Thank you for joining the Guggenheim Securities Healthcare Team at our sixth annual conference. I'm Debjit, and joining us from Beam Therapeutics is its President and CEO, John Evans. Thank you for your time, John, and maybe we can get started with a very quick intro.
Okay. Yeah, thank you. Yes, actually, just CEO. President is not here today. So, nice to be here. I'm John Evans, CEO of the company. Beam, as you know, is a next-generation gene-editing company using a new version of CRISPR called base editing, where we don't make double-stranded breaks in order to edit, but we use the CRISPR in a different way to target the genome, land there, open up the gene, and then use a deaminase to do a chemical modification of the DNA. So it's a very precise, well-controlled, and efficient reaction that allows us to have a much more versatile system, more precise, and do a lot more things with it.
And so that's led to, you know, a pretty broad pipeline with a lot of different applications that I think are quite differentiated from first-generation nuclease applications.
Got it. BEAM-101, first patient was treated and grafted. Any updates since then in terms of acceleration and the enrollment or... Actually, not enrollment, but more on the treating side of things?
Yeah. No particular update other than I think the acceleration in that trial really began kind of middle of last year, I would say, and it continues. So we continue to be very excited about what's happening there. So recall, we made some changes to our protocol to allow us to basically do many patients in parallel in terms of you know, screening, transfusions, mobilization, ultimately manufacturing, and then, of course, conditioning and dosing. And so at this point, we have many patients on trial. We continue to add new patients. No particular update to previous guidance other than I think the momentum, it remains quite strong with BEACON.
Just-
Yeah. And so, as you noted, patient one was successfully dosed and engrafted in Q4, which is where we thought it would be. So we'll be now doing the second two patients in the Sentinel cohort, one at a time, patients two and then three. Both doses have already been manufactured as we guided at JP Morgan. Then the Data Safety Monitoring Committee reviews, and then we are open the gates to treat as many patients as we want who are ready at that point. So I think that throughout the course of, you know, the middle and second half of the year, there'll be a fairly steady cadence of being able to keep treating patients over time.
Got it. And the CMC changes and the manufacturing improvements, does that alter the vein-to-vein time? You know, it's. People are normally saying it's three to six months.
Right. No, it does not. You know, the three to six months, I mean, it re-- and really, it's, I think, six to even eight months, actually. It's, you know, that, that's what a transplant is. I mean, there's just no way to do a transplant more quickly than that. But, of course, in that timeframe, I'm including everything from screening to transfusions, which is not really the procedure, it's just getting the bone marrow calm down. Maybe from the start of mobilization, is it three months? That's probably not crazy. So, you know, of course, the number of mobilizations is variable for a transplant, so there's, there's a lot of variability there. The manufacturing itself is very straightforward.
It's just a week process through the manufacturing, and then there's, you know, six weeks of release assays, basically, and then you do the conditioning and the transplant. So our process improvements are not designed to change that in a major way. What we do have a really good process, and we've been working quite hard on it, is it's a largely closed system, highly automated. So what that should mean is more reproducible, and more predictable. So if you looked at the CRISPR, Vertex trial, they had, I think, six patients who actually couldn't even complete to a dose, and then a wide range of number of sort of mobilizations and other things for the patients even who did.
So, you know, we'd like our process to lead to maybe, you know, better numbers than that, you know, where we're more predictably able to make sure we deliver doses to patients. The yields are higher, right? It, you know, it lets you get away with fewer cells, you know, and fewer mobilizations, things like that. So there's definitely a process story here that is important. And, you know, we're bullish about what we've been able to build.
Got it. And, given that there are no DSBs involved, and there was this particular concern from the FDA Ad Com on one particular subset of, you know, patients, that's not a consideration for base editors?
Yeah, that's right. So the ad board was very focused on off-target biology. And you know, it's the first ever gene-editing approval, so rightly so. I think it's a reasonable conversation. You know, in general, I think they were focused on a somewhat, you know... It's an important but somewhat sort of arcane topic. So basically, what they're saying is, "Okay, if we're worried about double-stranded breaks, then you know, could you have an off-target edit?
And specifically, what if there's variation in the genetics of the people around the world that you can't predict, and so maybe there's an off-target that you didn't anticipate, and what's the risk of that? And I think basically, the panel came to the conclusion that although theoretically, that's something that we will need to look at as a field, the risk is very low from that, and so it didn't pose a problem. For base editing, you know, we look at some of the same issues, but ultimately, for us, it's even lower because the consequence of a base edit in the wrong place is, at most, a single base change, as opposed to a double-stranded break.
I think that just gives us that extra, you know, margin of safety there, so I don't think that's a major concern point for us.
One of the things that at least we find attractive from a base editing perspective, the ability to multiplex.
Yep.
How do you plan to leverage that, and where are you going with that?
Yeah. Yeah, that's... You know, people often say, like, "What's the-... Why is base editing better than nucleases? And our answer is actually there's a, a lot of different reasons, and it kind of depends on the application, right? So, so, so one is, you know, double-stranded breaks scramble genes, right? And so you really can't go into coding sequences of genes if you need that gene to exist on the other side of it, 'cause you'll just knock it out, right? So for instance, our ESCAPE program, our Alpha-1 program, or GSD program, like these are actually editing the coding region of the gene to either correct the protein or to put in some modification. So that's a, that's a differentiator. There's the potency. You know, it's a very efficient and, and potent, process that helps us in some applications.
This point about multiplexing is absolutely another major advantage. You know, double-stranded breaks, I think, in general, are things you want to avoid in the cell. They're genotoxic, and you will always get some amount of chromosomal abnormalities, let's call it, right? Whether that be very long deletions that you can see sometimes if you look closely enough, or if you think about it, a single gene edit is still making two cuts. You have two alleles, right? So you can get swapping, you can get unusual recombinations of those components, and that's just for one edit. So all of those problems get much more intense as you go to two edits, three edits, and more combinatorially, right?
So if you think about it, making two edits, I mean, two cuts, you know, four different cutting sites, 'cause there's two alleles per cut, you now have four different spots that can recombine, things can get dropped out. So I think this is another important advantage for us. So it shows up in a bunch of different places. So for instance, even BEAM-101 actually has that advantage, because if you compare us to, for instance, Editas, where they're using a nuclease at the same target site, this is a duplicated gene. And so you're by definition doing a multiplex edit pretty nearby to each other. And so you're making four breaks, you're gonna have some complex outcomes there at the chromosomal level. Whereas base editing, we don't cut, we can go straight to the on/off switch of those genes.
We're making four different edits, and it'll work fine. It'll be important in something like ESCAPE, right? So with ESCAPE, we're gonna have that therapeutic edit, same as BEAM-101. We're gonna add a second edit, literally just adding a second guide, which will then make the modification to CD117, which allows us to have an antibody-targeted conditioning that, you know, very subtly only attacks old cells and leaves alone new cells. It's a big advantage for us that base editing is so efficient with multiplex, that we can just add that extra guide in, and we know it'll work, right?
Of course, in cell therapy, we've talked a lot about that, where, you know, the more engineering you want to do to cells, the more edits you want to make, and, you know, we can add as many edits as we want in that setting, and, you know, BEAM-201 is our quad-edited, CAR-T cell. It's the first four-edit cell in the industry. So I think, you know, looking ahead, you know, polygenic disease or hitting multiple risk factors at once, I mean, there's a lot of very cool applications where you're gonna want to stack a couple edits on top of each other, and that'll be a great fit for base editing.
You brought up ESCAPE, but before we go to ESCAPE. An allied question. There has been sort of a little bit of frustration, actually, a little bit is misnomer there. But sickle cell disease program—how do you think programs are differentiated currently, right? Because we still haven't addressed the principal challenge why these people, these individuals with sickle cell, sickle cell disease do not undergo transplants.
Mm-hmm.
Right?
Mm-hmm.
That's one of them is busulfan, busulfan conditioning.
Sure. Yeah.
So, and that ties back into that ESCAPE platform.
Yeah.
So, you know, BEAM-101, and then how quickly can you move from BEAM-101 to the ESCAPE?
Yeah. So maybe I'll before I get to ESCAPE, just to address the first point, I think there's no question that I think, now that we're in the conversation about one-time transformative therapies that permanently change your outcomes with sickle cell disease, the next thing we're gonna talk a lot about is cancer, is chemotherapy, you know, and busulfan. So that's absolutely true. But I don't want to move too quickly off of the revolution that's just happened. I mean, these are patients who have early mortality, and, you know, they're dying in their forties. You know, they're losing organs over time. They're having strokes. They are in the hospital constantly with these week-long pain crises. It is an absolutely devastating condition.
So the fact that we're even talking about moving past that to something that is, you know, looking at what's next from a non-med perspective, I think is really important. There are patients who will be very well served by this first generation of therapy, even with the chemo; that's the point, right? It's just a transplant. You know, transplant is not for everybody, but for patients who are really severe, and they urgently need treatment, this will be a good market. And so I don't know how many patients we're gonna learn that over time, but we think it could be meaningful in terms of a certain number of patients every year who are severe enough that they're gonna need these therapies.
And again, they're gonna be priced at $2.2 million and up, and so that very quickly becomes a meaningful market, okay? Just for those most severe patients out of the 100,000 total. And within that market, we think 101 can actually provide differentiation, even on top of what you're getting from Vertex and from Bluebird, as in all the ways I've talked about the higher level of editing, higher F, lower S, potential effects on, you know, hemolysis, hemoglobin, and obviously, the process advantages. So that's, like, a really important story. Nonetheless, to grant your point, if you talk to docs and patients, and they say, "Okay, what's the next thing you'd like to fix?" "Well, I'd really like to do all of that without busulfan," and we agree. So, so we-- that's what we, what we launched ESCAPE to do.
This has been a, you know, dream in the field for a long time, but it hasn't been possible until you have our technology, right? Because you can't use precise antibody-based conditioning, unless that agent can discriminate between old cells and new cells, okay? And that's been the missing piece. So ESCAPE allows us to do that with this extra edit that we add, where now the antibody will not bind to our edited cells. It will bind to old disease cells. So we think that's a breakthrough. We also think it's, you know, highly differentiated and have real barriers to entry because of the base editing strength that is needed to do that.
So, you know, we've always said it's a lifecycle plan, so it's going to be separated by a few years between 101 and, and ESCAPE, because it represents technological evolution. But this year, we've now guided that we will have effectively a development candidate disclosed, which will show you that we've got all the pieces working, and are moving towards development. And by the end of the year, we want to be in IND-enabling studies, to start moving that forward. So I think that's really, really promising.
There's no question that if ESCAPE works, it will be, you know, an even bigger and more important product for more patients, and will cause that market share, you know, out of the total sickle population of who's getting curative therapy. It's going to go up a lot if we can bring that forward for sure.
So if you get a little bit more granular. Let's say ESCAPE works.
Mm-hmm.
We know we need to get somewhere above 30%-
Mm.
-Fetal hemoglobin to avoid-
Yep.
sickling-related complications.
Yep.
Current editing modalities can get you 40%-50%.
Mm-hmm.
Right?
Mm-hmm.
Do you really need 40%-50%, or are you happy with 30%?
Yep.
If you can avoid yourself time?
Yeah, I think that's an excellent question. I think that is something that the field is going to work out with us over time. We've started some of those conversations. I would say that if you could get to 30%, and you're effectively reducing the vast majority of vaso-occlusive crises without chemo, I think that's an extremely competitive product, and it probably does, you know, compete for many patients. There may still be patients who say, you know, or doctors who say, "I really want to get rid of every sickle cell possible," right? And remember, it's not just the percent fetal hemoglobin. I even think about it in terms of number of cells edited, right?
Because that's where I again point to Vertex and CRISPR, where they're about 80% at, at most in the clinic in terms of number of cells edited, and we're in the 90%-95% range. I do think that matters, right? Because you don't want to leave sickle cells behind, hemolyzing and turning over and eventually giving you some kind of malignant event. So I think the more, the better. But nonetheless, you're exactly right, that there's some basic bar of, you know, maybe it's 30% of cells or so, that's commonly cited, with a sufficient amount of fetal hemoglobin upregulation that you would protect from many vasoconstrictions, you have clinical benefit. But, you know, with ESCAPE, we may just be able to keep titrating, and there's no actual reason to stop there.
Once you have that selection advantage, we can keep on going. So I don't think we know yet what our peak is in any real sense, for that system. That's something we'll learn over time.
Back to your 90%+ editing efficiency rates-
Mm-hmm.
Are you looking, specifically looking at stroke events in your study? Because that would be an easy differentiation if you can pick it up.
Yep. So not initially. I think, you know, we're going to really run the trial initially very similar to what others have done, because we think the technology will show itself, and there's no reason to—you don't need to change the script in terms of patients enrolled and the package we're going to bring to the FDA. Because as we've said very clearly, the BEACON trial is designed to be a registration trial, and we think now, after having seen the AdCom, that—and then the approval package, that we have that opening for us. So, so, so that's great. I mean, that is a gift, so we're definitely going to take advantage of that. That said, we're absolutely then looking at how do you expand from there?
And I think stroke patients are absolutely, you know, a huge unmet need, and, you know, we need to go study more in them. I think our, you know, our product could definitely bring something to that population, certainly going younger to pediatric patients, first adolescents, then pediatrics, that'll be an important focus point. So you know, bottom line is, yes, I think, you know, if, as the product starts to work, in addition to that core registration program, we would certainly look at some of these add-ons.
Got it. So far, we've just touched upon ex vivo.
Mm-hmm.
In vivo applications is obviously going to be the next big thing-
Yep.
for the entire field.
Yep.
Talk to us about delivery modalities, because, again, we are kind of struggling. Everybody's in the liver.
Yes. Yes. So we have—I mean, to make the point clear, we didn't start saying, "Let's start with ex vivo, and eventually, we'll get to in vivo." We actually started in all three in parallel. Basically, we said, "What are all the possible delivery modalities? And let's go after all of them in parallel." So that was ex vivo with blood cells, also with T-cells, of course, in CAR T, and then in vivo was lipid nanoparticles and AAV, right? Specifically, thinking about lipid nanoparticles of the liver and AAV to the eye. Those are the two places those had been, at that time, fully validated. And it's only that in vivo takes a little longer, that it comes out second in our pipeline, but because you have to get the vector done.
But now we have it. We feel really good about the internal process work, formulations. I think we're very, very good with LNPs. That is a favored workhorse of ours. And of course, now we're building on, you know, de-risking from first Intellia, of course, delivering CRISPR to the liver, now Verve, delivering base editing to the liver. So you know, we have high confidence that this, that this can work. To your point about where can we go next, you know, I like to remind people, I think what's nice about the Beam pipeline is you don't need to believe in any delivery innovation to really unlock a lot of value here. So the pipeline is really driven by things that we already know are achievable.
We are doing other kinds of delivery in-house in our platform, but that's all upside, right? I mean, if you think about it, Alnylam was built on one organ, which is the liver. So we have all of blood, and by the way, if ESCAPE works, there's a lot to do there in terms of other genetic diseases. Think about hematology, oncology, think about even immune disease. I think there's a lot there, and then, of course, the liver as well. So I would say we're quite happy with that, frankly. Nonetheless, we are certainly looking at other opportunities. We've been looking at LNPs going to other tissues. I think LNP access to the immune compartment will be next, you know, looking at both HSCs, which of course has benefit for sickle, immune cells as well.
Longer term, we'll see, in terms of putting, you know, more, more targeting to the LNP to try to get to other organs. But, you know, we, we can only move as fast as the technology moves, right? I'd say the one thing we're kind of in a watch and wait mode on would be viral vectors. So AAV works. You know, we, we have, we have really good, for instance, primate data of editing the retina for our Stargardt program. You know, we're not gonna go bigger into eye, and so that's a place where we're likely to seek a partner who's more ophthalmology-focused than that, but it works quite well. AAV can go other places, but AAV has a lot of challenges as well, and we're certainly not fixing those challenges.
I know a lot of people are working on them, so I think that would be something where if AAV kind of, if there's a next generation of AAV vectors that can package more, have better therapeutic index, don't have pre-existing immunity, can be redosed, like, there's a long list, then we'd be excited to build on that. Otherwise, there's some next-gen viral vector work that we and others are doing that at some point, you know, may open some of those doors. But we've got a lot to do even today, I think, just in hematology and liver for the near future.
Yeah, before we go on to the Alpha-1 program-
Mm-hmm.
-the hematology application, if the ESCAPE platform starts to work. I don't think you want to use, or the field wants to use double-stranded breaks and stem cells.
Mm-hmm. Yeah.
That's a, that's an organ, if I want to-
Yes.
If I may call it that.
Yeah.
Belongs to you if ESCAPE works?
Well, I mean, I think that's exactly the way to think about it. I mean, both the benefit of base editing as a cleaner, more well-controlled thing, and the ESCAPE piece, which is now we can start to change out elements of your blood system without chemotherapy, right? There are a lot of diseases where you might want to intervene, but you're not gonna quite get over that hump to do a transplant with chemo. But if you can remove the chemo, suddenly it makes a lot more sense.
So that is exactly the way we think about it, which is there could be a very big opportunity here that we could have a very strong position in between the strength of base editing, the capability for building and the relationships we're building in that hematology space, and the ESCAPE, you know, conditioning strategy, both itself and then how we might adapt it to other types of hematologic applications as well over time.
What's the threshold of edits or efficiency you would need with the ESCAPE platform to dramatically expand the scope of stem cell edits? Because that opens up CNS.
Right. I know what you mean. Yes, I think, I mean, I think we've got it from an efficiency perspective already. You know, I think that, you know, basically, the ESCAPE edit is very efficient alongside currently the sickle cell edit, so it would now be relatively straightforward to then just now start swapping out the sickle cell edit for other edits, you know. Or even no edit, just the ESCAPE edit alone to do a straight autologous transplant, which may be useful in some settings, or you're swapping in other types of things. So, and yes, you know, transplant can potentially address a lot of different things, right?
You could potentially, because the blood system repopulates the CNS with microglia, for instance, over time, the blood system can be used to, you know, generate proteins you're missing, as well as start to sort of, you know, reset things that have gone wrong with the blood system itself. So I think there's a lot of different interesting places that can take us.
So the Alpha-1 Antitrypsin program, firstly, the amount of hepatocytes you actually need to edit to have a curative therapy-
Yep.
Is the bar substantially lower than some of the other indications?
Yes, I think it is. And it was one of the reasons why we chose Alpha-1 and GSD as a lead program. I think there's no question that, you know, doing, like, for instance, a knockout with base editing is exciting. I think that they will be really great products. But you're up against nucleases, who can also knock things out. You're up against RNAi and antibodies and small molecules. So for us, you know, we were excited about for our internal program, moving some of these corrections forward. And there's no question with the correction, it's a much lower bar for clinical benefit. You don't need the 90%-95% efficiency, and the competition is less because nobody else can do it, right? So with Alpha-1, you know, we're looking to do that correction.
We do think it's a low bar. You know, we've said before, maybe 20%-25% editing gets you into the clinical benefit range. Obviously, the more, the better, you know. Our preclinical data, you know, we get much larger amounts of correction. So we're very bullish there. And, you know, with Alpha-1, it would be a potential, you know, address the lung pathology because you're upregulating more normal protein, address the liver phenotype because you're not producing that mutant protein. You're in a normal regulation, which is really important in Alpha-1, so the gene will turn on and off in response to infections and inflammation. That's what it's supposed to do. That doesn't happen with augmentation therapy or some of the other genetic approaches, and it's a one-time therapy.
So I think that we do see that as highly differentiated, and I do think it has a lower bar than some of the other applications that have been contemplated in that.
Does that lower bar automatically help you on the dose side of things? Because-
Yeah, absolutely.
Small molecule approaches have sort of stumbled because of hepatic dysfunction primarily.
Yes, hepatic dysfunction and chaperoning mutant proteins. You know, you can get to very weird biochemistry, where things can work for a bit and then they kind of top out. So, you know, here, there's no ceiling for us, it's 100% correction, but certainly, the low bar helps because, you know, LNP potency matters. You know, you're not gonna give 2-3 mg/kg of LNP to a person as far as anybody can tell right now. And so that's where we've been working really hard on potency. And, you know, I would love to have had Alpha-1 go a year faster, but, you know, at the end of the day, we needed it to be potent, right? So that we had that efficacy range, you know, well under 1 mg/kg.
I think we've now shown plenty of translational data that I think we're there, and that's when we, you know, threw it into high gear and we're moving to the clinic now.
Awesome. So the last minutes with your balance sheet-
Yep.
Walk us through 2024 and 2025.
Yeah. So we have strong balance sheet. You know, we made some, you know, tough decisions late last year, but we just felt in this market we needed to be conservative. So we've got cash now into 2027, which I think is a critical advantage, you know, well over $1 billion. And in that period, we're gonna do a lot. So we'll have data this year on 101, multiple patients with long-term follow-up. That should be very, very telling. And then, of course, the ESCAPE program, getting to development candidate and IND enabling studies by the end of the year. We'll have, on the liver side, 302. CTA filing is already done. That's a 90-day clock.
So trying to get that study open, towards the latter half of the first half of the year. Then other filings coming, Australia, New Zealand, maybe some other European countries, and so that'll start dose escalating this year. We generate some real data. That's probably data in 2025. 301 will follow in the U.S. It's an IND filing. Again, last part of the first half of this year. That's a... So getting a U.S. IND open, you know, that'll be a significant event for us. And then, of course, treat patients, you know, very, very severe disease. We will have data with 201. It's not as big a priority now with the CAR-T decisions we've made, but hope to really help some patients in need, and get a handful of patients' data out there.
Next gen, obviously, I've talked about ESCAPE. On the liver side, we have partner programs. We're partnered with Pfizer and Apellis, lead programs there in the liver, and those are moving nicely along, so we may start to see some of those programs start to move forward as well.
Awesome. Thank you so much, John.
Uh.
I appreciate the time.
Thank you.