Vor Biopharma Inc. (VOR) Earnings Call Transcript & Summary

Good afternoon, and good morning, for folks still here on the West Coast. So we'll get started with the 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. And for the audience, thank you for being part of this, and feel free to e-mail me directly questions at [email protected]. Obviously, that the team, Nathan, Tirtha, you've had a very productive end of 2022. On the back half of the year, you had initiated manufacturing in-house 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.

So we'll dig into all those different components one by one, but at the highest level, Nathan, could you get us started about -- at the highest level, how you think about Vor and sort of going into 2023, what should be the goals that you're looking to accomplish?

Yes. Well, thanks, Mayank. Thanks for having us here at the B. Riley conference. We're excited to participate but 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 in engrafts and it protects against Mylotarg, but we'll get more into that later. What I want to start out doing is just talking about our platform and what we want to do in terms of our approach. So what we do here is we solve one of the big problems for cancer drug development. And that's finding a cancer-specific target. And so our approach was founded by Sid Mukherjee. 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 an antigen and for our lead program, it's CD33. And then you can transplant that patient with those cells, repopulates the immune system. The immune system is -- now doesn't express that particular protein. However, any residual cancer still does. And so now you can target that cancer specifically. So our lead program, and we'll talk about it, we use an ADC Mylotarg, which was the first approved ADC. But what we ultimately want to do is combine that with the CAR-T. So we in-license a CAR-T. So it's a 2-step approach where we delete off an antigen to a patient getting a bone marrow transplant, and then we follow up with the therapeutic that targets that particular antigen. And what we do by this process is create that specific -- cancer-specific antigen, then we can enable treatment post transplant. And so we think this approach can enable a CAR-T in 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. And Tirtha will talk about that later. So very exciting broad platform, and we now can say that we have the initial proof-of-concept, we've [ added off ] CD33 out of one patient who transplant and then engrafted successfully.

Great. Thanks for that overview. And with any platform, as you guys know, process/product development becomes extremely important. So maybe we can start from there in terms of starting material, how you're thinking of manufacturing? What are sort of the targets for turnaround time and 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 [ that you have? ]

Yes. So our process is actually pretty simple, 7 to 10 days, vein-to-vein time. So in terms of cell therapy, it's pretty short. And with the process, it starts with an allogeneic transplant, at least for AML because that's standard of care. We find a match 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 want to introduce extra variables in our lead trial. So the process is we take those cells, [ there's a prep step ] but then we do a CD34 selection. So that pulls out all the stem cells. And then we can delete specifically the stem cells, and we use CRISPR/Cas9 in our lead program to lead off CD33. And then we take those cells and we can put them back in the patient. So when we can do this 7- to 10-day processing time in parallel as the patient is going through consolidation, induction and myeloablation. So actually, there's no impact onto the patient in terms of timing. And so then we can have those cells, put them back in the patient. It can [indiscernible] immune system, as I was just mentioning, and then we created our cancer-specific target. But a 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. So these are healthy allogeneic T cells. We then can use to create a CAR-T. Because 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 were with a healthy cells like the allogeneic. So we're going to create that CAR-T and use those post transplant. And I think that has the potential to really transform the outcomes of those patients.

And we will get into the clinical data that was out there last quarter. But maybe just if you could build on that sort of 2-pronged strategy that you're taking. I know the CAR-T effort with your system is extremely important to investors. So 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 because it looks like the CAR-T that you license is closer to IND. What are sort of the remaining steps there?

Yes. 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. So the construct is not being changed, but the cells are different because this is not from the patient and the NIH trial is happening with pediatric to young adult patients, whereas we are going to use else for this. And the allogeneic program, we are doing a monotherapy trial. The IND is required first as far as the agency's opinion was concerned, but the final aim is to do exactly what Nathan is saying, to put it as a treatment system in combination with the CD33 [indiscernible] hematopoietic stem cell transplant. Now we are filing the IND for the monotherapy for allogeneic CAR-T in the first half of this year. And 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. And next, maybe if we could dive deeper into the ongoing Phase I/II trial that you have, again, you're doing this to establish -- understand the proof-of-concept for the platform, but it does have important clinical implications. So in a setting very difficult to treat AML, most transplant. So could you sort of touch upon the trial, sort of design, the key objectives you set out? And how far along we are, then -- and what this initial data set kind of taught us about sort of next steps you take from here?

So, it's an ongoing Phase I/II trial, we're enrolling AML patients with intermediate -- who are intermediate and high-risk and who are MRD positive going into transplant. So this is -- these are patients with a lot of unmet need. And so what the trial is -- we enrolled 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. And then the first readout is engraftment. So this is just to show that we can delete off CD33 and it's safe. And the first patient we reported, we gene edited 88% of the CD33. And so that's much higher than our cutoff of 50%. And routinely, we get gene editing in that range, somewhere between 70% to 90%. So that was great to see that we were able to do that, get it into the patients. And then within 28 days, we were hoping to see engraftment. So this is neutrophil engraftment. And what we saw is around day 11 that it engrafted or met the traditional criteria of engraftments which are neutrophils above 500 per microliter for 3 consecutive days. So that was great to see, and that was important proof-of-concept because nobody has ever done this before. Nobody's deleted off CD33 off of bone marrow transplant. We know there are people out there without CD33, but we don't know if there's some compensatory mechanism. But at least in this one patient, it appears to say -- And then starting at day 60, we start dosing with Mylotarg ODAC which is actually day 60 to 90. So in that range. Here, we started dosing just shortly after day 60, well with 0.5 mg per meter squared Mylotarg. So 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 absolutely no neutropenia at all. No detectable myelosuppression. We also saw no evidence of liver tox. So this is great proof-of-concept that we can delete off CD33 in patients and protect from the Mylotarg toxicities. And 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 in the market, we could get to the clinic quick and demonstrate this. And so at least we have one patient. We'll be continuing to enroll patients throughout this year. So we have additional updates. It will be interesting to see PK data at upcoming medical conferences, repeat dosing of Mylotarg. We also look for CD33 selection because, of course, we didn't delete up all the CD33. So there is some residual CD33 in the bone marrow. Can we select against the CD33 expressing cells? So that's something to watch. And so we'll get those updates, and that will be an important surrogate as we go along here. But just to remind everybody that Mylotarg is usually not used in this setting. So 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 around Mylotarg demonstrating that. The issue is patients don't tolerate it, and that's why sales are just about $60 million a year in the U.S. But it looks like at least one patient we've shown he could tolerate it -- the patient can tolerate. Ultimately, 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 time frame we would see some additional data set, Nathan?

So we haven't been explicit in terms of what conferences, but you can look at the major hematology conferences such as EHA and ASH, and you can expect those are ones we're at least thinking through about releasing data and there's some -- actually more near-term conferences that we could release at least this one patient, worth of data ad because we just press released the patient. So we've never presented it at a medical conference. So we'll probably see that -- that piece of data more near term at a conference. But in terms of enrollment, there is a stagger that we're contending with here. And so we have to at least for the first 3 patients, see engraftment before we dose the next patient. So that's on the 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 3 and then it's 1.0 and then 2.0 mg per meter square. So at each new dose of Mylotarg, we have to go treat one full cycle before we can dose the second patient at that dose. So it will continue to contend with the stagger, which will mean that data will come in slowly. But we think throughout this year, we'll have actually a meaningful -- some type of at least larger data set than the one patient, obviously, by midyear. And what I will say is that once we have that one patient's worth of data, the sites that we have opened saw this and that there's a lot of demand and interest in this trial. So actually, we have more demand than we can meet in the near term because obviously, these patients can't wait like 3, 4 months to get a transplant. These are high unmet need or high-risk patients. And so we have all the slots up for the next few months all booked out. So the demand is there. We're just managing the stagger. We're pretty confident we'll have a reasonable data set by midyear, we can share with people.

And going to the conferences like [ ASCD, ] like some of these conferences could help with the investigators and to be clear, Nathan, the goal will sort of remain even with dose escalation, even with some of the more patients to kind of get this engraftment [indiscernible] depletion that you saw and then the other impact on neutropenia and terms 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...

Yes. That's fair. But this is a dose escalation, and we're doing PK studies to figure out what is the right dose of Mylotarg because we know that PK is going to be different in these patients that don't express CD33 in the bone marrow. So maybe actually 0.5 is the correct dose. That's why we're doing this trial and some subsequent trials, just to figure out what is the optimal dose of Mylotarg. And so I think that's where we're at in terms of Mylotarg. Obviously, longer term, we're really interested in the CAR-T. But there is a possibility that there may be a portion of patients that maybe mild target is appropriate for them and a CAR-T is appropriate for other patients, but it will be data dependent as we go forward depending on how these 2 different drugs work. I mean we know Mylotarg -- is it a perfect drug? I mean obviously it achieves complete response rates in relapsed/refractory AML around 25% of patients. So it's not an amazing drug. We could make it little better based on the dosing. But even if we made that look a little bit better, we think long term, the CAR-T is the future. And then, of course, it's not just single editing CAR-T. We have some very exciting work in-house. We're delaying up multiple antigens, CD33 in CLL1, we're developing multi-specific CAR-Ts. And we think that's very exciting as 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 and sort of what -- when would you sort of have to make that decision, what that visionary treatment system looks like [ trem-cel? ]

Yes. So 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. But fundamentally, it is a treatment system company. Treatment system means, on one side, we come in with a really powerful immunotherapy and to keep the nascent hematopoietic system safe, we come in with the next-generation transplant. Now in that setting, everything is allogeneic. The autologous is happening because we wanted to derisk as naturally the construct and NCI was moving forward with that, and we are in partnership with them. But the real deal is the allogenic. So the decision has been made. It's not a decision tree that we are waiting for any further. Now 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 our cells 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. So we want to truly own the AML transplant space by going as wide and as deep as possible.

So to that end, a choice of targets become interesting and CD33, obviously very well characterized and the expression profile, we all know -- very well understood. So how -- with your sort of multiplex efforts and some of the 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 2 years?

Very important question. So obviously, it has to be expressed on the AML cell surface. But as Nathan said in the beginning, there is hardly any tumor-specific antigen, which is truly tumor specific. So there is a great possibility. And in our guess whatever we have seen in all cases, basically, they are also expressed in normal cells. So if that is the case, then we need to delete them from the next-generation transplant that we are trying to create. So 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 2, 3 of them, which also have turned out to be biologically dispensing. And some of these things we have already published and also presented in various conferences. Now 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 multipronged CAR-T to complement this transplant. So CD33 directed plus something else.

So in that context, Nathan, collaborating with 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 strategic collaborations and -- and sort of partnerships that could kind of make sense for you to -- obviously, this field is very broad and you were opportunistic with the NCI program to kind of do the autologous stuff? And like how much you think you could kind of do independently with the -- obviously, starting with the allogeneic CD33. But if we are going into multiple targets, is doing sort of a broader collaboration and tapping into expertise externally is also making sense?

Yes, it does make sense for our platform. So our platform, the core part of the platform is the EHSC, so deleting off CD33 and then we chose to pare it with a CAR-T that we in-licensed, as you mentioned, because we thought it was such a great fit. But we're open to other parents. 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 biospecifics because 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. And so 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. But what we really want to do is just pay our eHSC with the best asset afterwards. And we're going to be data-driven as we go forward. And keep our eyes open and our BD team is out there, scouring the earth, looking for these assets that are CD33-CLL1 and some of these other targets. But that's externally. Internally, we also are developing our own binders and have some collaborations with third parties to develop our own binders because actually, for some of these targets, they are just not good binders or CAR-Ts out there in existence.

And maybe to just close on the corporate question. Obviously, with the recent data set, Nathan, you did do take care of the balance sheet at least to extend the runway. How sort of are you thinking about the manufacturing scale up and some of the trials expanding about the R&D expenses and what have you said on the runway guidance?

So we -- as of third quarter, that's our last earnings reported, we had $136 million, and then we just raised $116 million with this financing. And that's gross. So you got to take out some of the bankers' yachts and houses in Colorado. But then when you add that extra quarter, we still will have well over $200 million in cash, after you net everything out. And that gets us easily into 2025. So we have a lot of runway to prosecute the development of both the CAR-T and the eHSCs, including expanding into multi target. So I think 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 going to be the redose Mylotarg, additional patients on -- engrafted and with Mylotarg than the CAR-T IND. And then 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. So...

Great. And just a quick inbound question, if I may squeeze in. The regulatory dialogue and input you've had in sort of taking this through the finish line and what might be some of the common framework discussions that we have for gene editing platforms, could or could not be applicable for you? Could you also touch on that?

So we've done a lot of work here. And 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, and the bar could be lower for us. But that's not our assumption from the FDA. In fact, we think we have some of the best-in-class in terms of trying to understand off-target editing, but I'll let Tirtha respond to that about everything he's done to provide confidence to FDA that our program is safe.

So it started actually even before I joined Vor. He 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. And 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. So we have done a deeper analysis, and we continue to do so for off-target impacts because that's one of the concerns for gene editing because you are editing stem cells. They're going to stay there forever. So -- and 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 carrier had learned what they were expecting and we have gone further than that. And we are not lowering our standards even though we are in the malignancy theme, right now. So your question is very well put, and we are ahead of the game.

Okay. With that, I think we've run out of time, but I really want to thank you for being part of the conference and doing this fireside chat and look forward to the update in -- over the course of 2023. And also, thankful to our audience for tuning in. With that, we can end this session.

Thank you, Mayank. Great questions.