Hi everyone. Thank you for joining us on the last day of the 44th Annual TD Cowen Health Care Conference. I am Joe Thome, one of the Senior Biotech Analysts here on the team at TD Cowen, and I am joined by my colleague, fellow Senior Analyst Ritu Baral. And we have three great panelists for the Emerging Genetic Therapy Approaches Corporate panel today. We have CEO of Beam Therapeutics, John Evans; President and CEO of Prime Medicine, Keith Gottesdiener; and CEO of Metagenomi, Brian Thomas. Thank you all for joining us. So we're going to start the discussion with a few overview thematic questions, and then we'll go into some round-robin between the different companies on some company-specific issues. But maybe just overall, we've seen a number of novel genetic therapies advance over the past year.
Maybe do you get a sense that the FDA is feeling a little bit more comfortable with these novel approaches now? And maybe what are the biggest pain points that remain, or maybe reasons for caution from the FDA? And maybe we'll start alphabetically, and John.
All right. So first of all, thank you for having us, and I'm really looking forward to the conversation today. So yes, I do think that the FDA has come a long way. I think it's something we always expected would happen. I was laughing at the JP Morgan conference, remembering a year ago when literally the only question we would get asked and have to answer was whether the FDA would ever open a gene editing IND. And sure enough, over the course of the year they did. But at this point you have Intellia open for pivotal trials in TTR. You've got Verve now open. We're planning on filing our Alpha-1 program will first go ex-U.S. for some Alpha-1 specific reasons. But our GSD program, 301, will be filed in the end of the second quarter in the U.S.
I think if you just listen to Peter Marks's commentary, I think generally it does sound like yes, they are welcoming of gene editing trials, and I think that we're seeing the field really start to move more quickly.
Yeah, I might even add to that a little bit. But I agree with everything that John said. One year ago, that was the only question I got asked also, and I wasn't even talking about an IND yet at that particular point. So it was a little bit premature. I would say it's probably even more just that Peter Marks is talking about it. They're starting to do stuff about trying to really understand what's going on. We've been lucky enough to have a whole number of formal and informal interactions with the FDA as we move to file our first IND in the first half of this year. I've been incredibly pleasantly surprised at how knowledgeable the FDA has been about our work.
Not that there aren't some places where we have some touching up to do, and I think there's going to be a question about that a little bit later. But they've really given us an amazing amount of advice on particular areas. I think they're getting past just about everything that people worry could be a potential issue. It doesn't mean that they're changing the bar, but it's more they're starting to feel comfortable with the kinds of questions they're asking and the answers that they expect companies to do. And if there's one thing I think we've learned, all of us, is if you know what the FDA really wants you to do, you can generally do it. And all of this craziness where there's miscommunication really starts to disappear. And I think we're seeing some good examples of that.
Keith and John, actually, open it up. What are those pain points that you're describing? We attended a Prevision Policy event where Peter Marks said he seemed actually very comfortable with quantifying the risk of off-target editing. So what else is there that may be sticking points? And how has this staffing situation with CBER evolved, and is that holding programs back?
So maybe I'll just start in, but I think John will probably have more important things to say in this case, so I'll get my sentence or two in first before he tells us more definitive answers. There's no question in my mind that off-target editing remains a clear issue with them, but I think they're starting to understand it at a different level. Listen, I watched the CRISPR Vertex, AdCom. The discussion of off-target editing was not what I had hoped it would be. Probably a little more direct and private. I think the company tried their hardest, but the company also did off-target editing at a different level than I think any of us are really doing that work. We're now working with 15, 16 assays. They talked about three.
There was really no discussion about translocations and rearrangements, which probably maybe isn't as big an issue as individual point mutations. So I think they've really gotten to a point where it's a little bit really quite different. I don't know what the staffing problem is, but what I would say is maybe we've been lucky, and maybe it shows some interest on the part of the FDA. The folks we've interacted with there are very senior people. I don't mean senior like Peter Marks, but within the division, the folks who are doing our reviews. They've been there for a long time. Many of them head their groups as opposed to being the junior reviewer there. I'm kind of hoping that meant they signed up for that and they were interested in stuff, but it could be just the luck of the draw.
But as a result of that, they've really given us very, very thoughtful advice, really pointed us in the right direction. It doesn't mean everything's OK. The FDA is sort of like the Delphic Oracle. They say things, and you have to apply a little bit of interpretation to it. But I feel like the staffing and the people we're dealing with are really top-notch.
John?
Yeah, I would just basically echo that. I think the field is advancing. I often say that off-target is obviously a I wouldn't even say it's a pain point. It's a focus point, right? The FDA's job is to characterize risk and potential for benefit, and the risk side is off-target editing. Because we know that these gene editing therapies don't have any acute effect, right? The delivery procedure might, but you kind of understand that. They're gone from the system in a couple of days. So really, it's only that I have a long-term impact on the genome. And so that's off-target editing. But the strength of the field, I think, is the assays we now have. The FDA doesn't have to pick and choose winners here.
We can just bring them an increasingly sophisticated set of assays and fully characterize with amazing depth everything we're doing in the genome, and they can see it, and they can get comfortable with it, characterize it, and move forward. The FDA just needs to know that you've adequately explored all of those questions. As the field advances, the FDA will get more sophisticated, and that bar will move up. Outside of off-target editing, I think it's really delivery modality specific. We obviously had open INDs with sickle cell disease. We're now one of them. We have CAR-T products. We have our 201 product. And now we're doing in vivo editing with liver. I can tell you with liver, one of the additional things they're interested in is biodistribution, where you're going in the body.
But again, we have a good sense of what they need to see, and it's not a complicated set of experiments to do. Progeny, do you have any impact on reproductive editing transmission? Again, you can do those trials. We've done them, and they indeed show no transmission through generations. And so we're just sort of checking these boxes off increasingly. And then the next piece is not just about open INDs. It's about pathway to market, right? And so now you've seen with sickle cell disease a path to approval of endpoints that you can measure from a gene editing product, and now a full approval for Vertex and CRISPR. So we're obviously excited about that with our sickle program, and we think other programs are going to follow where there's a fairly normal development pathway despite this being a transformative one-time gene editing treatment.
Yeah, I would just echo briefly what John was saying. I do think it's a little bit technology delivery specific, too. And so we have the benefit of not being first, and so a lot of our interaction is we're learning from what we're hearing from them. And so we have the luxury of really being able to go very exhaustively in how we think about off-target and the types of assays that we want to get ready. And so we have the advantage of now building that into our development process as we move forward, so.
Maybe I'd say just one more thing. I think last year people worried a lot about this issue of germline transmission and other things. And I don't want to suggest that isn't something the FDA doesn't focus on. But keep in mind, I don't really think at heart the FDA is concerned that we do a therapeutic edit in the germline. They're really more concerned about the issue of you doing damage in very plastic cells, or you're doing other kinds of things that are going on. And I think one thing that's happened is the programs are getting more and more specific. They're getting better in the way they can assess that off-target. And so in some ways, I think that whole issue is going to calm down just a little bit, is these new technologies or some of the old I'm laughing. Old technologies are five years old.
But just to put it into perspective, those old technologies, as people are finding better ways to do them, I think that some of that I definitely get the feeling some of that anxiety is starting to fade away.
Several companies in the gene editing or gene therapy space do leverage outside pharma partnerships. Obviously, it provides a good source of funding for programs. How do companies decide which technologies they want to keep in-house, which indications they want to keep in-house? Maybe Brian, we'll start with you, obviously, because you have the Ionis and the other partnerships.
Sure. Listen, gene editing is a new technology, and it's revolutionary. It's going to fundamentally change health care as we know it. And my philosophy from the beginning has always been to try to bring in partners to move it more quickly. I mean, at the end of the day, the goal is to get these technologies translated so that we can develop therapeutics and save lives. So we've been very aggressive in how we have approached partnering, and we really want to see partnerships that can help us move in a direction that we couldn't do as either a small company or a technology limitation. Or we want to see partnerships where we can get into other organs, for example. When you think about the broad applicability of gene editing in health care, the liver, we can solve that problem.
We know how to get into the liver with LNPs, and there are a variety of ways to do that. But there are obviously a lot of other genetic diseases that you can't treat by treating the liver. And so we're really thinking about partnerships in that way. I think one of the luxuries of having a variety of tools in our toolbox, too, is we can be very thoughtful about the strategy around who we're partnering with and when and on what indications.
Yeah, I would say it is a difficult problem, and we get asked that quite a bit. We have not yet done a major deal, though I hope that we'll be able to share information over the next year, really, because we do think BD is an important part of where we're going. Probably the main reason is if there's one thing Prime Medicine has, prime editing has, it's lots and lots and lots of targets. And so if you have lots and lots of targets who you can work and you know you don't have the capability of doing so and by the way, I think I share this problem with each of the gentlemen on either side of me. If you're in that situation, you really do need partners to move these programs forward.
Some of the most interesting things have happened, and I think this probably applies to John as well, where people have come to us and said, "These are things we think prime editing could solve, a problem for us." Not, "Let me look down your pipeline and see number one and number four, and your menu is places we want to work." But we have a problem. We have a program. We have a disease we want to solve, and we think this is the tool to do that. Some of our most interesting conversations occur that way as well. So these are things you can think of almost off-balance, off-balance sheet type of things. I don't mean in a financial sense, but in a portfolio sense, off-portfolio. And those are places that, to all intents and purposes, are pure gravy for everybody because they're good for us.
They're really good for the field overall. And frankly, I think they're good for the environment because companies have to dip their feet in a little slowly in some cases with new technology, and so they try it. And every time we talk to a company that way, we create something, and we leave a white space around it. So if this works out the way we hope, it can really expand into that white space, and it could be good for everybody involved.
Yeah, I think I'll just build on that. I mean, I think these are real platform companies, right? So you have a fundamental technology. It can be applied in many different places, but you also have a lot of capability you need to build in order to create a functioning development engine and ultimately a sustainable business. And so you have a lot of options, and you need to then choose, right? Where are we going to keep an asset because we think it's the best fit for us to hold it, move it forward, get it to patients? Where are we going to share it with someone else, right, where they can help us, but we're still very much in the game, and we're going to together reach more patients more quickly? Or where is it actually not make sense to hold on to it?
We're going to give it to somebody else, and then they can run with it. Do they have the capabilities to do that, by the way, right? So that's an open question. We did a deal with Pfizer, I think, which is a good example, that last piece, where they came to us, and we're really interested in base editing. And actually, we looked at Pfizer and said, "Okay, they've just done COVID. So they know how to do mRNA. They know how to deliver the nanoparticles. It's not that far a jump to go from there to putting an editor in that package." And they would be a great partner then for some of those programs.
That program or that collaboration is now a couple of years old, and we put targets into that that we were unlikely to do ourselves, that we thought would be better fits in Pfizer's hands. And they were not targets we were working on. So kind of as Keith was saying, it was what I call white space. And that expands the pot. And now, but yet we benefit by the technology moving forward, obviously, by capital. We have an opt-in on any one program, so there's some strategic value there as well. Beam has been fortunate enough to keep all of our core pipeline at this point wholly owned. So all of our BD has been done outside of that.
We've chosen those programs to be in that core because we think they can be really meaningful value creation engines, revenue drivers, and ultimately have a big impact on patients in a way that we ourselves can move forward, that being our hematology franchise with sickle cell disease and then obviously our liver franchise with Alpha-1, I believe.
John, have you publicly defined what those disease states were with Pfizer that you've given them that you maybe weren't interested in but maybe weren't feasible?
Yeah, no, we haven't. I'm going to disclose that. What we said was there's three targets. They're named targets. One is a liver target. And then one was a CNS and one muscle. So sort of the design of that was liver, we knew, low-hanging fruit. Delivery is going to be possible. And again, we know the target. We know it makes sense, and that Pfizer will be a great partner for it. In CNS and muscle, more exploratory, where we're trying to figure out delivery. I mean, as has already been mentioned, delivery beyond a few of the organs in the body is still a major unsolved problem. And we had a bunch of technology we were eager to apply, and that's been exploratory work that's been ongoing. But the specific nature of the targets, we'll have to wait on Pfizer to disclose at some point.
So we talked about the level the assays needed, the level of safety characterization needed to head into IND and clinical study in the U.S. What do you believe is going to be necessary ahead of a potential approval for a gene editing treatment? Is there clarity here yet, and how might unmet need factor in as CBER looks at this?
Well, no, you go first, John.
Oh, sorry.
Oh, I thought you were about to speak. If you're not, I'm always happy to jump back.
I mean, I'll go first. You can make it better. So I think I was just going to basically go back to we've now seen it happen once, right, in the case of sickle cell disease with Vertex and CRISPR. So we're very close to that. And in fact, I think that that approval for Vertex pretty much was our base case, which was that a single trial ought to be sufficient to serve as an approvable endpoint for that disease because there's high unmet need, for sure, but also because the effects are so profound, right? You don't have to squint to see the efficacy here, right? You're seeing transformative impacts on vaso-occlusive crises and some other parameters. Now, I think we do better. I think 101 that we have, Beam 101, is a deeper cure. It represents potentially a better product.
But when you have something that is precision medicine, you know who to treat, you're right on the mechanism of the disease, and you fix it, you should see a dramatic effect. And when you see a dramatic effect, you should be able to run a small targeted trial that generates a clear delta for patients, and the FDA should be comfortable moving that forward. Now, obviously, we're going to follow patients for the long term and make sure long-term safety is there. But for an urgent unmet need situation like a sickle cell disease.
They're not going to hold it up on one.
Definitely not going to hold it up. I think for the vast majority of the kinds of applications we're all talking about, that same paradigm will apply.
Yeah, I would agree. I would just add one other thing to it. I think one of the advantages of being in a gene editing space, maybe two things, maybe three, but I'll try to keep it to two. One of the things in gene editing spaces, I don't think anybody finds it hard to believe that if you actually make a genetic correction, you move a patient with a rare genetic disease back to wild type, Okay, and you get to them before end-organ damage has occurred, that in the end, that cell is going to behave as if it's cured, and the results of those clinical trials are going to be obvious. You still have to do a great trial. You still have to agree with the FDA and what those endpoints are. But I feel like there's an element of risk that comes out of this.
Now, you still have to deliver and get to the right number of cells. There's lots of technical issues. But if you truly do that, I think the outcome is not a foregone conclusion, but you just have an extraordinarily high probability of success overall. And I think that translated, as John says, is in almost all cases to extraordinary efficacy. So it's totally clear. So that's the first point, I think. And I will only make one other. I personally believe that with new technologies, it's very important that you pick very careful places where you apply it. I think regulators feel best when they really understand the risk-benefit. And I do think that that happens in places where there are huge unmet medical needs.
Trying to stretch the envelope too quickly has the potential to be a disaster for the field because if anybody ever gets that wrong or things that are unrelated to the particular indication you're going can kind of confuse things, you're really setting the field back. So I think it's very important to really think about indications where you can look patients, doctors, and the FDA in the eye, and you could say, "These people have nothing. We have something to offer them. When we're done, no one's going to use this in hundreds of thousands of people, and you're going to have to withdraw it in the future, or some disaster is going to happen." It's just really a place where I think having those conversations for a couple of years is really important.
If I'm hearing you correctly, you guys don't think there's some huge step change on safety between IND clearing and approval?
I really don't.
On the other hand, you'll actually have, hopefully, substantial clinical benefit to make that risk-benefit.
I do. As a matter of fact, I think the work we're doing now for IND on off-target editing is 90% or 95% of the work, maybe even 99% of the work we're going to do. Obviously, the FDA will, in some cases, want you to follow these patients, even from a genetic point of view. And I don't spend a lot of my life worrying about.
It's like the 15-year follow-up thing.
It is. But they may ask you to look at certain mutations and just make sure that some clonal event is occurring around it or whatever. There are pieces we just don't know the answer to. The animal data suggests in our hands, and I'm sure in other people's hands, that that doesn't happen. But if it was, that would be a problem. But like I said, I don't lose a lot of sleep on that. And that means that most of the work we've done upfront and from a safety point of view now, that's not the same as de-risking the delivery part of things. I'm just talking about the pure genetics.
Go ahead.
I was just going to add that adding on to what both John and Keith have said, I think it also is really important to pick the right indication because you need to have a biomarker so that you can generate that important data to get that confidence.
So what can be done preclinically with the gene editing program to best de-risk in-human development? Yeah, is there something in particular, other than the assays that we talked about, beyond that FDA is focused on? Brian, maybe we'll start with Keith.
Sure. From a preclinical point of view, one of the things that we've seen having a large toolbox of gene editing capabilities that we can bring to bear is really the variation between specific targets that you're going after and how a particular technology will work in that specific target. And so one of the things that we've built into our company is really trying to take a traditional drug development approach here, where we have a variety of technologies. We're screening for ones that show the highest degree of effect. And then I think going back to the previous questions, making sure that we're following that immediately in the setting of a particular gene target with the off-target characterizations and everything because we do see uniqueness between different locations in the genome and different targets that you can go after.
I think that's not a surprise to the field of gene editing.
So I would just add that one of the hard things about gene editing is you're dealing with a genome that varies between species. And so the issue of what are you actually testing and what species is something you have to give a lot of thought to. So for example, with prime editing, we use non-human primates primarily as a test for delivery because we really can't use them to test our machinery in many ways. Of course, we can work with surrogate guides, but surrogate guides can only be such a good predictor. So we do a lot of work with completely humanized mice loci and recreation of models. But mice are not humans. And so there is clearly some risk of translation one to the next to the next.
But on the other hand, what we do do is a humanized mice model, for example, is a perfect way to test your machinery. It still has to get there. Delivery may be different in the human. But once it gets there, the question of can it actually make the corrections you want at a high enough level with enough specificity? If you're really dealing with a humanized mouse, you're really dealing with exactly the genetic code that's there at that particular spot in humans, and you're really testing what will happen. So there's a lot of de-risking that does happen preclinically. The problem is, and it's only a short-term problem, is there's still not a lot of preclinical-to-human validation yet. And I think over the next five years, we're going to get a much better handle on that particular question.
Yeah, let me maybe add maybe picking up on that last theme with translation, which I think is so critical because we talk a lot about off-target risks. And of course, the other piece of the package is, well, what's your prospect for benefit? And I think, just as Keith said, that is rapidly changing. So now, if you think about LNP to the liver, we have Intellia across multiple programs. You now have some first data from Verve using base editors. We're going to be in liver patients for Alpha-1 in the middle of the year and then glycogen storage disease a little bit after that. So pretty quickly, we'll start to have a good set of information there about how well this is going. And so far, the translation has actually been pretty robust.
And so you can look at your primarily dose projection in a primate, I think, as Keith is right to say, and extrapolate what you expect to see in people. In our hematology programs, right, same sort of story. We've been editing human cells just as if they were a human product. We just put them into mice before people. And those models have been quite predictive, actually, if you look at both bluebird, but then in the editing field, obviously, CRISPR and Vertex, and then Editas, and now us. And so we have a lot of hope that we will see a predictable translation there. The final point I wanted to make on this topic is also then, if you think about it, once you have that straight, now think about what that does to programs two, three, and four if you're delivering to the same order, right?
So the beauty of these things is they are platforms, right? So that the technology, once you work them out, you can make a very, very minor change, and suddenly you have an entirely new medicine. And yet, 95% of that program or more is identical to the last one and has the same de-risked, high probability of success of delivery and on-target translation as your first program has now proven, right? So although it is expensive and complicated and new to do these things, once you've done them once, you can then do them again and again with very high confidence. And you'll know relatively early in the clinic whether you've been successful again. So that leverage, when you think about being a biotech in a capital-intensive industry in a market that goes up and sometimes is very down, we have to be really efficient with our capital.
I think that that platform advantage is actually going to be really important as we build these companies. In some ways, like, speaks for Beam, I know this is true for all of us, we're just getting to the good part where we've actually done it once, and now we can do it again and again.
It's like buy one, get three free.
Yeah, exactly. Could I just add one more point on that? I agree with John. This modularity, I call it, as opposed to platform, is important because we're speed and efficiency. But I can't tell you how much it actually impacts the bottom line. For example, we built out our 15, 16 assays for off-target activity. We have spent a year or two or three really intensively building them out. We're going to use them over and over and over again. In our first IND, we have something like 90 release assays to get the material out to humans that we have to go through. Most investors have no idea how many there are. More than 80 of them are generic assays. And I know that's true for Beam because they helped us to develop that particular approach by giving us advice.
What it means is those assays are up and running. We've worked out the bugs for them. You literally get to use them over and over and over again in many ways. Frankly, our hope is to convince regulators, you don't need 90 assays next time because a guide has sequence information. But when you really think about it, you can think about it the old days of magnetic tapes and computers, right? Obviously, every tape had different information on it. For the maker of the tapes, the magnetic tapes, every tape was exactly the same. You didn't have to reprove that the next tape was exactly as good as the previous one. You just had to deal with the new information, which is the stuff that was encoded on it.
I think it's going to just be an extraordinarily efficient and cost-effective way to bring new programs behind.
So let's move now to the program-specific, company-specific questions. John, we'll start with you. You guys recently prioritized your focus to SCD and AAT. In your first clinical trial with 101, the first patient was dosed and grafted in 4Q. Could you discuss the overall trial design? Are you staggering dosing? And where are you with that patient dosing ahead of promised data, which I believe is second half?
Yeah. So maybe just to pick up on the portfolio prioritization, so that was some stuff that we did last year in the fall. And actually picking up on this exact theme, we were doing many different kinds of delivery, right, including cell therapy RT and novel organs, as well as hematology, liver, and other places originally doing some eye work. And that's where there isn't leverage, right, because every one of those delivery modalities is different. And so they need their own infrastructure. So we ultimately concluded with the market impact and just looking at cost of capital for us that we needed to be a little more selective than that, at least in the near term. And then we can go on that later. And so we ultimately chose hematology and liver as the two kind of core anchors, which had a couple of things for us.
One was they had lead anchor projects with sickle cell disease in Alpha-1 that we feel are really significant. They make incredible impact on patients. We think they are generally de-risked, both in our own hands as well as building on what's happened in the field, and commercially can be quite significant. We can build a sustainable business around these programs. That's important for us, given that we want to be self-sustained from a revenue perspective at some point. It does not mean we're not going to do these other things at some point. But we may do partnerships, or we'll just wait a little bit longer to get to them. But within those two areas, we have all the capabilities now built and the infrastructure established so that we can do not just those lead programs, but many over time and follow that innovation out from those anchors.
So within hematology, as you noted, sickle cells, the main lead program for us, so BEAM-101 is our lead program there. We're upregulating fetal hemoglobin. But we do it with higher levels of editing, higher levels of upregulation, more precise and uniform changes to the cells, lower levels of sickle globin. And you can see all of that head-to-head in preclinical studies that have become the gold standard. So we feel very confident that BEAM-101 is potentially best-in-class profile for this disease. So dosed our first patient in Q4 last year. The patient was successfully grafted.
Patient's doing well?
Patient's doing well. No other updates to give. We will be dosing patients two and then three in sequence over the course of the first quarter of this year. Then there would be a data safety monitoring check. Then you move forward to expansion. Once you're in expansion, you can dose as many patients as there are. After three, then you can use many.
What is the DSM be looking for in particular?
Just confirmation of engraftment success and just overall, obviously, health and prognosis of the patient. Transplants, we really do understand pretty well now, including in the context of genetic intervention. So I think we know what we're looking for. So we have many more patients on trial now than just those three for the seminal cohort. So then starting later in the spring, we'll be able to just start to dose multiple at a time as we go and continue. That puts us in position for the data event you mentioned, which is second half of the year. So if you think about it, later in the second half of the year, we would have a handful of patients out six, nine, 10, 11, 12 months. And then more patients dosed more recently.
Six plus months. I would say like five patients, Six plus months with.
I mean, so if you said ASH, right, just as an example, then it would be that. So you'd have probably six patients at six months plus, not several patients more recently than that. And that's what our goal is, to give a really meaningful update so you can really see what's happening and understand the drug. And our goal is to not just share that with the investment community, but ultimately share it with the patient community and the investigator community, get them excited about what base editing and BEAM-101 can do.
What's good data?
Yeah. So good data has hopefully all of the great editing features that I mentioned, right? Obviously, with base editing, we're not making double-stranded breaks. We're non-viral. We'd like to see that very high editing efficiency. We'd like to see higher levels of F. We'd like to see lower levels.
Higher than what? I mean, you showed 65%.
Higher than our competitors.
Okay. So you showed 65%. There's a certain point after which it doesn't seem to. I think it's like after 55%, 50% or 55%, you can be like a pan-cellular or something like that, right? But after a certain point, it doesn't seem to.
I mean, I think if you think about a sickle trait patient, right, so a patient is a carrier but does not have the disease, if you actually measure their blood levels, they're actually 60/40 normal to sickle, okay? And so I think that getting towards that higher number of F and then having a lower level of S is actually a good target. And that's not where the current clinical programs are. They're more like 40%+ normal or F and then more like 55%-60% S. So we'd like to flip that, okay? And I think if you look at the Vertex Adcom, I think you see a really transformative drug and room to improve, right? They're about 80% editing across the cells. You're seeing, again, only about 40% F. You're seeing hemoglobin is not quite normal. You're seeing hemolysis not quite normal.
Retics are still high. You still have some vaso-occlusive crises. This is room to improve.
LDH, retics, all that stuff is going to come out?
Yeah. Yeah. We're measuring all that, as well as things, of course, like time to engraftment and how many mobilizations did it take, the whole package, thinking about the whole patient experience, so.
Has the Casgevy and Lyfgenia approvals impacted interest in enrollment?
Yeah, we're certainly watching that. I think it's still early days, frankly, for their approvals. It hasn't impacted interest yet. In fact, if anything, it probably helps get people excited about checking in with their doctor about these things. And we continue to see a lot of demand for the trials. The investigators we're working with are all investigators on some of those other programs. So they know the field really well. And I think they are excited about what base editing and Beam can bring to the table. So enrollment is going well. We have a very broad site network. And again, this trial, we have high confidence can be a potentially registration trial. We're going to enroll 45 patients. And at this point, we have a pretty good idea from the Adcom what that package looks like for filing.
It's probably no more than 30th patient followed for the 12-month vaso-occlusive crisis endpoint, plus the additional 15 patients for safety. That's a plausible package to consider bringing in.
Perfect. Maybe we'll jump over to Brian at Metagenomi. The company has shown already the ability to generate therapeutic levels of Factor VIII in non-human primates out for over four months. Obviously, with the gene therapy approaches, you do see sort of that decline in factor level over time. So what would you like to see preclinically in non-human primates in terms of durability and maybe number of non-human primates before making candidate selection for your HemA program?
Yeah. So our Hemophilia A program, just to remind everybody what it is, it's a program where we're specifically targeting a location in the genome that is behind a constitutively on promoter. And then we're delivering in a donor Factor VIII gene. So the Factor VIII gene is under the control of a native promoter in the liver. And we're seeing very good levels of efficiency of both the editing, but also then the integration. And so the integration then allows us to get ranges of Factor VIII that are therapeutically relevant. The big concern for us is obviously durability. When you look at gene therapies, they have a tendency to go into the liver and then, with time, be essentially washed out or diluted out. That's the nice thing about the gene editing approach that we're pursuing is we're making a change in the genome.
That will then, as the liver grows, continue with the gene edit and the integration that we have. So we have shown multiple times with rodent models that this system works. And now we have our first very exciting NHP data showing not only the editing but the integration. We are continuing this study for a full 12 months. As we've talked previously on the panel already, the importance of this NHP data in translating to the next steps is very exciting for us. Obviously, durability is something that's critical. And as we compare ourselves to a gene therapy-based approach, we want to make sure that we can solve the durability problem before we're confident. And right now, we're seeing very good signs and plan to announce that in the second half of the year.
Perfect. And then maybe moving over to the PH1 side of things, if you could walk us through a little bit, just the collaboration maybe there with Moderna around that program and maybe where are you in terms of preclinical development and candidate selection?
Yeah. So the partnership with Moderna is focused around Primary Hyperoxaluria Type 1. It's a knockout program. And so it's a nice program because it gives us a very clear mechanism to read out how effective our knockout is by measuring glycolate. And so we have a good biomarker there. That program, we've really been exhaustive in using the variety of nucleases that we have in our toolbox in order to really focus in on the exact location that we're trying to make the edit, as well as attaining the degree of efficiency that we want to see for this program. And we're in the final stages of declaring a DC there where we'll then move into NHP studies.
Perfect. And then the other part of the platform, maybe a little bit longer down the line, is the company's CAST-based programs. I guess maybe what sort of indications lend themselves most to a CAST-based approach? Maybe on the preclinical side, how is development going?
Sure. Sure. CAST, I think, are one of the really exciting technologies. Another one of the areas that this field is really amazing and revolutionary. And there's a lot of ways that you can approach gene editing. CAST, for those of you that don't know, it stands for CRISPR-associated transposases. And so these are a naturally occurring system. They're not a manmade construct. They're not an engineered system. But they're a natural system that has a programmable CAST-based enzyme. So you can program it to go where you want it to go in the genome. But it's naturally defective. So it won't actually cut when it gets to that location. And instead, it recruits three additional transposase components that then make a targeted integration at that location. So this is very exciting. Transposase systems have been around for many, many years.
One of the big problems with just a pure transposase system is they tend to hop around. They don't have the specificity of where they will integrate in the genome. That obviously will cause problems. So what's nice about the CAST is you can restrict the location of where they can target. What we've been able to show, and we have a publication pending right now that we've been able to demonstrate, we can get these systems to work in human cells. We've been able to achieve 1,000 base pair integration at a specific location. This is, I think, just the beginning. When you think about transposases as a class of enzymes for doing DNA integration, they can go up to the 10s to even 100s of kb in integration. Obviously, this comes with a real challenge in terms of delivery.
How are you going to get these components into the right organ and then into the right cell? And so for the current state of our development, we've got human cell proof of concept and are going to be working towards our first animal models soon.
Maybe we'll jump over to Keith. You mentioned earlier that the company is obviously getting close to filing the first IND for the 359 program. Earlier in the conversation, it sounds like the FDA interactions are progressing well. But maybe what's left until that IND submission? And do you think does it seem like the FDA has a good sense for what they want for the first prime editing IND?
I probably can't be very specific about what's left, as you can imagine, because the only guidance we've set is it'll happen in the first half of this year. I told you what was left. Everybody here could probably figure out, to a day, the day of this submission. I do get that question quite a bit, as you could imagine. But I would say, generally speaking, there are many different activities one needs to put an IND together. Your CMC be in place. You have to have a particular protocol the FDA agrees with, preclinical work, off-target, et cetera. And I think we're very happy with the way all of those activities have progressed, are progressing, and in some cases, will progress as we go forward. I think the FDA has given us. We have a pretty good idea of what they want.
There are a couple of reasons for that. The FDA itself has taken a very interesting look at some of these technologies. I know they did that with base editing. They've had David Liu down to the FDA, I think, three times to talk about prime editing, including twice privately, to really talk about that, to get them up to speed. I know that they did that also for base editing at an earlier point as well. I think that's very, very useful to do that. We've taken our general approach, the FDA is anytime they're willing to talk to us, we're willing to listen. And our approach for the first IND was not to argue with the FDA about what they want or they don't want. It's a new technology. We said, "Help us understand what you want. And if we can do it, we're going to deliver it.
If we don't agree with you, and there are clearly things that we think are very, shall we call them redundant? Maybe that's the right word. "We're going to discuss them with you in our second IND. But now we'll have data in hand to help you to understand why that's the case." So for example, in off-target editing, there were a couple of places they carried things a giant step further than anything we did. We did the work. We showed them it added. We haven't shown them yet. But we are going to show them that we have added zero value to that particular approach. And hopefully, the next time, we will have a different discussion with them overall.
I think the hard part with the FDA is no matter how much you talk to them, in the end, there are always a few places of uncertainty. So in each one of those cases, we have sat down, very carefully considered the science, put forward an explanation for what we want, what we think we are delivering, and why. We also have taken the approach of offering them an alternative, if need be, because in almost all of these cases, there was a, "We could do this," or, "We could do that." So we've explained to them what that alternative is. And frankly, we have backup plans for every one of those alternatives to provide that data if and when it was needed within very, very short periods of time, days in most cases. Does that mean everything will go smoothly? I don't know. The FDA is the FDA.
But what I do think is we're pretty confident that we really are going to put in a great package to them.
Maybe can you talk a little bit about the unmet need in the first indication, CGD? What are the shortcomings with the allo-HSCT? And where can a prime editing approach be beneficial there?
Well, just to explain, CGD is a disease where children, in fact, can't fight off infections. They grow a little bit older. The infections get worse. It has an awful lot of inflammatory and autoimmune phenomena that are associated. It's not just an infectious disease type of indication overall. So it's really quite a bad one. People's lives are absolutely miserable. There's just no other way to describe it. It literally hits them from all places. The infections get to the point they really don't respond to some of the therapies, like antibiotics. It happens very quickly. They settle in. You could think of it almost like you have cystic fibrosis of your whole body in some ways. So it's really quite a bad need and a huge unmet medical need. Today, the only treatment of choice, the only treatment, is an allo-HSCT, bone marrow transplant.
So in order to do that, in most cases, they get an unrelated donor. So they live with long-term immunosuppression for the rest of their life, as well as graft versus host disease, all sorts of terrible things. And yet, people line up to get this on a pretty regular basis. It says something about the caliber of the disease overall. What we'll be offering people is an autologous bone marrow. So they still go through a period of immunosuppression, like all autologous bone marrows. But when they're done with that, assuming the therapy works the way we want, that's it. No more immunosuppression, really nothing, okay? It's a once-and-done curative procedure. And we know even very well what the target we want for the amount of editing because through all this work with allotransplants, many of the patients have chimerism.
Their bone marrow is a mix of the new donor cells and their old cells. And it only takes 10%-15% of the new type of cells in the bone marrow to actually deliver what looks like a cure for these folks. So it's a wonderful place to start out. Genetics is one only prime editing can do, I believe. Brian might have an argument with me with this toolbox. But we certainly believe that's the case. There's a great unmet need. The current therapy is absolutely horrible, okay? And yet, as a result of that, people are willing to line up for the autologous approach that we're talking about. And really, two months, three months after we treat them, we should unequivocally know whether they are cured.
Perfect. We'll be back if you want to have some better information.
Yeah. John, one last thing on the competitive landscape now. You said enrollment is fine and on track. How do you see the ideal patient for BEAM-101 with the other two on the line?
Yeah. I think we generally feel that there is a population that will be good fits for what we call wave one of the sickle market, which is the most severe patients who are really eager for cure. And they have to go through that same transplant process that Keith mentioned, which is myeloablative chemo. So it's not an easy decision. But I think there are patients for whom actually it is pretty easy. They are very eager to get into one of these trials. So we've shared numbers that are illustrative. But maybe is it 10,000 out of the 100,000 in the U.S., about 10% of the population that will be looking to that therapy? We think that it will not be an overnight fit where you treat everybody. It'll be more every year you treat some.
As this market evolves, there's a lot of operational infrastructure to establish first. Be cautious on how fast the Vertex launch will kind of establish that. I think it'll more be every year we get a little farther. We will then enter at some point. So from our perspective, every one of those patients, we think, is a target patient for us. And if we have a better product than what Vertex has or Editas or Bluebird, then we will argue for 100% share. We'll see. We'll be also becoming several years later, right? So there's obviously a competitive dynamic that will have to play out in the market. At the same time, our then future job is then to try to expand that market. And this comes to our next-generation versions, which are coming along nicely as well. So ESCAPE is our second-gen where.
I was going to ask about that and just expanding that market with more tolerable conditioning agents. Everybody knows they're vastly preferred to chemotherapy. So can you describe the ESCAPE approach in your.
Yeah. So with ESCAPE, we add a second edit. So we're taking advantage of that facile multiplex editing that you get with base editing, very high efficiency. And so this second edit allows us to use antibody conditioning rather than chemo to create space for the new graft to take hold.
That's the CD117?
Yep, CD117. And yet, that graft will then not be affected by the antibody anymore. And so it really takes advantage of the precision and subtlety of the base edit. And so if we're successful in that, it'll basically bring that same curative approach that you get with BEAM-101, but now to patients who are maybe more in that moderate bucket where they wouldn't quite reach for the curative therapy just yet. Depending on when we arrive, of course, if there's anyone left of the 10,000, they will, of course, opt for the ESCAPE. And so we'll certainly cannibalize wave one if it arrives. But it also adds more patients. And we talk to patients and physicians. And so we've said maybe that's 30,000-40,000 patients out of the 100,000, right? So that's really exciting. Of course, third gen is then in vivo.
We have an in vivo effort ongoing as well, trying to get nanoparticles to get to the marrow. This is more research stage. It's a challenge for the whole field. It's not going to be easy. But if we're successful there, of course, then you have an infusion, very, very easy, highly scalable. And that could go global. And now, literally, all 100,000 patients are eligible for that. And of course, we could really think about going to every region of the globe as well. So it's a progression. I think in the next decade or so, we will make our way through all of these generations. And ultimately, my vision is that every patient with sickle cell disease is going to have an option for curative therapy from one of these generations of technologies that we're advancing.
I want to also just touch on 301 for GSD1a, glycogen storage disease 1a, and 302 for Alpha-1. Can you talk a little bit about well, let's start with 302 for Alpha-1. Can you elaborate on those timelines? Because I believe you're going to start patient dosing in the first half.
Yeah. So 302 is currently the lead. 301 was DC first. But as soon as 302 was ready, we've accelerated it. Alpha-1 antitrypsin deficiency is a huge market, 100,000 patients in the U.S. who have the Z phenotype or genotype, rather. And the Z allele is what we correct with the base editor. And so this is the first time, actually, in the industry that we're going to attempt to correct a mutation in one of these diseases, not just knock something out or elevate it. And we'll do that in the body. And so that was a CTA filing in the MHRA right in the beginning of the first quarter. It's a 90-day clock. So by early spring, we hope to get word back from them that we're able to proceed. We'll see how that goes. Then we start to open sites.
By around the middle of the year, we expect to be dosing patients to classic three-patient dose escalation, very similar to what Intellia and Verve have gone through as well.
Do you have the potential to hit? I mean, the liver is the liver, right? So into the liver. But can you hit the lungs?
Absolutely. So this is the critical piece. So liver transplant is curative for these patients, right? Because the liver is the factory for the Alpha-1 protein, which is circulating in the body and protecting the lungs. And so if we can correct enough alleles in the liver, then we will simultaneously stop production of toxic protein that will damage your liver. We will start producing normal protein that will secrete and protect the lung from elastases and be under normal regulation, okay, which is really critical for this gene because you need it to go up and down when you're sick. So you get this sort of surge in the protein levels to protect you and all of the one-time care. So I think that is ultimately the package, I think, of benefits that you really would like to have in this disease.
So there's a lot of people going after it. But no one has been able to do that set of things. That's why, of course, we're so excited about the program.
And Brian, maybe back to you. Can you talk a little bit about the ATTR program that you do have? And maybe how do some of the competitive data sets upcoming kind of factor in your decision to opt into the program? Obviously, we have the Alnylam HELIOS data coming up. Ionis has their own data coming up. I guess, how are you thinking about that program overall? And maybe a good time to also just touch on the Ionis partnership and the opt-in potential there.
Yeah. I was going to say this is really a byproduct of the partnership that we have with Ionis. They obviously bring significant disease biology knowledge in the TTR space. That business development deal was really a target-specific deal that includes a couple of tranches. The first tranche includes four targets, two of which we've disclosed. One of them is TTR. So we have the option to opt into that program as a full co-co. And we're obviously going to be looking forward to the readouts from Alnylam coming up here. I think that will have a big impact on our decision to go forward. However, where I would think we would differentiate is we've been able to really demonstrate some amazing data showing very specific gene editing in the locus and very good outcome from that gene editing.
I think the other area that we would really be able to potentially be a good, fast follower there is it's a big indication. And we could be learning from the clinical trial designs of the other companies in the space and the other modalities in the space. The real excitement for, I think, Ionis was being able to look at that as an indication that they have extensive experience in and then see a set of tools that allowed them to really have the comfort that they were going to be able to efficiently and very specifically knock that gene out. And so that, I think, is one of the areas that we pursued. And I think the nice thing about this partnership, and it ties back to a previous question, is just the speed at which we've been able to accelerate these programs.
When you have the deep disease knowledge of a partner coupled with a powerful technology like gene editing, is, you can really move things quickly. And I think that's one of our driving forces at Metagenomi is to take the technology towards the clinic as quickly as we can.
Perfect. And you did just complete the IPO process. You indicated three years of cash runway. Maybe just to take a step back, obviously, we've taken a dive into some of the programs. But what does that cash runway get you in terms of development across the platform?
Sure. As Joe mentioned, this is, I think, day 30. We converted from private to public 30 days ago. We're very proud of that. It's a real hallmark for the company and something that, I think, really accentuates the amazing growth that we have put into the company. Also, we'll just restate, gene editing is very revolutionary. I'm really honored to be up here on stage with Keith and John because they represent two companies that are really cutting edge in the space. I think the potential of gene editing is truly that revolutionary. We're excited to have the IPO behind us because it gives us three years of runway. This will allow us to take of our lead programs in of our top lead programs, we'll be able to file two INDs. Then we are also expecting two additional DCs with that as well.
Perfect. And maybe back to Keith. The company has outlined its clinical trial for CGD. But maybe if you could just hit the high points in terms of the cadence of patient enrollment, maybe some of the neutrophil readouts, and then obviously eventual clinical outcomes. And the company did guide for initial data in 2025. What should we expect?
I won't be able to answer all your questions. I can certainly give you an outline of that. This particular disease, it's fairly rare. We don't have to do any dose ranging in this particular study. What we do have to do is we have to do very sequential dosing at the beginning, the FDA, and I might add other regulatory agencies who agreed literally almost dynamically in terms of sequencing and approach to staggering. Really no difference between the ex-U.S. and the U.S. regulatory agency so far. Clearly, we want to take the first patient, make sure that we can actually show engraftment and return of the cells before we can go to the second one. They haven't been very prescriptive to the exact timing of that.
They haven't said, "We want to see," or, "You need to see day 30 data," or whatever. What they've really said is, "You need to really demonstrate that you can do this safely. And then you can go on to the next patient." In our case, it's very important to step down to younger age groups because all of the current allogeneic transplants are done in adolescents or children, usually over six. And so the FDA has also asked us to step down carefully between our adults into each of those. But the trial is designed to move through those things relatively quickly with a very quick transition, sort of as John had said, for sickle cell disease to a pivotal trial. And we expect actually less patients in our trial than we were talking about just a moment ago for sickle cell.
Though it's important to point out, we haven't had formal discussions with the FDA about any of our pivotal trial designs. That's a company supposition, our opinion, as to what we think we're going to need. So I think that what we expect we'll see is a number of patients coming through. The FDA has also done something that I find not that helpful. But they've made it very clear that we can't do any patient preparation of any of their materials or reagents until the IND is open. They've made it very clear. They want to be sure that they fully blessed everything about our manufacturing methods and such before we can start. So this is cell therapy. So in practice, when we open the IND, it'll be many months or so before we actually have the material that's ready to go.
We don't expect that'll ever happen again during the course of our trials. John went through this, I think, as well at Beam. And it's particularly annoying because, frankly, we don't see any reason for it. But in practice, it is what it is. So when we say that we'll guide to data in 2025, I think it's really a little bit of the uncertainties about those things that make it very, very hard for us to really know exactly when that data will come forward. But we're pretty excited about it. It'll be the first human prime editing data. And for us, that's a major milestone.
Perfect. With that, we are a few minutes over the hour. Thank you all for staying with us. Thank you for the great conversation.
Thank you, everyone.
Thank you, everyone.
Thank you, Joe.
A real pleasure.