our cutoff of 50%.
Routinely we get gene editing in that range, somewhere between 70%-90%. That was great to see that we're able to do that, get it into the patients. Within 28 days, we were hoping to see engraftment. This is neutrophil engraftment. What we saw is around day 11, that it engrafted or met the traditional criteria of engraftment, which are neutrophils above 500 per microliter for three consecutive days. That was great to see, and that was important proof of concept because nobody's ever done this before. Nobody's deleted off CD33 off a bone marrow transplant. We know there are people out there without CD33, but we don't know if there's some compensatory mechanism. At least in this one patient, it appears safe.
Starting at day 60, we start dosing with Mylotarg, all right? Which is actually day 60 to 90. In that range here, we start dosing just shortly after day 60, well, with 0.5 migs per meter squared Mylotarg. This dose would typically cause severe neutropenia if you go look at the Mylotarg phase I, II trial or the old phase I trials with Mylotarg. What we saw is that absolutely no neutropenia at all, no detectable myelosuppression. We also saw no evidence of liver tox. This is great proof of concept that we can delete off CD33 in patients and protect from the Mylotarg toxicities.
That's really what we wanted to show by this trial, and that's why we moved forward initially with Mylotarg, because it was already on the market. We could get to the clinic quick and demonstrate this. At least we have 1 patient. We'll be continuing to enroll patients throughout this year, so we have additional updates. It'll be interesting to see PK data at upcoming medical conferences, repeat dosing of Mylotarg. We could also look for CD33 selection because of course, we didn't delete out all the CD33, so there is some residual CD33 in the bone marrow. Can we select against the CD33 expressing cells? That's something to watch. We'll get those updates, and that'll be an important surrogate as we go along here.
Just to remind everybody that Mylotarg is usually not used in this setting. This is just showing that we can use Mylotarg in this setting is a huge step forward for these patients because we already know that Mylotarg is an effective drug. I mean, there's multiple phase III trials run on Mylotarg demonstrating that. The issue is patients don't tolerate it, and that's why it sells at just about $60 million a year in the US. It looks like at least one patient we've shown we could tolerate it, the patient can tolerate it. Ultimately, you know, we will show additional patients later on this year.
Have you said, in terms of, how you expect the enrollment and sort of what conferences or what timeframes we would see some additional data sets, Nathan?
We haven't been explicit in terms of what conferences, but you can look at the major hematology conferences such as EHA and ASH, you can expect those are ones we're at least thinking through about releasing data. There's some actually more near-term conferences that we could release at least this one patient worth the data at, because we just press released the patient, we've never presented it at a medical conference. We'll probably see that piece of data more near term at a conference. In terms of enrollment, there is a stagger that we're contending with here. We have to, at least for the first three patients, see engraftment before we dose the next patient. That's on engraftment side. In terms of Mylotarg dosing, it's a dose escalation trial.
It's a 3x3 dose escalation of 0.5 for the first three, and then it's 1.0, and then 2.0 megs per meter squared. At each new dose of Mylotarg, we have to go treat one full cycle before we can dose the 2nd patient at that dose. It will continue to contend with the stagger, which will mean the data will come in slowly. We think, you know, throughout this year we'll have actually a meaningful, some type of at least larger data set than the one patient, obviously, by mid-year. What I will say is that, you know, once we have that one patient's worth of data, the sites that we have open, you know, saw this and, like, there's a lot of demand and interest in this trial.
Actually, we have more demand than we can meet in the near term because obviously these patients can't wait, like, three, four months to get a transplant. These are high unmet need or high-risk patients. You know, we have all the slots up for the next few months all booked out. The demand's there. We're just managing the stagger. You know, we're pretty confident we'll have a reasonable data set by mid-year we can share with people.
Going to the conferences like ASTCT, like some of these near conferences could help with the investigators. To be clear, Nathan, the goal will sort of remain even with those escalation, even with some of the more patients to kind of get this engraftment, the % CD3 depletion that you saw and then the impact on neutropenia and some of the safety advantages. That sort of like set the bar now and we just have to see that replicate with more subjects as you go higher doses. Is that kind of fair to-?
Yeah. That's fair. You know, this is a dose escalation, and we're doing PK studies to figure out what is the right dose of Mylotarg, because we know the PK is gonna be different in these patients that don't express CD33 in their bone marrow. Maybe actually 0.5 is the correct dose. You know, that's why we're doing this trial and some subsequent trials just to figure out what is the optimal dose of Mylotarg. I think that's where we're at in terms of Mylotarg. Obviously, longer term, we're really interested in the CAR T. There is a possibility that there may be a portion of patients that maybe Mylotarg is appropriate for them, and then CAR T is appropriate for other patients.
We'll be data dependent as we go forward, depending on how these two different drugs work. I mean, we know Mylotarg, you know, isn't a perfect drug. I mean, it achieves complete response rates in re-relapsed/refractory AML of around 25% of patients. It's not an amazing drug. You know, we could make it look better, you know, based on the dosing, even if we made that look a little bit better, we think long term, the CAR T is the future. Of course, it's not just single editing CAR T. We have some very exciting work in-house. We're deleting out multiple antigens, CD33 and CLL-1, and we're developing multi-specific CAR Ts. We think that's very exciting as, you know, our second generation asset where we could even drive deeper responses in patients and prevent antigen escape.
Could you talk a little bit more on that decision tree for the CAR T, autologous and allogeneic, sort of how that progresses in the next year and couple of years? When would you sort of have to make that decision, you know, what that, you know, visionary treatment system looks like with DM cells?
Just to make it clear, how do we describe VOR? What kind of a company is it? It is a company of next generation transplant, fundamentally it is a treatment system company. Treatment system means on one side we come in with a really powerful immunotherapy, to keep the nascent hematopoietic system safe, we come in with the next generation transplant. In that setting, everything is allogeneic. The autologous is happening because we wanted to de-risk as naturally the construct, NCI was moving forward with that, we are in partnership with them. The real deal is the allogeneic. The decision has been made. It's not a decision tree that we are waiting for any further.
The next layer of decision that we need to make, to Nathan's point, what kind of molecules are we combining together to get a deeper response and protect ourselves or protect the patient from potentially untoward consequences as people in the B-cell field have already encountered? When you hit a target really hard, like CD19, there are events that can happen, for example, antigen escape, that the field was not prepared for. We want to get ahead of that kind of a situation and prepare for it. We want to truly own the AML transplant space by going as wide and as deep as possible.
To that end, choice of targets become interesting and, you know, CD33 obviously very well characterized and the expression profiled, we all know, you know, very well understood. How with your sort of multiplex efforts and some of the, you know, next generation work that you're doing, what sort of other targets and, sort of characterization that you're doing with them, should we expect to hear in the coming, say, year and two years?
Very important question. Obviously it has to be expressed on the AML cell surface. As Nathan said in the beginning, there's hardly any tumor-specific antigen which is truly tumor-specific. There is a great possibility, and in our case, what we have seen in all cases, basically, they're also expressed in normal cells. If that is the case, then we need to delete them from the next generation transplant that we are trying to create. Biological dispensability of these molecules is critical. CD33, we know, and has been shown by multiple publications and our own internal work that is biologically dispensable. We have other prominent AML surface antigens that we are exploring, and we have found at least two, three of them, which also have turned out to be biologically dispensable.
Some of these things we have already published and also presented in various conferences. One possibility is very high that CD33 is going to be a partner for any of the new molecules for multiplexing work, but we are also going to create multi-pronged CAR-T to complement this transplant. CD33 directed plus something else.
In that context, Nathan, you know, collaborating with, you know, other innovators who are trying to do that, from a CAR-T standpoint, could be a direction you could go in. Just maybe touch on what sort of, you know, strategic collaborations and sort of partnerships that could kind of make sense for you to, you know, as obviously this field is very broad and, you know, you were opportunistic with the NCI program to kind of do the autologous stuff.
And like how much do you think you could kind of do, you know, independently with the, obviously starting with the allogeneic CD33, but, if you are going into multiple targets, is doing a sort of a broader collaboration and tapping into expertise externally also making sense?
Yeah, it does make sense for our platform. Our platform, the core part of the platform is the eHSC, deleting off the CD33. We chose to pair it with a CAR-T that we in-licensed, as you mentioned, because we thought it was such a great fit. We're open to other pairings, and so we could continue to bring Mylotarg forward, and develop it as with the eHSC. We also have a collaboration with J&J to look at their bispecifics. A lot of people have gone after these same targets, but ran into CRS or myelosuppression issues, and we could fix a lot of those toxicity issues. We're open to all these different collaborations.
Of course, we don't want to give away the farm in terms of some of these collaborations, so we'll try and be very smart about how we go forward. What we really wanna do is just pair our eHSC with the best asset afterwards, and we're gonna be data-driven, you know, as we go forward and keep our eyes open, and our BD team is out there, you know, scouring the earth, but looking for these assets that are, you know, CD33, CLL-1, and some of these other targets. That's externally. Internally, we also are developing our own binders and have some collaborations with third parties to develop our own binders. 'Cause actually, for some of these targets, they're just not good binders or CAR-Ts out there in existence.
Maybe, to just close on the corporate question. With the recent data set, Nathan, you did do take care of the balance sheet, you know, at least, to extend the runway. How sort of are you thinking about with the manufacturing scale-up and some of the trials, expanding about the R&D expenses and what have you said on the runway guidance?
As of third quarter, that's our last earnings reported, we had $136 million, we just raised $116 million with this financing. That's gross, you gotta take out some of the bankers' yachts and houses in Colorado. You add that extra quarter, you know, we still have well over $200 million in cash, you know, after you net everything out, that gets us easily into 2025. We have a lot of runway to prosecute the development of both the CAR-T and the eHSCs, including expanding into multi-target. You know, I think we're in a, we're in a really good spot.
We're very fortunate to be in a very good spot here with a bunch of data readouts this year, which as we mentioned earlier, is updates on our trem-cel program, which is gonna be that redose Mylotarg, additional patients on engrafted and with Mylotarg, then the CAR T IND. It shouldn't take us too long beyond that to generate data in addition to other platform work in terms of looking at new editing enzymes, looking at multiplex and other targets to go after. It's gonna be a quick year.
Great. Just a quick inbound question, if I may squeeze in. The regulatory dialogue and input you've had You know, taking this through the finish line and what might be, you know, some of the common framework discussions that we have for gene editing platform could or could not be applicable for you. Could you also touch on that?
We've done a lot of work here. Of course, if you compare what we're doing to some of the other programs who aren't going after in areas of such high unmet need, the bar could be lower for us. That's not our assumption from the FDA. In fact, you know, we think we have some of the best in class in terms of trying to understand off-target editing. I'll let Tirtha respond to that about everything he's done to provide confidence to FDA that our program is safe.
It started actually even before I joined Vor. I was the head of hematology at CRISPR Therapeutics, where we developed the hemoglobinopathy program practically for the first time in the world with gene-edited hematopoietic stem cells. What we learned from the agency is that their expectations were already very high. We took that platform, which was a non-malignancy platform, and raised the bar even higher, even for ourselves, because what we learned there, not only that we applied it here, but even pushed it further. We have done a deeper analysis, and we continue to do so for, you know, off-target impacts, because that's one of the concerns for genome editing, because you are editing stem cells. They're going to stay there forever.
The agency, when they came back after we filed our IND, didn't have a single question about off-target analysis because we had learned, some of us, being in our previous career, had learned it, what they were expecting. We have gone further than that. We are not lowering our standards, even though we are in the malignancy field right now.
Okay.
The question is very well put, and we are ahead of the game.
Okay. With that, I think we've run out of time. I really wanna thank you for being part of the conference and doing this fireside chat and look forward to the updates in over the course of 2023. Also, thankful to our audience for tuning in. With that, we can end this session.
Thank you.
Thank you, Mayank. Great questions.