All right we're going to go ahead and get started. I'm Stephen Willey, one of the Senior Biotech Analysts here at Stifel, and glad to have with us for the next session, Robert Ang, who is the CEO of Vor Biopharma. We're going to have an informal discussion. If anyone has a question, feel free to raise your hand, and we'll get your question answered. Robert, before we jump into Q&A, I know we've done a bunch of these over the years, but any opening comments you want to make about the Vor story?
Yeah, sure. Take a seat. Thanks for having me, firstly. Great to be here. So I just want to remind people what Vor is and what we're trying to do. So Vor Bio, we're trying to cure cancer. We're essentially focusing on.
Trivial mandate.
Indeed, very much. But we're quite serious about it. So we are focusing on acute myeloid leukemia and myelodysplastic syndrome, AML and MDS, which are terrible blood cancers. And in these blood cancers, as people may well be familiar with, these cancers look a lot like healthy bone marrow. And that's the reason why we can't kill this stuff, because you kill it, and you also kill your reason to survive. And so we're trying to fundamentally change that equation by making shielded stem cell transplants and essentially replacing the patient's blood system with a blood system that now is immune to certain anti-cancer drugs. And so by doing that, we're trying to totally reverse the way you think about treating cancer patients, aiming for cures, we don't say that lightly, by essentially providing a shielded blood system that can really allow you to treat cancer in a wholly different way.
I think it's a really exciting time for Vor, because now we're in the process of not just putting science fiction into the clinic, but now we're actually starting to read out patients as they continue on our study, receive a drug that should be extremely toxic, but turns out it isn't. But more importantly, that we can look at longer-term outcomes of these patients and see how they're doing. It is a very exciting time for where we are.
OK. So I know at next month's ASH meeting, you're going to have a pretty meaningful update from the phase 1/2 VBP101 trial, so this is evaluating trem-cel transplantation, followed by Mylotarg dosing in the AML population you just spoke of, so how will this data build upon the update that you provided back in September? What will be incremental in terms of patient numbers, duration of follow-up, and then what are some of the data points that you think investors should be paying particular attention to?
Sure, so just to level set, our clinical trial involves AML patients who are all transplant eligible, and they're receiving our gene-modified stem cell transplants, so these are cells that have undergone a process to delete out CD33 permanently from these cells, and then we put that in as the transplant. Now, what we have read out previously are the following: that firstly, these cells do migrate to bone marrow and start producing a blood system, which seems to be very similar to the same blood system they would receive from a regular stem cell transplant, but on top of that, we're also providing a drug called Mylotarg to these patients. Now, Mylotarg is a marketed drug by Pfizer. It attacks CD33-expressing cells, and in our patients, because we've deleted it out from their blood system, we're hoping that Mylotarg is relatively safe.
But what we found in the prior data disclosure is that even at higher doses of Mylotarg, we don't see that typical blood toxicity. And then, of course, as we have read out in the very last data release dated in July, that we're starting to see some early results where these patients who should be relapsing, that they are not. Now, our prior data set contained 18 patients. Now, we've just disclosed that we have treated 25 patients with trem-cel, so there's an incremental seven patients on top of what we've disclosed before. But more importantly, there's now longer follow-up. So as we continue to track these patients, every few weeks is super meaningful, because these patients all should be relapsing between month four to six. Now we'll have a median time of follow-up of over seven months.
That could be very interesting as we track these patients and how they do. There's more patients, but more importantly, longer follow-up for these patients.
OK. So you said your median time or median duration of follow-up as of the ASH presentation should be around seven months?
That's correct.
OK. And I'm guessing you've also indicated that these additional patients in the presentation will have seen Mylotarg at the higher 2 mg/m² dose, which is interesting, because we know that this is the dose for which any appearance of hematological toxicity should be very well known, specifically given the exposures that you guys are generating. So how important is it for these additional patients in terms of tightening that confidence interval around the exposure data that you have? And then how many more patients' worth of data do you want or think that you will need in order to externally validate the shielding hypothesis of trem-cel, whether that's to an investor, whether it's to a regulator? How big of a data set do you need at that 2 mg/m² dose?
Sure. So yeah, we had previously disclosed three patients who received two mg. We'll have many more. I can't tell you exactly how many in this new data set. There will be patients who receive multiple doses of that two mg, so that's going to be really important. I think when we tackle the question about what do we need to understand at two mg, I think there's a couple of questions we have to answer. One is the pharmacokinetics. Now, again, we had released data on three patients. I think we need to see the reliability of that data with a greater data set. But I don't think it's a huge number. I don't think we need, for example, more than even five or six patients to really understand what that PK looks like. The second is safety. We have to understand, is Mylotarg causing untoward toxicities?
We know that Mylotarg is famous for causing liver toxicity. How well are these patients doing? Again, I don't think we need a massive data set there, because so much is understood about Mylotarg already. What do we need to understand in terms of efficacy? Well, again, I think we have reason to believe Mylotarg is going to be efficacious based on the PK that we have. But even now, I think we're seeing hints that even lower doses may cause some good relapse-free survival. So again, I don't think it's a massive data set. But I think most important is that we are seeking feedback from regulators. We haven't disclosed exactly when, but that should give clarity on exactly what FDA is looking for prior to starting a pivotal trial.
OK. And the relapse-free survival data that we saw for the first time in September, I think, was pretty interesting. Again, not only because it outpaced some of those historical benchmarks that you referenced, but I think also because these patients in the 1/2 VBP101 trial just had really bad prognostics to begin with. So should we expect that the incremental patients who get added to that relapse-free survival curve, that ASH, are going to be a continuation of that trend in terms of poor prognosis?
Yeah. Obviously, I can't tell you what it would look like. But what we would love to see is that the relapse-free survival trend not just continues, but potentially strengthens. Since our follow-up was so limited in their initial data set, less than six months average follow-up, that we want to see an affirmation that these patients are not relapsing when they should.
OK, and yeah, no, I guess I wasn't asking about the trend in RFS, because I don't think you'd obviously make a comment about that, but just whether or not these next seven patients fit that same trend of being very poor prognosis.
Oh, I see. Yeah. So we're probably going to give even more color on the risk factors these patients are bearing going into the study. And I would say our trial, there's very little for patients out there with AML, especially those who are undergoing transplant. And so our investigators have actually inundated us with patients.
The worst of the worst.
Yeah, who need help. And so it's not surprising that we had a patient with 78% blast going to the study, or with p53 mutations. And so we are still fielding these kinds of patients. And we're glad to, because these are the patients who are eligible for the trial. I think going into phase three may be a different story, because, of course, we need to be a little stricter about the way that we control patients across groups.
OK. I know the pace of enrollment into this trial has picked up considerably over the last four to five months. And I think it now appears to be tracking to your manufacturing capacity, which is about a patient per week. So has that capacity become rate limiting now to enrollment? And I guess, are there investments that you either want or need to make on the manufacturing front to improve that capacity?
So the math on capacity is really simple. It takes about seven days for the product to be made. After seven days, you can start a new batch. So that means you can get roughly four batches from one manufacturing suite. And we actually have two suites set up at our CDMO to do this. But we only have one live at the time, because that's all we need to supply a phase I study. We're not planning to expand that at this point, again, because we think we have almost the data set that FDA may want to look for prior to starting phase III. Now, starting a phase III study is a wholly different game. We would love to ramp up as quickly as possible.
So we can simply just activate that second suite, double that capacity, and that would be plenty enough to supply a phase III study.
OK. And then how scalable is that expansion in terms of just expediency? Is there some beta testing that needs to be done first, or?
No. We have a relatively locked-down manufacturing process right now. We are making some tweaks before we enter phase III just to make it that bit more reliable. But there's no fundamental changes to the process. And we're instituting these changes prior to the phase III, which I think will de-risk the trial even further. And that's a very scalable process. We simply just need to add a facility, add one suite, and it immediately adds four slots per month.
OK. So I know you had also amended the protocol a while back to include the enrollment of MDS patients.
Yes.
Have you seen any MDS patients come in? And I guess, would you expect that trajectory of post-transplantation outcomes to look any different?
Sure. So we'll provide an update there on MDS enrollment in this next data update. MDS, as you can appreciate, they have 1,200 transplants a year for very aggressive MDS. And these patients face the same kind of prognosis as do AML. So they need all the help they can get. These MDS tumors are also very strongly CD33-expressing. So we think that this could be of great benefit. At this point, we're not thinking about integrating MDS into the core phase III trial, but that we could potentially tack on MDS in a way that could still leverage the data that we're generating in the phase III. But we'll have to see as we keep going.
OK, so I know back when you provided the update in September, you kind of proffered some registrational trial design proposals. You've indicated that you'd be soliciting feedback from FDA before the end of this year. Will you be in a position to communicate any of that feedback at time of ASH? And I guess, does the data that we see, or does the data that we'll see at ASH, does that comprise the totality of the data that you've brought to FDA to seek feedback on?
Yes, so as you can probably tell, cycle times of FDA are a little longer, just based on when you request a meeting and when you propose data versus when you actually receive feedback. What we have publicly guided towards is that we expect to have a regulatory interaction prior to year-end. We're still absolutely on track for that, and so we may or may not have some of that feedback in hand when the time ASH comes around.
OK. And I know back in September, you had offered up a couple of different registrational trial design proposals, with I think the differences being what a control arm might be. I think as of your most recent corporate update, you now seem to be perhaps settling on what looks to be a randomized control trial against an active control arm, or I guess a matched control arm. Can you maybe just talk about the shift there? And is there a preference at the company for you to pursue that randomized trial design as opposed to the use of, say, like an observational cohort?
Yeah. So we've been asking these questions about what would be not just most expedient, but also the most rigorous. Our current thinking is that FDA may well want a randomized design just because it has the best kind of control. There are pros and cons of it, though. It's like, for instance, if we were to move forward with the same patient population we've been using today with the 101 trial, we would introduce bias into a randomized design. Because if, say, a very high-risk patient were to be randomized to the control arm, there are compelling reasons why that doctor may well want to withdraw the patient's enrollment, because they would never want them to move to a standard of care transplant. And we cannot have those kinds of biases going into the study. So our current thinking is that the best control would be a randomized design.
The control arm would be receiving a standard of care transplant. We would then be providing trem-cel , which would have many advantages, including hopefully lower relapse rate, longer survival, but also even lower GVHD, and that we can more definitively demonstrate those endpoints in that randomized trial design. Based on discussions, we think we could enroll this pretty expediently too.
OK. Again, I think you mentioned at the outset that these are very difficult to treat patients. Presumably, a phase III trial will not include a patient who has active disease with a 78% blast count at baseline. But what are some of the collars that you're thinking about putting around patient eligibility criteria in the phase III to maybe better homogenize the patient population?
Yeah. So we still want to look at for patients who are of high risk of relapse after transplant. So that means, as we've looked in the phase I trial already, patients who are MRD positive, so this is between 0.1% and 5% blasts, patients who may have relapsed previously, patients who have a high mutational risk profile based on different criteria. So all of these would still be valid. The primary difference is we would not be taking these active disease patients, whether it's a 78% blast or even 6% blast. Often, in today's standard of care, those patients are not transplanted. And so I think limiting it to that patient population should not hurt enrollment.
OK. And given again that a lot of these patients are at risk of relapse, very high risk of relapse, is there any interest in maybe trying to pull forward the administration of Mylotarg ? So as of right now, you're doing it at day 60.
Yes.
I think if you look at the kinetics of trem-cel and engraftment in terms of platelet recovery and chimerism, it looks like you have everything in place well before that. So is there going to be an effort on your part to try to pull that administration of Mylotarg forward? Again, I would think you probably don't want to do that in the context of a phase III. But is there an additional phase I design that you would look to do to maybe get some data there?
So at this point, we're not planning on another phase I prior to the phase III. What we have been looking at is compressing that timeline. Because as you probably saw from the data, there were a couple of patients who relapsed just prior to that day 30 mark. And these are very aggressive cancers. Both of these patients had active disease going to the transplant. And we want to prevent those kinds of relapses too. So on discussion with our investigators, they felt that the safety profile of the day 60 Mylotarg was so clean and that the engraftment, as you mentioned, was so robust, they're comfortable moving towards something earlier. So what we're going to be hopefully baking into this phase III protocol is a way that the docs can dose as early as day 30.
And that way, we can hopefully prevent some of these earlier relapses. So that's something that we'd like to build in. And fortunately, the investigators are very supportive.
OK. And just by way of curiosity, those two patients who relapsed early, I guess just right before Mylotarg administration, was there anything about the editing efficiency of the graft that they received? So were those patients at the lower end of editing efficiency, whereby they had more of like a CD33 positive disease burden?
No.
No?
No. So those patients had high editing efficiency in the 90% range. And we don't think that the editing efficiency dictates the probability of relapsing.
OK. How do you think about the requirement, presumably you execute on this phase III if it hits? How do you think about the requirement as Mylotarg or for Mylotarg as post-transplant maintenance therapy, where it's currently not labeled?
It's not labeled.
Could that prove rate-limiting to the adoption of trem-cel transplantation in the commercial setting? Do you think that there's a stigma that currently exists around Mylotarg? And do you think that the data that you could generate in a phase III study would be sufficient enough to change that narrative?
We've tried to tackle this question by asking docs who are not familiar at all with Vor or trem-cel and asking their opinion of Mylotarg in light of certain data. What we showed them is the data that we've generated to date in the 101 study. What came back really surprised us. I think, yes, there's some skepticism about Mylotarg, but yes, it was launched 20 years ago and all this other history. Based on the profile that we gave to these docs, it was overwhelmingly positive. I think what they care about is less so the history, but more so about, can I do something for these patients that demonstrates reliable efficacy in this post-transplant setting where nothing is labeled for these patients? That's what they care about.
And so that's what we're trying to do here, is shift that standard of care based on data. So I think if we can generate data that in any way replicates what we've been seeing in the 101, I think we have a transformational treatment here.
OK, and going back to the notion of Mylotarg being used where it's not approved in the maintenance setting, we know that that's the case for a lot of AML drugs, specifically the targeted agents. So would you anticipate a phase III trial that uses a randomized control arm? Would you anticipate that the use of targeted therapy in the maintenance setting would be occurring in that control arm? And is that in any way to you a potentially confounding variable?
Yeah, so I think probably the FLT3 agents are probably the most pertinent here. Of note, the latest phase III did read out negatively in that setting. You could argue that the MRD positive patients, there was a little bit of a signal, but it still wasn't significant, at least in overall survival. They are used, though. I mean, lots of different drugs are used. Even chemo is potentially used in the post-transplant setting. I think most people are just very hesitant to use anything just because they can make the patients so sick and cytopenic. So we're expecting some degree of post-transplant maintenance in the control arm, but that being said, because of the cytopenias, I think the use is going to be very limited, and again, we're expecting an outsized efficacy signal trem-cel mylotarg.
OK. Maybe we can shift gears to VCAR33 (ALLO), so this is another post-trem-cel treatment option that you're developing, CD33 targeting, CAR-T. I think the goal here is to eventually marry this trem-cel into kind of this integrated treatment system, but has the success that you've seen with Mylotarg now in the phase I and obviously moving forward into a phase III, has that impacted at all the urgency with which you want to move VCAR33 through the clinic?
Not at all. Yeah, so we're all guns blazing with the VCAR program. It is in a separate protocol called VBP301, and that has been rolling very strongly, so what we need to see for 301 is we want to see the CAR-T being active, meaning it can control disease, reduce blast counts, hopefully cause complete responses in patients in this post-transplant setting, and that the safety is manageable. Our ambition is absolutely to eventually marry trem-cel with the CAR-T approach. We still need to generate that data set before we do so. In the meantime, I think it's fair to say that the data we've generated with Mylotarg is even better than we may have assumed, which fully justifies the phase III approach of Mylotarg, but it certainly doesn't preclude us moving forward with a CAR-T approach as we collect data going forward.
OK. I know you've shown us some of the first cohort of dose escalation data.
Yes.
I know that this was previously evaluated as an NIH-sponsored study, or?
Correct. Yeah. There was an NIH-sponsored study that looked at the same CAR-T construct.
And so how does that NIH clinical experience inform where you think you might need to push dose with this?
The NIH study was a slightly different drug product because it used autologous cells from the patients. We used allogeneic, which we think are a healthier phenotype. They saw efficacy at 10 million cells per kilo. We're starting at the dose of one million cells per kilo. We think our drug is potentially more potent because of the cell source. Again, they saw it at 10 times the dose. I think we'd like to explore that. We're in a dose escalation study that can escalate up to that 10 million dose. We'll see as the trial keeps on progressing.
OK. I know you constructed the VCAR33 (ALLO) trial, at least in terms of site selection, so that there was this possibility that a patient who relapsed trem-cel could find his or her way into the VCAR trial.
Yes.
Is that maybe proving a little bit more logistically challenging than you had thought? I mean, obviously, the trem-cel relapse data looks good. So perhaps there's not as many options there, but.
So I would say the logistical hurdles are not terribly high. But the fact is we just have had very few patients relapsing on the 101 study. So I think that's a really good thing. But we'll see as we go forward opportunities to treat patients on both programs.
OK, and then I know you also disclosed the in-licensing of a recently new asset.
Yes.
It's a CD45 targeting ADC.
Yes.
Why is this a good asset for Vor to develop? And what are the potential development opportunities that you're thinking about here?
CD45 is a very interesting target. It's expressed on virtually all blood cells aside from mature red blood cells. It's also expressed on pretty much all blood cancers. It is also a target that's expressed on early progenitor cells, true stem cells. The original purpose of this asset was as a conditioning agent where you don't need to use necessarily chemotherapy to ablate the bone marrow. We think that use is very interesting. It also could be useful in other blood cancers like AML or other things. In addition, we're looking at this from a Vor perspective where we are epitope-modifying CD45 and potentially moving down that pathway, which would open up to even more blood cancers than just AML or MDS. All of those are ongoing.
But this is an asset that we opportunistically purchased that we think has a lot of promise and is relatively close to the clinic.
OK. You've previously talked about multiplex editing.
Yes.
Where does that fit into the strategic list of priorities right now at the company?
Yeah. So multiplex engineering is going ahead, as is a dual-targeted CAR-T approach that is complementary to the multiplex editing. We're not entering this trivially. Multiplex engineering is tricky to do safely and reliably. We want to engineer without significant off-target editing or translocations. The dual-targeting CAR-T, we also want to do the right homework to make sure it's not just the right targets or the right binders, but it's also the right construct. And we're doing it in a way that can transduce efficiently. So all of that work is still ongoing. We hope to provide further updates soon.
OK, then maybe just lastly, can you give us a brief overview of what the balance sheet looks like right now, runway, and what that runway allows you to execute on?
Sure. So we have cash into the second half of next year. Clearly, we'll have cash needs going forwards into phase III. But I think, again, with data catalysts very short term, with ASH coming up, we're looking forward to seeing the different possibilities of financing the business.
All right. Robert, appreciate the time. Looking forward to ASH. And thank you. And take care, everyone.
All right.