All right. Welcome, everyone. Thrilled to have you here and very excited to share with a little more depth and maybe some interaction the exciting data that we have at ASH this year across our sickle cell programs. So the order of the event, I'm going to start off and share a little bit about our strategy, reminding you of our long-term vision for sickle cell disease and the therapeutic technologies we can bring to bear to give patients some very important new options. Then we're very privileged to have Dr. Matt Heeney with us today for an encore presentation. He's Associate Chief of Hematology at the Dana-Farber/Boston Children's Cancer Center and Blood Disorders Center and, of course, an investigator on the BEAM-101 study.
We will also hear from Amy Simon, our Chief Medical Officer, going a little deeper into some of the exploratory science we're doing, really trying to bring a real depth of exploration, not just in the headline numbers of the trial, but in what the blood looks like, how we're modifying it, how it performs. Then we'll pass it to Pino Ciaramella, our President, to talk a little bit about this exciting next-generation version we have in sickle cell disease using our ESCAPE technology, which will follow on to BEAM-101, but potentially create a product profile that can dispense with chemotherapy and expand the applicability of what we're doing with base editing to many more patients. And then I'll be happy to close, and, of course, we'll then open it up for Q&A.
So as a quick reminder, I will be making forward-looking statements today, as will other members of the panel. So at Beam, just as a reminder of who we are, our vision is to provide lifelong cures for patients suffering from serious diseases. This is a real mission that we think is achievable. Given the technologies that we now have, these would be potentially one-time curative and transformative therapies. Of course, we're beginning with rare and genetic diseases today, but we do see over the long term the potential to move towards more common disorders. And importantly, this is a platform so that we can rapidly create new versions of these technologies over time. That means that once one of them works in a given organ, let's say, the next one is very likely to have a similar performance.
And so once that flywheel begins to be in motion, we can create successive waves of products. And that's quite relevant today as we talk about BEAM-101, followed by ESCAPE, which very much builds on that exact principle. So, as I'm sure you're by now familiar, we are at Beam working on a new technique within gene editing and CRISPR called base editing that really tries to build on and improve on the state of gene editing. So gene editing, of course, begins with nucleases, most famously CRISPR-Cas9. And what these nucleases can do is solve one important problem, which is precision targeting within the genome. And it works very well. But once the nuclease gets to the target site, there's really one thing it does, and that's to create a double-stranded break. And the control at that point is lost.
You end up scrambling the genome at random across the cell, so certainly it will disrupt a gene, but very difficult to reprogram it, so with base editing, we now have a technique that adds more power and control, so we use the same precision targeting you get with CRISPR, but now when we get to the target site, we're going to make a single base conversion at that site, never losing control of the rest of the sequence, so now we're truly rewriting deliberately and predictably at that site in all cells, and again, this is going to play an important role in the way in which our programs and some of their applications come about, so as you know, this technology has led to the creation of a very exciting pipeline covering both ex vivo and in vivo opportunities.
We have BEAM-101, of course, moving through the clinic, as you'll hear the data today, followed by the ESCAPE technology coming next, now really on the precipice of preclinical studies moving to the clinic. Then on the in vivo side, of course, we have BEAM-302 for alpha-1 antitrypsin deficiency, BEAM-301 for glycogen storage disease Ia, both now clinical stage programs, as well as collaboration programs on top of that. Then, of course, a research platform that's quite active behind it. What I want to focus on out of that pipeline is really our two core franchises, in hematology and liver. We think these two platforms are really areas where we can focus, we can go deep, and we can drive significant value creation over the long term.
So in hematology, of course, it's led by BEAM-101, where we have potentially best-in-class potential in sickle cell disease. I think that is data that you're going to start to see today from Dr. Heeney, and a relatively increased and high probability of technical success, obviously with the data we're sharing today, but also the progress that's been made in the field and a very clear regulatory pathway in the U.S. with the FDA that has now been validated in the industry. So that gives BEAM-101 a very clear path forward. It will be followed by ESCAPE, which again has the potential to eliminate chemotherapy from transplant altogether and dramatically expand the reach of base editing. From there, if ESCAPE works, we really have the platform to do many different things in hematology, which is quite exciting.
So, of course, today, in this weekend, we're sharing the initial data from these programs at ASH, and that'll be the main focus for our conversations today. On the liver side, very similar story. We have an exciting lead program in BEAM-302 for alpha-1 antitrypsin deficiency. That gives us a very exciting program, again, we think with an increased probability of technical success, based both on our own preclinical work as well as progress that others have made in the field with liver targeting, gene and base editing programs. Again, potential for rapid clinical proof of concept. As a reminder here, we're just looking in patients to raise the endogenous production for the first time of normal alpha-1 protein and lower Z protein. That would all be visible relatively early in clinical development.
And then long term, BEAM-302 has the potential to be the first and only one-time treatment for alpha-1, treating both lung and liver disease. And again, with success here, many other liver programs can potentially follow. So here, we're very excited to give an update to our guidance for this program for BEAM-302. Recall, we've been talking about having data in 2025. So tonight, we're going to narrow that guidance to the first half of 2025. So that trial is enrolling very well. We're excited to set that up as, again, another potentially very exciting and transformative event for the company in the first half of next year. In terms of operational catalysts, it's been a busy year. I'm very excited about the progress.
I won't belabor this, but obviously with the data coming out this weekend, very much on track to achieve the goals we've been talking about, and that sets up, again, for a lot of other good things to come in the following year, so let me pivot us back to sickle cell disease now and talk a little bit about our vision for transformative therapies in sickle cell disease. We're clearly in a time of great change. There are amazing therapies already, of course, on the market and coming for patients, but at the same time, it's also clear that this is not a product category that is going to stop at a single product or two products. This is like any good medical therapeutic category.
This is a place where technology is going to continue to bring innovation forward, hopefully continue to bring new options for patients that address unmet medical needs that are still significant. So our vision for contributing to that is as follows. We see a multi-wave strategy, as I've talked about before, starting in what we call wave one of this market. And that's the patients who have the most severe disease, who are good fits for transplant with chemotherapy. And in our estimation, that's about 10%. So in the U.S., you have 100,000 sickle patients. So we think about 10,000 have the severe disease that would make sense for a chemotherapy-driven transplant. That's BEAM-101, with a potentially, we believe, best-in-class profile for that patient population as a new cell product.
Wave two uses the ESCAPE technology, still an ex vivo product, but now, rather than chemotherapy, would use an antibody to do the conditioning and transplant process. This dramatically increases the patient population we can potentially serve with this product. We think up to 40,000, or about 40% of the patients, could potentially be a fit for that and would be a really dramatic and revolutionary product profile. Finally, we are also active on in vivo delivery. This, of course, is going to be required to get to the most mild patients or patients around the world in different parts of the globe where the hospital infrastructure, the ex vivo process, is going to be less viable.
And so we see these really building on each other, ultimately treating every patient and bringing to them the potential for the kinds of transformative long-term cures we know are possible here in this space. So focusing today on waves one and wave two, I want to just highlight this point I made before, which is the fact that this is a true platform, and the components of that platform build on each other directly. So everything we're doing with BEAM-101 is, of course, now moving very quickly and is clinically validated, as you're going to see momentarily. When we bring forward ESCAPE, which the cell product for sickle cell will be called BEAM-104, it really shares all of the components of BEAM-101, almost an identical product, with really just a couple of exceptions.
We basically add one additional guide RNA targeting CD117, as you hear from Pino, and we bring forward an antibody, and that'll be the conditioning agent rather than the chemotherapy. I just want to highlight that so that as you go through BEAM-101, you can also recall when we cover ESCAPE later that really all the successes we're having with BEAM-101 are also going to put us in a position to succeed with BEAM-104 as well. All right, so now, as a setup for Dr. Heeney, what have we been trying to do with BEAM-101? Of course, as you know, with sickle cell disease, you have a mutation in hemoglobin causing a high degree of this sickle form of the protein, which causes these vaso-occlusive crises, and that's what we're targeting with our therapy, so what's the goal?
The goal is to get patients from a disease state into a non-disease state. That non-disease state is really defined. The threshold is defined by a carrier, a trait patient. What do they look like? It turns out a carrier with a sickle cell mutation, who's generally asymptomatic, has a 60/40 ratio of normal hemoglobin, in this case, generally hemoglobin A, to the sickle form of the protein. Effectively, all cells are a mixture of A and S. Clearly, with our product, where would we like to be? We'd like to get to those kinds of thresholds or better. That would move us into this range of non-disease. In addition, some of the unmet needs in the field that we know about are, we'd like to have the cell collection process be as efficient as possible.
When patients are going through the transplant, we'd like to see the time to engraftment be as rapid as possible. So we think a lot about the patient journey and the care we can give to them throughout the process, in addition to the end goal, which is going to be shown here in terms of the blood parameters. So with that as setup, I'm very excited now to hand the mic over to Dr. Heeney, and he'll walk you through the initial results of the trial.
I apologize to those of you who heard this before if you're sitting here, but those of you at home in your pajamas can listen in anyhow. So I'm pleased to present the initial results from the BEACON clinical trial on behalf of our co-investigators.
As John just told us, BEAM-101 uses a novel base editing mechanism to enable precision editing of the gamma-globin promoters without requiring double-stranded DNA breaks or disrupting the downstream non-erythroid pathways of BCL11A. Preclinical data have demonstrated that these editing results in highly efficient and predictable gene editing outcomes, leading to uniform induction of fetal hemoglobin and corresponding reduction in hemoglobin S and fewer sickled cells. My friend in the back here is going to roll it up. As you can see here on the right, the real goal of BEAM-101 therapy here is to increase fetal hemoglobin and have a compensatory reduction in the sickle hemoglobin. That change is really the most important part of this therapy. It's not just adding another hemoglobin.
BEAM-101 is a phase I/II study evaluating the safety and efficacy of BEAM-101 in patients with sickle cell disease and severe vaso-occlusive events. The study is ongoing. More than 35 patients have completed screening, and 11 have been dosed. It says here 12 have been dosed, but I believe it's 11. Eligible patients were between 18 and 35 years of age with sickle cell disease and a history of more than four vaso-occlusive crises in the previous two years, similar to other trials. Key safety and efficacy endpoints here include the proportion of patients with successful neutrophil engraftment, the time to engraftment, and the proportion of patients who are severe VOC-free for a 12-month period consecutively. We'll also look at markers of hemoglobin production and RBC red blood cell function and viscosity and so forth, which you'll hear more about from Amy.
The BEAM-101 study unfolds in four stages. This is, you can see on this slide, including six to eight months of management prior to dosing. After confirming eligibility, patients undergo mobilization with PK-guided busulfan therapy. The hematopoietic stem cells that are collected after plerixafor mobilization are then subsequently base-edited ex vivo, as John described. Then the patient undergoes the myeloablative conditioning prior to reinfusion of those edited cells. Following engraftment, the patients are followed in the study for two years, and then they're converted onto a long-term follow-up for a total of 15 years of follow-up. In this table, we see the baseline demographics shown here. As of the cutoff date, seven patients have been treated between the ages of 19 and 27 years. The range of follow-up is between 1 to 11 months. The majority of patients here are SS, homozygous SS.
The majority are African American or Black. You can see there are the alpha-globin genotypes as well. The main investigator reported VOCs in the two years prior to treatment was 10.3. You can see the range there, 7 to 13. Here are some of the treatment characteristics in tabular form. All patients required two or less mobilization cycles to achieve the target dose, with a mean administered dose of the BEAM-101 edited cells of 10.7 times 10 to the six CD34+ cells per kilogram. The PK-guided myeloablative conditioning with busulfan was within the protocol target area under the curve for all patients. The median day of the final red blood cell transfusion was day 15, with one outlier patient who required transfusions up to day 122 related to ongoing critical care.
All patients achieved a very rapid neutrophil engraftment, resulting in a low number of days with neutropenia, and they also had very rapid platelet engraftment, including two patients who didn't require any platelet transfusions, so this slide demonstrates the swimmers' plot, if you will, of each individual patient, and so you can see here the number of cycles of engraftment that the patients required, and then after treatment, the patients had rapid neutrophil engraftment, as you can see here, and the number of neutropenic days were very low, and then finally, the time to platelet engraftment is shown here, which on average, very rapidly. The neutrophil engraftment was by day 21 in all patients with a mean of 17.1 days and a mean of 6.3 neutropenic days, and the time to platelet engraftment was 19.1 days on average, which is great.
Then the duration of total follow-up of these patients as of the cutoff date is shown here. So this is a summary slide of the initial safety data. So as you can see here, the safety profile is consistent with busulfan conditioning for autologous hematopoietic stem cell transplantation. There have been no serious treatment-emergent adverse events or Grade 3 treatment adverse events greater than Grade 3, greater than or equal to Grade 3 treatment-emergent adverse events related to BEAM-101. There was one death in the study determined not to be related to BEAM-101, which I'll go over more on a subsequent slide. And excitingly, at least early on, no patients have experienced any investigator-reported vaso-occlusive events post-engraftment. So this is the one patient who died during the study.
This was the third patient in our sentinel cohort, the third and final patient in our sentinel cohort. She was a 21-year-old young woman with homozygous SS disease who had had fairly severe disease, including frequent vaso-occlusive events, acute chest syndrome, and had comorbid obstructive sleep apnea, and she'd also had some e-cigarette use. Her conditioning was unremarkable, as was her cell dose is right in the middle there at 6.2, and her time to engraftment and discharge to the hospital was as expected compared to the previous patients. Unfortunately, she was readmitted about two months after infusion of cells with a gastrointestinal febrile illness, and she developed respiratory symptoms, was briefly discharged, then readmitted primarily for respiratory symptoms and developed hypoxic acute respiratory failure, leading ultimately to ICU care and mechanical ventilation.
She had multiple investigations during the time, including bronchoscopy, all of which was negative for hemorrhage or infection. And then she died about four months after infusion. The investigators on site determined that this event of fatal respiratory failure was not related to BEAM-101, and it was more likely related to busulfan conditioning and its known pulmonary toxicity. And then the DMC had a similar feeling. The study was not stopped, and we were continued on. This slide shows in aggregate the population's hemoglobins. You can see in dark blue, there was a rapid, robust increase in fetal hemoglobin starting at month one. And you can see in the gray the diminution or the gradual waning of the transfusion support hemoglobin A, and then the sickle hemoglobin there in the lighter blue color.
So you can see that all patients achieved greater than 60% of endogenous fetal hemoglobin production by one month, and that the hemoglobin S levels were less than 40% of the total endogenous blood hemoglobin as well. This is similar data now, but broken out by each individual patient. On the left, it shows total hemoglobin. On the right, it shows fetal hemoglobin, endogenous fetal hemoglobin production. The dashed line is patient three, who I just described, died at four months of age, four months after infusion. And so you can see that all patients had resolution of their hemoglobin, of their anemia on the left, and that the fetal hemoglobin induction was very uniform throughout follow-up and quite stable. So this slide shows the fetal hemoglobin, and on the left panel, that shows sort of a pan-cellular, if you will, the number of F cells.
By the time the waning of the transfused hemoglobin A cells has gone away, the patients are basically almost 100% F-cell-containing cells. And on the right, you can see the amount of fetal hemoglobin per F-cell, and that all patients exceeded the threshold of 10 pg per cell, which is thought to be anti-sickling, or at least the threshold. And that, again, making less cells available to potentially sickle. So this slide here shows the high rate of A-to-G on-target editing in the Beam product. On the left, you can see it's over 90% in all the patients. There were only six patients here that had data prior to the data cut. And on the right-hand side, we can see here the on-target A-to-G editing in the patients, showing very stable engraftment of those edited cells.
And this summary, I won't go through them all, but these figures all show the improvement in hemolysis that you expect to see with this correction. And so a reduction in indirect and total bilirubin, a normalization of haptoglobin, a lowering of LDH, and a lowering of reticulocyte count. And so in summary, patients treated with BEAM-101 required a low number of mobilization cycles and achieved rapid neutrophil and platelet engraftment with a low number of neutropenic days. And the initial safety data is consistent with busulfan conditioning and autologous hematopoietic stem cell transplantation. And there were no vaso-occlusive events reported by the investigators after engraftment. All patients achieved a rapid and robust increase in fetal hemoglobin and total hemoglobin. And the fetal hemoglobin was pancellularly distributed. And this was maintained above that threshold for polymerization and sickling.
All patients achieved a rapid and robust decrease in the sickle hemoglobin on the opposite side, and all markers of hemolysis were improved. So in summary, the initial data from the BEACON study demonstrates the real potential for base editing, and it shows that the treatment with BEAM-101 results in robust and sustained fetal hemoglobin expression increase and resolution of anemia in this patient population. I'll pass it over to Amy. I feel like I should watch that for you.
Thank you, Matt. So I think I'll continue on from where Dr. Heeney left off by going a little bit deeper. But I do want to have a declaration that some of this data is still embargoed. And so you're going to have to go tomorrow to see the poster to actually see all the data. So I'm really going to show you just teasers and give you some of the overview of the conclusions. But to actually see the data for yourself, you will have to visit the poster, which will be posted tomorrow, I think, by 9:00 A.M. So this is to get you interested in that. So Matt already mentioned that we have a very high level of fetal hemoglobin, 60%. We have a decrease in sickle globin of around 40% in the first seven patients treated.
John indicated that that was a great threshold to try to achieve because those are more equivalent to patients who might have trait, who have very little in the way of symptoms, if at all. And so what does this mean that we've taken someone and now gotten them to 60% of F and residual of 40% to their red blood cell health and function? So before I get into exactly what that shows, we'd have to think about all the different aspects of red blood cell function that are disrupted in people who have sickle cell disease. So in the middle in orange, the pathophysiology really shows that because you have hemoglobin S, you lead to polymerization. The polymerization of the hemoglobin S then changes the whole shape, right? So the cells now become sickled. They are very dense. They no longer are deformable.
So when they're trying to flow through your circulation, they can't flow readily. They're sticky. They get stuck. That leads to the vaso-occlusion. That leads to infarction because when there's occlusion of your vasculature, the downstream organs do not have enough oxygen. They even get oxygen reperfusion injury once that is resolved. And on top of it, they have systemic inflammation. All of this in the end is what leads to the organ dysfunction that is seen across multiple organs, such as the heart, the lungs, the liver, etc., and leads to early mortality in these patients. So what would a really deep cure look like? It would be something where we could potentially show that those dense RBCs, that the sickling itself of the RBCs, that that improves, that the RBC deformability goes back more towards a patient with trait or who doesn't have sickle cell disease.
In addition, that adhesion, that stickiness is no longer there. And then, as already shown by Dr. Heeney, that the hemolysis that's really contributing to the shortened lifespan, to the anemia and the disease pathophysiology, that that would be resolved. So we showed you some of that already, which is great. And that there's a lot of inflammation going on in these patients. So we'd want to see that that systemic inflammation also is going down. On this slide, as part of our exploratory red blood cell function assays, on the left panel, this is from two patients. You can see that once the patients are treated, that nearly all the RBCs express HbF by month one. And that's seen in the green line of patient one and patient two. So now you can see that their HbF is going up close to around 100%.
This occurs early and is persistent. Similarly, when we actually look at what happens to cells that just express hemoglobin S, so that would be cells that have SS, we now see that those go from the 65%-75% range or 79% range down to almost undetectable by month two, so at like 0.1%. So this means that there's very little left of cells that are going to be just SS that are the most susceptible during hypoxia or other insults to sickle. So other things that are important, as I already mentioned, is this whole sickling process that leads to a lot of these abnormalities. So what you can see here are two patients. Pretreatment is listed in the orange. And you can see that those patients have sickling that is quite significant.
And then after treatment in green, you can see that there is a significant decrease in the maximum amount of sickling in these patients. Importantly, the dashed line represents what would be the equivalent of sickling that would occur maximally in trait patients. So these are obtained from 10 trait patients that have had the assay also run. And so you can see now that we're actually getting sickling down to below what is seen in trait samples. There are other improvements as well in RBC function. And I think I'll go to the next slide to show you some of those because otherwise I'll be a little bit redundant because these are all of my data slides.
So just to get you guys all to come to the poster to see for yourself, what we did see, of course, is that 98% of the non-transfused RBCs have HbF at month one, which I showed you, and that there's really an elimination of cells just expressing HbSS alone. What I didn't show you, which you'll have to come see, is that cell adhesion was reduced significantly below this critical threshold that is thought to be something that is predictive and at risk for VOCs. So the adhesiveness of the cells has gone down. In addition, we saw changes in maximum sickling, which I showed you already. And those were close and actually better than what was seen with cells stressed that had trait. So the way they stressed those cells is by exposing them to low oxygen.
In addition, not shown is that the dense red blood cells go down, the blood viscosity decreased, and that RBC deformability improved. In addition, oxygen affinity, which is low in sickle patients, increased. Finally, there was an increase in red blood cell number and resolution of the abnormal RBC morphology that you can see very well with sickling and all kinds of other abnormalities just under light microscopy. Hopefully, I've encouraged you all and got you excited to go see this poster, which is really quite an incredible amount of work that's really trying to get at this red blood cell function and the impacts of this high hemoglobin, low S, and showing that in some instances, this is actually even better than trait. This will be tomorrow from 6:00 P.M. to 8:00 P.M. I believe the posters go up at 9:00 A.M., and it's abstract 4957.
So I'll turn it back over to John.
Thank you, Amy.
So just to build on that, one of the principles of Beam is we really want to be a very high-science company. And I think it is hopefully a sign of the confidence we have in the cell product from BEAM-101, that the more ways we look at it, the more ways we will see some of the benefits of the base editing and the manufacturing and all the quality that we've tried to build into this product from the beginning. And so I think these deep assays start to show that. So before we turn our attention to ESCAPE, I wanted to just highlight a couple of operational points to illustrate the momentum that we have in this trial called BEACON. So I think, as we disclosed before, we have had really strong enrollment momentum for this program.
So we're now over 35 patients who have enrolled in the trial, cleared screening. There are, of course, additional patients above that number who have already consented and are moving through that screening process. So we really see, again, strong momentum to add patients to the trial. We thought we would share one data point. We won't update this frequently, but in terms of from there, we actually have over 20 patients where the drug product has been manufactured, right? So that means that it's ready to go into conditioning and dosing, right? So that gives you a sense of how imminent dosing may be for a large number of these patients. And as of today, actually, 11 of those patients have already been dosed. That's up three from when we had the abstracts shared earlier in November.
So you can see, again, the pace of dosing is actually quite high, and it's going to pick up pretty quickly. Finally, on the regulatory side, we've actually had a recent review of the whole trial, our data, our safety information by our data monitoring committee, and then submitted all of that to the FDA. And that was in the context of asking for moving into adolescent enrollment for the trial. So this would be to add patients from ages 12 to 17 into the trial. And that was approved. So we're very excited about the speed with which we've been able to do that. And I can, again, say that there's a lot of excitement from that patient population to join the trial as soon as this is open. So that'll now become part of our enrollment plan going forward. So lots of momentum here.
As a reminder, with the BEACON trial, we've really designed this to be a trial that could potentially lead to registration using the regulatory precedent already set by exa-cel with the FDA. All right. That's BEAM-101. Now, coming back to where I opened, let's turn to the second piece of our long-term strategy here. That's the ESCAPE program. To share some really exciting proof of concept preclinical data on the ESCAPE program, let me ask Pino to come up here and share a few words.
Thank you very much, John. And so, as you heard from John before, obviously, we are committed to provide the best-in-class opportunity and product for patients who are suffering most severely from sickle cell disease. But we're also committed to expand the opportunity of many more patients, even those less severe, to actually benefit from the, hopefully, you will see some of the quality and the treatment opportunities that base editing has provided. And so this is where the ESCAPE program comes into play. As you know, conditioning is an important step, is a critical step, actually, in transplant in general, in order to generate that niche within which the edited cells can actually engraft and ultimately provide the benefit for the long term. Typically, the conditioning agent that is most used is busulfan. And actually, this is an agent that was launched in the mid-1950s.
Actually, if you think about it, there hasn't been that much of a difference since the '50s that has occurred in transplant that could benefit these patients. So we feel that ESCAPE, if we can take it all the way to a launch product with all the features that we believe we can dial in, could actually be a paradigm shift in transplant science, if you will, in the last 70 years. So we feel that this is really an important opportunity to provide patients that really need an alternative to this chemotherapy. And so we'll talk about specifically how busulfan is used and how we can deploy ESCAPE in sickle cell. But this has opportunities for many indications beyond sickle cell disease. Particularly, imagine those that right now, because of the risk-benefit profile, it's not really sort of acceptable to do a transplant as a solution.
But if you were to eliminate that toxicity, it may open up opportunities, actually, for transplant in those settings as well. So, as I mentioned, busulfan is really the most commonly used chemotherapy that is used to enable that essentially niche in the bone marrow for the edited cells to engraft. And it's typically used just before the transplant. And in this case, the same cells from the patient that have been edited are reintroduced in the very same patient in order to engraft for the longer term. The unfortunate use, as we've already mentioned, is that busulfan suffers from several toxicities that limit the opportunity of this particular treatment to only about 10% of the most severe patients, which are about 10,000 in our estimates. So what we're doing with ESCAPE is shown in this cartoon.
Basically, all stem cells require a stem cell growth factor in order to essentially proliferate and differentiate. This is called SCF. And this particular growth factor binds to a receptor on the cell surface called CD117, or c-Kit. What we have developed is an antibody that actually can bind to that CD117 receptor and blocks the opportunity of this growth factor from binding. Now, if we left it alone, this would be an impediment not only for the unedited cells, but also for the edited cells. So what we do, we introduce an additional change to the CD117 receptor such that that antibody we developed now can no longer bind to the edited cells. And it leaves them alone.
And it provides, therefore, a survival advantage of the edited cells over and above the unedited cells, which would be starved of the growth factor as a consequence of the antibody that we've developed. And so what I'll describe to you is a series of experiments that has confirmed some of the features that are necessary to dial in into that sort of change and antibody pair that ultimately allows us to do the experiment in non-human primates, which I will show you at the end. So first of all, what we have confirmed is the opportunity to be able to do this edit in a multiplex fashion. In this case, basically, we deliver the same editor, but now instead of one guide, there are two guides. One guide is obviously the 101 edit that we already do and we have shown.
And the other one is the edit on the CD117 receptor that changes a single amino acid that prevents the antibody that we develop from binding to them. And as you can see, that additional guide does not interfere with the very high editing rates that you can see now, both for CD117 as well as the HBG1/2 edit. As a consequence of that, we also do not interfere with a very high level of hemoglobin F, which we now express, as you can see, still around the 60% in this case. Importantly, what we confirm is the fact that this antibody can very specifically bind to the wild-type unedited cells, but leaves those edited cells alone. The edited cells on the left-hand panel are shown in green, and in gray are the wild-type unedited cells.
Importantly, we're also showing the panel in the middle that this antibody actually does effectively starve the unedited cells by the opportunity to bind to the growth factor, as you can see from the prevention of the activation of that receptor with increasing levels of antibody, and finally, that binding to the receptor is shown functionally on the panel on the right-hand side, where you can see that the unedited wild-type cells are actually killed as a consequence of the binding, and the edited cells in green are left alone. The other important component of that edit that it's important to dial in is it's important that the edited cells with that additional CD117 edit can still benefit from the growth factor, because otherwise, they would not be able to have the survival advantage, and this is shown in the data in this particular experiment.
What you can see in the absence of the antibody, which are the two lanes in the middle, both the wild-type cells as well as the edited cells can effectively activate the CD117 receptor as a consequence of the phosphorylation of c-Kit. However, in the presence of the antibody, which are the next two lanes towards the right, you can see that only the edited cells can actually benefit and activate the receptor, versus the wild-type cells are unable to do so. We also demonstrated, and this was a little bit of a fortunate component for us, I have to say, but I'll take good luck as well as I take all the skills, is that actually this particular antibody is cross-reactive to rhesus, to non-human primates, and actually, not only cross-reactive, but equipotent.
As you can see in this case, we can actually kill both human and rhesus cells with equivalent potency that allows us the opportunity to actually do more meaningful and more easily translatable experiments in non-human primates, which are the ones that I'll show you in a minute. So what we wanted to do is essentially to mimic in a non-human primate ultimately what we would be doing in a human and using the antibody treatment as the only conditioning setting as opposed to a busulfan setting. And so there were a couple of different things that we wanted to make sure that we did before we actually went into the experiment. The first one was to reassure ourselves that actually, even in rhesus stem cells, we were able to achieve the very high editing in a multiplex fashion, both for the gamma-1 and gamma-2 edit as well as CD117.
You can see that in all three animals, that was the case. We also wanted to confirm that that edit led to the high levels of upregulation of hemoglobin F that you would expect as a consequence of the gamma-1 and gamma-2 edit. You can see that that is the case on the right panel. An important consideration is also the safety of the antibody. What I can show with that is that this antibody dosing was actually very well tolerated in all of the three animals. Actually, it was remarkably different from when you use busulfan in these animals, where they need very significant care. Potentially, they need antibiotics, transfusion, and a lot of supportive care. In this case, the animals were completely healthy and didn't require any treatment whatsoever.
That's basically the results of that experiment in which we essentially dosed the antibody only as the conditioning agent. Then we performed the transplant with the cells isolated from those very animals. Then they have been obviously edited for both the CD117 and the gamma-1 and gamma-2 gene. As you can see, that we achieved very rapid and complete replacement of the erythroid cells by the edited cells. The levels of cells expressing hemoglobin F achieved in excess of 60% as early as eight weeks post-transplant. Obviously, we also achieved therapeutic levels of hemoglobin F, in this case, about 40%. Importantly, particularly from the first and second animal, you can see the long-term persistence of that edit that is obviously an indication of engraftment having occurred.
To our knowledge, this is really the first time that an antibody-only conditioning has shown engraftment in essentially immunocompetent animals, such as non-human primates. In summary, busulfan-associated toxicity continues to be a major obstacle to expanding the use of autologous HSCT-based therapies for sickle cell. ESCAPE can essentially potentially address this unmet need by enabling this without a genotoxic conditioning agent. The CD117-based editing showed normal receptor function in vitro, specific binding. All of the features and characteristics that we need in order for this to be achieving what we need was demonstrated both in vitro and in vivo. Essentially, rapid and complete replacement of those erythroid cells was observed. We saw induction of hemoglobin F expressing cells to a level in excess of 60% with a concomitant upregulation of hemoglobin F.
Essentially provided proof of concept that this is possible to achieve. In terms of next steps, we have essentially started the phase I enabling tox studies for the antibody-only, which we plan to take into a healthy volunteer study to determine essentially not only the safety, but also a PKPD understanding of the dose regimen that we would like to then use in human studies. In parallel, we're conducting additional non-human primate studies to better refine the pre- and post-transplant dosing regimen for the antibody. When we have those two combined, we will then go directly into patient studies where we will use both the antibody and the dual-edited cells for our next set of studies. I'm happy to bring it back to John for wrapping it up. Thank you.
Thank you, Pino. All right. So in summary, and just a reminder here of all of the different activities here at ASH. So of course, we have the BEACON study results you just heard, as well as the ESCAPE preclinical data that Pino covered. As Amy previewed, we have the exploratory biomarker data, which is tomorrow night as well from 6:00 P.M. to 8:00 P.M. We do have a fourth poster, which is on BEAM-201, which is our quad-edited CAR T cell for T cell malignancies. As a reminder from the abstract, it's clear that as an active drug, we have multiple complete responses with the drug. So we'll just highlight that and send folks to take a look at that as well. That'll be from 6:00 P.M. to 8:00 P.M. tomorrow night as well.
So for me, just to wrap up and thinking about where we stand as a company, we've made really significant progress on our vision and on specifically our base editing platform and our pipeline. So with hematology, obviously, with BEAM-101, very excited about this emerging potential for real clinical differentiation that we see in sickle cell disease for BEAM-101, and pairing that with really significant momentum in the trial, now moving quite quickly on what could be a potential registration pathway. And then, of course, adding to that the opportunity to create a second version of this a few years after that, which would remove chemotherapy and reach many more patients with these types of transformative functional cures.
Then on our genetic disease portfolio with BEAM-302, leading the way as the potential one-time treatment to address both lung and liver disease, now for alpha-1 antitrypsin deficiency, and now offering a potential near-term clinical catalyst with data now expected in the first half of 2025. Finally, just in general with our base editing technology, which we continue to believe, and I think now you can see the emerging evidence as a more precise, more efficient, predictable, and versatile tool than previous gene editing technologies like nucleases, now, of course, clinically validated and continuing to show really strong translation from our preclinical results into clinical, which we're quite excited by and look forward to more in the future. So with that, let me say thank you for your time and attention. And we'd be very happy to open it up for Q&A.
One second. Oh, there we go. So for Q&A, we'll start here. And we also have a couple online that I can read live.
Hey, Greg Harrison from Scotiabank. Congrats on the data. Thanks for taking the question. How important would you say it is to get patients to normal hemoglobin levels, both for long-term outcomes and also for uptake in practice? It looks like all the patients achieve that, or at least were close for their sex. Is it your expectation going forward that you would see that in most patients?
Certainly based on what we see now, it looks very robust, and so our hope is that, yes, we'll get into the normal range. Obviously, sex differences in the normal ranges. Low hemoglobin is bad even without sickle cell disease, and so getting into a normal range is also very good for long-term mortality and so forth, so obviously, we'd love to get it to that point, and if by reducing the hemolysis that contributes or is the main driver of the anemia and the disease, that we would expect that. I would expect that.
Great. And then maybe a quick follow-up. How are you thinking about the technical hurdle in general to deliver a base editor in vivo?
Yeah. So we obviously us and others in preclinical experiment, but also now in the clinic, have demonstrated that through the use of lipid nanoparticle is actually possible to effectively deliver an editor and guide combination, certainly to the liver and potentially even to other tissues. So that's the technology of choice that we are deploying right now for both 302 and 301. And also others have used Verve, have used an LNP technology as well. Intellia used also an LNP technology that delivers, in that case, a nuclease. So I would say that the opportunity of delivering that to effective levels is definitely there. Obviously, then it depends on different edits and locations on the genome that you want to go after in order to see whether you achieve the efficacy that you need.
But I would say that certainly the LNP technology is now validated in order to do that in a meaningful way.
Thank you. Yanan Zhu, Wells Fargo. Congrats on the great HbF and engraftment time data. I was wondering about the first two patients, their total hemoglobin levels. I was wondering, is there any underlying factor for these two patients to have relatively high level compared with others? These are obviously males. I think there's another male patient that doesn't get to a high level. But you also have a beta S, beta 0 patient in there. I'm not sure whether that's the male patient or not. Just in terms of the high levels, do you expect that to be that has plateaued? Will that come down, or will it go up? It doesn't matter. Yeah, thank you. A lot of questions there.
I don't think we fully understand the mechanism of it. But certainly, the first patient is mine. And he's a 20-year-old strapping young man with presumably high testosterone. And I think that probably is he's at that upper limit of normal of hemoglobin, which is certainly something we see in our general clinic as well. A lot of referrals for concern for erythrocytosis in that age group and sex. So I'm not too worried about that at the moment. As you say, it's been very stable. I expect, as he ages, hopefully very healthily over the next decades, that we'll see it come down a little bit potentially. But I don't anticipate any major problems related to that. Clinically, they're doing very well. They have no symptoms of viscosity or headaches or anything that would sort of you'd think about in a more polycythemia sort of symptom group.
The hemoglobin, of course, is very different than the hemoglobin that we worry about in sickle cell disease. We would never want to get to a level like that if there were sickling cells around. These cells now are generally, as Amy showed you, much better off. They're less dehydrated, less dense. They're less likely to be as sticky. They're rheologically more favorable. He's got no symptoms related to that. We chose as investigators not to phlebotomize them as others have or to react to that. They're doing very well at the moment. I actually don't know your answer. Maybe somebody else says whether the other male is S beta 0 or not. That could be a potential explanation for the difference too. I'm not sure the age of the other male in that.
Right. Does this correlate with cell dose of those patients?
Not that we've asked the same question. It doesn't appear to.
Okay. Got it. Thank you. I have a follow-up question on ESCAPE. So for the NHP data you showed, I was wondering how many rounds of antibody did you give? If you just gave one round, could you potentially increase the HbF levels further afterwards, after all the stem cell has already been in there, and then come back in with antibody again? Thanks.
Yeah, maybe I could comment. So in this case, actually, the antibody, the first two was given one dose seven days prior to the transplant. And the third was two doses prior to the transplant. But they were basically doses that we've shown in presentation today to achieve about 80% receptor occupancy as part of that. And then we subsequently dosed the antibody in this experiment once a month for the duration of the experiments. However, what we are doing in subsequent non-human primate studies is we're further exploring different pre- and post-dosing regimens in order to understand what is the optimal paradigm. The important thing, this was one of the first few experiments that we did in collaboration with Dr. John Tisdale at NIH. And so that's essentially, if you will, there is a further optimization.
And we can dial in into that and represent, if anything, probably the underestimate of what could be achieved. And potentially, higher F levels could be possible. Obviously, without doing the experiment and demonstrating that, I can't categorically say that. But we're hopeful that that is the case. Having said that, those are already and that's the remarkable part of it. They're already almost therapeutically level. We're 40% already without that much of an optimization regimen. So it really speaks really well to the opportunity and the potential that this technology really has, I think.
Thank you, Mani Foroohar from Leerink . Thanks for taking the question and for including us in presentation of the data. I'm going to hop over. I've got two quick ones. I'll start with ESCAPE. I'm looking at the in vitro data on slide 40, where you talk about there were no CD117-only edited cells in that data. It looks very clear. I hop over to the rhesus monkey data on slide 44. Looking at the third NHP, the CD117 editing bar seemed a little bit higher than the HBG1/2 bar. Not surprising. These aren't perfectly representative data sets, but walk us through how to think about that translation from glass to non-human primate, and how do we interpret that, to be fair, very small inconsistency between the two?
From those two data sets, how should we look forward to behavior in a healthy normal volunteer, eventually in a human, eventually in patients?
So the first thing to say is that there is going to be some degree of variability in these animal studies. For obvious reasons, non-human primates. There are a limited number of animals that you can include in a given study for a variety of different reasons. The other point to stress is also that if you think about it, the degree of optimization that we have been able to do in human cells, including the manufacturing of the cells and the treatment of the cells, is not something that we could have been able to do with non-human primates. Part of our team to focus on the human side more so than non-human primates, and that's why actually we also collaborated with Dr. Tisdale, so it's not trivial to do those kind of things.
My expectation would be actually that you will see not only a good translatability, but that this particular experiment are somewhat an underestimate of what you are likely to see in human with whatever you think is going to be optimized, including the manufacturing and importantly, including the manufacturing of the CD34 cells that come from that. The other important thing is that if you think about it, all the experiments that have been done preclinically so far are in immunocompromised animals. But they use obviously human cells in that setting. In this case, because of the equipotency of the antibody between human and non-human primates, we've actually done an immunocompetent study that it's an equivalent really of what you would expect to see in human. I think it's as stringent as an experiment that I can think of doing in that setting.
So that should give us a lot of confidence that we are expecting to see some translatability in human. I think the parameters of pre- and post-dosing of the antibody will be actually the key important ones to be able to achieve and optimize kinetics of engraftment, which I think is part of where we want to go.
That makes a lot of sense. And one quick follow-up. Moving to humans, actually what we're trying to achieve here, a question from I got emailed in from an investor listening in. When you think about reestablishing new hemoglobin biology in these patients, which is sort of the whole goal, is there a ceiling at which you start to worry about a hemoglobin result that's too high, 17 too high, 18 too high, hypothetically 20, et cetera, plus too high? Is there a question of getting hemoglobin to too high of a gram per deciliter number? And how do you think about that in determining dosing patient selection, et cetera?
There are lots of graphs and nomograms looking at the oxygen delivery versus hemoglobin, so there is an inflection point when your hemoglobin gets too high. The viscosity and so forth will decrease your oxygen delivery, but we're nowhere near those levels really in this, and what's very different here in the underlying disease is that there's other contributions that that curve has very much shifted because of the abnormalities in the cell, the rheology, and the hemoglobins in those cells, so yeah, I don't think I'd want to see it getting into the 20s for sure, and we're not there, but I'm not terribly worried about these upper range kids, again, given their clinical features that, again, young males, and then also that they're not having anything that seems to be resembling any consequences of this clinically. We're watching closely, though.
Hi, Sami Corwin, William Blair. I was really struck today during your talk about the physician excitement for the time to neutrophil engraftment. And so I was hoping you could provide a little more context there as to how that could translate to the duration of hospital stay, health care costs, as well as patient reported outcomes? And then one for John, I guess, how many patients would you like to have treated? And how much follow-up would you want to have on hand before kind of going to FDA and discussing a regulatory path?
So less is always better, right? So the less neutropenic days, the less susceptibility to infection, which is really the major post-transplant complication, is huge. And so every day that you're neutropenic, you're a sitting duck. And so I think that the less we can make that, the better. And even incrementally smaller neutropenic day is really important. I think it's also true of the other cell lines as well in terms of support. And that all does translate generally to a shorter length of stay, which I don't have the luxury of not worrying about that as much. But for the overall price of the drug and the price of the treatment, that's a very important part. At least apparently, our hospital is the most expensive hotel in the city for nightly costs.
So I think all those things are very important for those reductions, even though they may seem not all that wildly clinically significant. Even a few days is important.
Yeah, well said. So in terms of the package that we would be looking for for filing, so we haven't given formal guidance on that. We also haven't had the formal conversations with the FDA yet to confirm that. So I think you should take all this with a grain of salt. But I think we have fairly good confidence in what that could look like because we have a precedent that's just been set. So exa-cel with Vertex and CRISPR to the FDA was granted approval. And you have the package. It was 30 patients followed for this VOC-12 endpoint, which is a number of patients who have a VOC-free period of 12 months measurable. And so that presumably takes approximately 15 months to measure if you have patients who are all responding.
And so now it may be a little more than that, maybe a little less than that. The FDA can, of course, tweak it. But I think that's a pretty reasonable base case guess. So that's why I keep pointing to the operational momentum of the trial. Because if you look at where we're at, we've already got more than 30 patients on trial now. And so it's not too hard to imagine that that 30th patient gets dosed sometime next year, if you think about starting today, going through the process to the transplant dose. And then from there, it would be a 15-month-plus follow-up period. Then you've got your core efficacy data set. We'll, of course, keep treating patients up to 45, maybe even a little bit more, particularly as we add some adolescents into the mix. But most of those are for to continue the experience.
For safety database, you don't need the full follow-up time. So we see that now fairly clearly laid out. And we're actively preparing for all the activities that would go along with that as we execute.
[Sale Chen] from Kostas team at BMO Capital Markets. So I have two questions, if I may. So one is basically on the VOC events. So it seems like in your study, you included you're measuring the severe VOC events, which is, to our understanding, it's a little bit different from what Casgevy was reporting from the total VOC events. So can you provide any comments on that? Would you possibly, in the future, provide both in your data updates? And the second one is about the requirement. It seems like you guys are requiring patients to be hospitalized until at least when they are no longer like a neutropenia. So would you imagine in future, in a commercial setup, you will still likely to ask people to stay in the hospital when they're having the neutropenia? Or that's not going to be the case? Thank you.
So we are following all VOCs. I think the severe VOCs are slightly defined differently in different studies. However, our severe VOCs are defined as having an acute chest syndrome, a pain crisis of any sort, priapism lasting a certain duration of time, or any kind of severe VOC, which means you had to go to a health care facility and received some type of opioid treatment. So in that case, our severe VOC requires that you've had some interaction with a health care provider. It could be an outpatient clinic. It could be the ED. We will collect all VOCs because we think that's important. Those will be collected as AEs. All of our VOCs will also be adjudicated, similar to others. So we'll have a separate adjudication committee as well. I think your next question was about.
I hope the committee is very bored.
Yeah, exactly. Your next question was, just remind me?
Is that a requirement for patients to be hospitalized?
Matt can handle that one. But in general, just from my experience as well, being a clinician, people are kept in the hospital typically until their neutropenia resolves as a way to kind of protect them from opportunistic infections and keep them in a more sterile "environment." I don't think that will change.
Once you see the beginning of engraftment and the ANC gradually rising, it's almost quite predictable. You can sort of start planning to buy your bus ticket. But it usually doesn't do a lot of this. It usually sort of steadily climbs. But I think it would be unlikely that we're going to discharge patients before their ANC of 500 for several days. And I think that would be a major change in probably clinical care. I think one of the things that's sort of interesting is these patients are engrafting so quickly, it's sort of catching us by surprise. My last patient who's not in this was discharged before he could overcome his opioid use that he'd been using for his mucositis. So he was still withdrawing, coming off opioid. So that's what kept him in the hospital, nothing to do with his hematology.
So it's really quite amazing how well they're doing.
One thing that you do bring up, which I think Pino has mentioned, is this idea about using ESCAPE may ultimately be something that could translate to an outpatient setting. Because in this case, using ESCAPE does not lead to that profound neutropenia and other cell depletion, and so that would be something we could aspire to there. It wouldn't necessarily be something to start with. This is something we'd have to learn to kind of figure out what the right dosing paradigm is for patients, but that could be something that we could aim for in the future.
Wishing we just hadn't expanded our transplant unit by 10 beds.
We'll find new uses.
We'll find an outpatient facility instead. Dream of a dream.
All right, great. Luca Issi, RBC Capital Markets. A few questions here. So maybe first, Dr. Heeney, obviously great to see most patients just requiring one apheresis. Can you just talk about what's driving that? I believe in your talk you mentioned higher doses of plerixafor versus one of your competitors. So just wondering if you can expand on that and whether that can come with any trade-offs in terms of potential risks. And then maybe John, bigger picture. We've seen Editas deciding to potentially out-license their sickle cell disease program despite pretty reasonable data overall and obviously focusing on in vivo gene editing. What was your reaction to that news? Is that something that you may consider should maybe the launch for some of your competitors continue to be somewhat sluggish? Any thoughts there? Much appreciated.
And then maybe lastly, can you just maybe expand on why you decided to move Alpha-1 earlier from 2025 to the first half of 2025? Thanks so much.
All right. So I think our successes with mobilization collection, there are probably multiple reasons why. I think there's more experience in this population now. Up until recently, there's unable to adequately do peripheral apheresis in these patients because of the contraindication of G-CSF. So I think plerixafor has really helped a lot. And we all rely heavily on our apheresis doctors and our stem cell whisperers. We're lucky to have one of the best in our group. So we're seeing, I think, iterative improvements in all of those processes at that level. As I mentioned in the talk today, I think that our center, we really strongly believe that preparing the patients with transfusion quiets down the disease and therefore allows a better collection. Certainly, that's what our group also feels. So we're learning these things along the way. Obviously, plerixafor has changed the game for this particular disease.
That's great. In terms of the dosing levels, it's a little bit based on weight. Amy knows more about this than I do, so I'll probably better answer. I don't think that's playing as big a role probably as those other factors as we're seeing.
Yeah, just.
Go ahead.
Oh, just to add on to what Matt's saying is I think this is where it's good to not be first or second in kind of the process. I think we've learned so much from Bluebird. Bluebird, if you keep in mind, was doing bone marrow aspiration to get cells out of patients. No one thought it was safe. They were giving GMCSF to patients. So I think now coming in, we even have apheresis experts. So not just doctors, but we have a whole team of nursing consultants that will go on site. A lot of these sites have now had experience doing this. This is very different than apheresing, for example, for other indications. And so there was a kind of lesson that had to be learned about where to get these cells from.
These cells behave differently than, let's say, if you're doing these for CAR-T or other reasons. And so I think that the whole, as you've indicated, whole field has learned a lot and benefited from this. As far as the plerixafor dosing, we really are just using it on label. But the difference is that we'll allow for a mg per kg dosing versus a fixed dosing for certain weights that are below a threshold. That overall winds up giving a higher dose to those who are lower weight. So is that, in fact, being helpful to those who are lower weight to actually get the dose that they should get? We have not seen impacts from this. There have been no safety signals related to this at all. And this is, in fact, how the label is written anyway. So it's really in conjunction with those recommendations.
And so, actually, if I could complete the trifecta, I think you've heard about the importance of the site team, the apheresis, and then Pino, maybe if you want to talk a little bit about the manufacturing process itself, which I think contributes.
Yeah, I think there has been a significant amount of optimization that we've dialed into the manufacturing process to the extent that there is a significant amount of automation that we use. That allows us to have a very high yielding process. And what that means is that we require fewer cells as an input in order to generate basically the dose that we need. And I think to some extent, you can see that from the fact that we were able to dose very high levels in general, 10.7 million cells, which means that we have a very efficient process that actually achieves that. And so I think that that obviously remains to be seen as we expand the number of patients that we do. But so far, we've seen that that is the case.
Our understanding is that the process in other setting and with other products is not yet as automated as the process that we have available for us. It's a combination of many factors that come together to be able to do that.
Then picking up on your other question about Editas out-licensing and sort of some of the competitive dynamics, which I think are quite important. Yeah, the Editas program looked good. It was working. I think they'd done a really nice job. And the data was good there. As a nuclease similar to exa-cel, I think it sort of does raise the question of, was there enough differentiation there when coming in years later than exa-cel to establish a position entering that market? When we look at the BEAM-101 opportunity, we're asking, of course, ourselves the same question. And when you have a coming-after market position, that raises the bar for clinical differentiation. You have to really become convinced that you have something really different and meaningful to bring to the table to make that worthwhile. And BEAM-101, the more we look, the more we like what we see.
We've always known we had potentially quite significant differentiation on the F levels and the S levels. That's been clear since our preclinical data. But now to see the robustness of the resolution of anemia, the rapid time to engraftment because the base-edited cells appear to be less disturbed, even these operational components we were just talking about, like mobilization cycles. And all of that adds up, we think, to a package that's quite significantly differentiated, probably at the high end of our expectations of what was possible heading into the experiment. I think the other thing to say is that in addition to our confidence in BEAM-101 as essentially best-in-class product here is the fact that it forms part of this larger strategy.
So I feel much more excited about being part of the sickle therapeutic landscape here because we have our wave one, wave two, wave three strategy. I think there's going to be a really significant opportunity here with wave one to help a lot of patients who are very severe. But also, the field is going to move forward. And we need to be the leaders in moving it forward into wave two. And then ultimately, there may also be an in vivo transition. And again, we bring those capabilities, as Pino said before, already able to deliver lipid nanoparticles to the liver. And we've been doing work for several years on retargeting to some of these other organs. So for me, we don't have to put all of it onto 101.
We actually have the package of all these different capabilities to keep us, I think, bringing new options to patients for really the long term.
Why Alpha-1 earlier?
Yes, sorry. That was your fourth question. Yeah, so I think with Alpha-1, obviously, I think investors are quite interested, no surprise, in when we might share that data. The trial is going well. I think we disclosed it in November that we had completed the first cohort. We're obviously continuing now. So we just felt it was time to give a little more clarity into that. I think we've always said that we would expect if we're able to dose escalate and if we're sort of on track with the trial, that two to three cohorts of data would probably be sufficient to get a sense of what the drug is doing, and at this point, it looks like we'll be on track to deliver that in the first half.
David Nierengarten from Wedbush. Just one question. The ESCAPE program, would it make sense to dose the cells again at some point to boost it up? If you're not conditioning, so.
Yeah, I mean, it's definitely a possibility. I think we have a good sense that it might be possible actually to achieve a very significant level of engraftment benefit with that, particularly when we further optimize the dosing regimen. But it's definitely an opportunity for us to consider that for sure. I think also there is an opportunity for continuing dosing of the antibody to some extent to provide maybe some continuous survival advantage. You probably have seen a little bit of that in that initial study.
So it's going to be a combination of the initial dose, how deeply can one create the surgical, what I call a surgical niche, in this case only of the stem cells, and leaving the rest of the bone marrow essentially there to continue to protect from an immune point of view the patient, but then also maybe continue to provide a little bit of a survival advantage even beyond the transplant so you can actually see an increase in engraftment over a certain period of time. So those two things are really two parameters that we're further optimizing with the non-human primate studies.
Eric Schmidt from Cantor. On BEAM-101, it looks like the cells are very viable. You said the base-editing process is producing clean product. You're getting good engraftment. Have you thought about pulling back on the busulfan conditioning regimen and using a little bit less chemo? And then second, can you just talk about where you are in the manufacturing readiness for potential pivotal trial requirements, assuming this is going to be a viable BLA? Thanks.
Do you want to take the?
Sure. I mean, the scientific method, don't change two variables at once would be what I would say. But I think if you had the perfect gene therapy and then you screwed up the conditioning, that would be awful. So I think obviously for this trial, it would be no change, but you could consider looking forward. But as someone who sits in the clinic with parents looking at their child and making the decision to sterilize them or not, it's still a major impediment. And that's why I think things like ESCAPE are really will be a paradigm shift. And hopefully, it's this one. But we have lots and lots of interest in these transformative therapies in our population.
But when you sit with them and the rubber hits the road, and some of them are vain teenagers who don't want to lose their hair, and some of them are thinking more about secondary malignancy and other things, mostly it's the consequences of the busulfan that we think we saw in our one patient too. So I think that's really the big impediment. But the patients who are getting through are doing very well. And so this is a stepwise approach. It's iterative the way things happen, as described. So the sooner we can get rid of all myeloablation, it would be better. I think a half dose of poison isn't still a great choice.
To your other questions about the manufacturing facility, so our North Carolina facility is actually designed to be able to not only do the clinical supply but also the commercial supply. We already have both the process and the capacity to support the launch and for a certain period of time. We're also further adding an additional suite to be able to take what we expect to be the demands even beyond that. We're very confident that that's going to be really the site that can support us for a while.
I do have a question online. So I'll just ask that one really quick from Dae Gon Ha from Stifel. Given that you're applying multiplex editing with ESCAPE, can you talk about your assessment of off-target editing and/or bystander editing? To what extent does your BEAM-201 experience set a precedent for off-target and bystander editing assays? And any concern or question we have of what bystander edit may look like with BEAM-104?
Yeah, so basically the off-target biology package that we deploy, and certainly we have deployed in the context of BEAM-201, where just to remind people, we do full simultaneous edits, are certainly things that we deploy even in the context of multiplex editing here. Remember that even BEAM-101, by the way, is a multiplex editing because the two genes are duplicated. So there are actually a total of four edits in there that occur simultaneously. But obviously, this will be two other that are added to that. The important thing in the context of multiplex editing is actually the ability of not making double-stranded breaks. That's the most important component of that. Because when you make simultaneous double-stranded break, there is an increasingly high probability that you get chromosomal rearrangements. And that's like translocation, for instance, which occur. So we monitor that.
We basically ensure that it's not the case. There is no rationale why that should happen, by the way, since we don't make the double-stranded break. In terms of off-target biology and bystander edits, that's not an issue. Certainly not an issue. 101 is not an issue for the CD117 edit. As part of that, remember, this is a single amino acid change. It needs to be very precise in order not to disrupt the functionality of the receptor. As I've shown you the data, we have not done that, which speaks to the fact that the edit remains very precise. Then the overall other guide dependent off-target biology, whatever is the package, obviously is satisfactory to several regulatory agencies now. We have an opportunity to really very well articulate what is the off-target biology package.
So far, it has not provided any impediment to moving this program forward.
Hey, guys. Matthew Ong for Alec here from Bank of America. First question for me on the patient death for 101, is there any known interaction between busulfan and e-cigarette use, especially given the relatively young age for the patient? And anything from any studies sort of informing care for the future? And then second question, from a capital allocation perspective, when do you think about shifting resources from 101 to ESCAPE, assuming ESCAPE looks positive in phase I? Would it be at that point or another point in the future? Thanks.
Certainly, busulfan in the autologous transplant setting as a monotherapy for conditioning has certainly been associated with acute pulmonary toxicity. And in this case, with the idiopathic pneumonia syndrome, it's been described. And so it's estimated sort of 3%-6%. And so certainly, that seems most likely the link. The contribution of e-cigarette use or vaping is not entirely clear. But as I mentioned today, my transplant colleagues are getting increasingly concerned about it, that that may contribute to the pulmonary toxicity that busulfan may be here. And so it's something we think about in this case, but it's very hard for us to actually know that that mechanistically.
During the post-mortem analysis, the patient had fibrosis and alveolar damage pretty typical of the IPS and didn't have fat-laden macrophages, which is apparently something that can be associated with vaping use and also with acute chest syndrome from underlying sickle. So it's not entirely clear the contribution here. But I can tell you we're all asking every patient, but we don't have a threshold of what to do about it or an objective measure, like you could imagine, for an exclusion criteria or something of that nature. But I think we're all nervous a bit about it, not just in this study, but across the field and allogeneic transplant as well.
Yeah, and then capital allocation. I think BEAM-101 and ESCAPE are fully resourced. There's not a competition for resources between them. So when we give runway guidance, they're both in there at the full clip. And again, I've tried to emphasize, I think it really that you can't overstate the amount of efficiency between the two. In fact, so almost anything that ESCAPE needs, we're putting it in place with 101. So you actually kind of get twice as much leverage from that investment, right? It's not only going to move 101 forward, which has the potential to be a near-term market entry, the first base-editing product. As a reminder, these are going to be profitable on a per-patient basis. The prices that are currently being generated, cost of goods for an autologous product are healthy. They're like a CAR-T. But the pricing is very different here, right?
And so we have real opportunity there. And of course, to get experience in the real world working with sites, working with patients, delivering product, doing the cell collection, that's incredibly valuable. And then all of that is then leverageable with ESCAPE and moves ESCAPE in and raises the trajectory. So we are full steam, all systems go on the whole franchise at this point. And by the way, beginning to think even beyond where we go with these technologies. ESCAPE, haven't talked about it much, but with ESCAPE, we are going to add in beta-thalassemia already. So with 101, we decided to be very targeted. Currently, we're doing U.S. only, sickle cell only, just because we think that's the most attractive place to be for this initial wave. With ESCAPE, you remove chemotherapy.
I think the risk-benefit in beta-thalassemia is now much more clear at that point for a transplant process. And equally, we could start to think about other regions as well. And then, of course, beyond hemoglobinopathies, the ESCAPE technology has really a lot of potential application across a range of diseases. So as I've often said, as with liver, this is a franchise where we can clearly see the lead program, but then it will grow over time as these investments accumulate.
Jonathan Grinstein, Inside Precision Medicine. I had a question about the patient. I noticed in the markers for HbF and some of the other indicators for a successful edit, it looked like the patient was kind of crashing a little bit in HbF. Was the patient sequenced again or was evaluated for the edits upon time of death? Was that part of the report?
I could mention about the F there. I think that that's because that was the patient who was also getting transfused. And so I think that that probably reflects more the hemoglobin A that was part of the transfusion. I think that's how I see it.
Yeah, I mean, the patient was admitted to the hospital two months out. And at that time, they were not anemic. So there was all systems. And I don't know if you saw their F threshold was quite high. So that patient, for all intents and purposes, early engraftment, recovering hemoglobin until the hospitalization. And once you're hospitalized for two months, you're just a pin cushion where you're getting blood drawn every day. From the post, at least the bone marrow was entirely within normal limits.
Anyone else?
And one other thing I just want to mention. No evidence of sickling whatsoever in that patient despite being critically ill. That's really important. So this was a huge stress to the patient who was hypoxemic on very high doses of oxygen and a ventilator. And despite that, there was no evidence of sickling, which I think in itself is quite amazing.
Hi, this is Gena Wang from Barclays. So quick question for also around manufacturing. So we were wondering if Beam performed like a side-by-side analysis to compare the cell survival rate of this base editing versus CRISPR and Cas9. And what's the cell survival rate after the electroporation? Could you remind us about this?
Yeah, so we haven't done a head-to-head comparison in the context of sickle cell cells, but we have done head-to-head comparison in the context of BEAM-201, which is the quadruply edited product for the treatment of T-ALL, which we were talking about before, and we've done head-to-head production of the cells, if you will, using the same four edits, either using the nuclease. Remember, in this case, the edits are knockout. So you can do effective knockout with the nuclease as well as with base editing, and then what we did was an RNA-seq experiment on each one of the cells to look at basically dysregulation of a variety of different genes.
Basically, what we found is that in the case of the base editing, the only genes that were reduced expression were actually the four genes that we were targeting for knockout. Versus with nuclease, there were in excess of 1,500 genes that were either upregulated or downregulated. Several of those genes involved in DNA damage repair. We also then compared viability. We did another experiment in which we gradually dialed one extra edit at a time. Started from one all the way to four. If you do it with base editing, essentially, the viability does not change. If you do it with nuclease, the viability after two simultaneous edits goes down by more than 40%.
Both sort of from a viability as well as a genomic evidence point of view, what we have found basically is that base editing does not disrupt basically the cell significantly. In terms of viability, what we do, we treat the cells that are in culture for two days prior to the electroporation and then for two more days post-electroporation. The cells are frozen.
OK, well, with that, I want to thank you all. It's been wonderful to discuss this exciting science with you and look forward to giving you additional updates in the future.
Thank you very much.