Welcome everybody to the next session of our first day here at the 2024 Leerink Global Biopharma Conference, our inaugural in-person year here in Miami. So I'm glad to be hosting everybody. Giuseppe, as we talk about where Beam Therapeutics is now, obviously, the company has gone on a fairly remarkable journey from-
Thank you.
the relatively early stage of development, in the days of the IPO, to where we are now. And it's tracked sort of the evolution of other gene editing technologies broadly, written broadly, to the cusp of a pivotal data set. Talk to me a little bit about how the company's infrastructure and scale has evolved, and what additional, like, investments, build-out infrastructure is going to be necessary as you approach potential, potential SCD pivotal data, potential Alpha-1 Antitrypsin pivotal data, et cetera.
Yeah. First of all, thank you very much for having us here. And you're absolutely right. We're at the cusp of some important pivotal data, and, you know, what we say, at the cusp of realizing basically all the fruits of the investment that we've made over the last 6.5 years or so. The infrastructure and the build of the company has gone through what you would expect to see in other companies that move from initially from a research focus environment towards an environment which is still research focused to some extent in Beam, because we believe in the future and the ability to create a portfolio which is sustainable in the longer term.
But, bolting on onto that, you know, all the capabilities to be able to do, what is required from, regulatory, clinical, quality, and importantly, also manufacturing. And frankly, this is one of the things that potentially slightly different from, some other companies. We have decided very early on that investing in our own manufacturing facility was a strategic investment for us. And in fact, we have a facility in North Carolina, which is about 100,000 sq ft, which is now fully GMP operational, which is capable of doing both the autologous production for sickle cell and 101 in particular, also LNP production for the 302 Alpha-1 program, and in the not-too-distant future, also messenger RNA production as part of that.
This facility has actually been built to be able to support Beam all the way to clinical launch to commercial launch, because we believe that the control, both from the quality as well as the timeliness of production, is actually a strategic asset in these complex drug products that we have. So that's, that's basically where we are.
So let's talk a little about what that investment in manufacturing means in terms of launch readiness. Should we expect that, you know, presuming that we have a pivotal data set that's approvable in sickle cell, should we expect you to reach out and look for a European partner or U.S. commercialization? Do you have enough capacity in-house to supply what you see as demand in the U.S. market, or is that going to be a sort of a further incremental expansion, regional manufacturing centers, etc ? What is the strategy there?
Yeah, frankly, the global strategy, you know, is still evolving, and there are things that we need to look into for sure. For sickle cell disease, initially, we are focusing in the U.S., and the capabilities that we are building at the manufacturing site are consistent with supporting a launch in the U.S., for sure. Beyond that, obviously, it's something that we need to, you know, firm some of our assumptions on, but also depends to some extent how we will deploy the... We'll see basically the life cycle expansion and evolution of the treatment for sickle cell disease.
We believe, obviously, we're very excited about the preclinical profile that, if confirmed in the clinic as we expect it to be, would generate essentially a best-in-class product for sickle cell disease, particularly in the context of a busulfan conditioning regimen, which is currently the standard of care. And even in that context, which we believe it's a multi-billion-dollar market, given our best-in-class opportunity, we believe that we have the ability to carve a significant proportion of the market. Having said so, part of our strategy is also to look at the longer-term sickle cell disease treatment, and we see a future in which we develop essentially a conditioning regimen that overcomes the toxic consequences of busulfan.
We call this approach ESCAPE, which is essentially a bespoke antibody that we have generated that has the ability to benefit from the multiplex editing or base, base editing without double-stranded breaks in order to provide a survival advantage to the edited cells, and do that in a very specific manner so that it would not cause the toxicity. By that time, with that paradigm, we feel that the market opportunity will expand very significantly, and because obviously, we've eliminated one of the major impediments to at least a proportion of the patient population that would eliminate the toxicity and importantly, the sterility associated with busulfan.
Then in the future, of course, we're also looking at the ability of using our lipid nanoparticle technology to actually do an in vivo delivery of the editor and the guide. In this case, overcoming the need for transplant altogether, and at that point, it opens up the market for sure, to a worldwide, you know, opportunity. And as you can see, given those paradigms, there is also a way to adjust the commercial readiness and needs that we will see.
Let's talk a little bit about ESCAPE. Obviously not something we have a ton of data in-house for, given where it is in development, but an important part of long-term growth story. Let's talk about what we're gonna see from ESCAPE on a long-term time horizon. So what are the metrics you need to see to say that, "Yes, we're achieving what we need, and we're actually going to take busulfan out of the conditioning regimen"? Like, are there specific endpoints you need to hit? Is that still a discussion you need to have with regulators? Like, what informs those decisions and that thinking?
Yeah, great question. So first of all, the important thing to say is we've guided that we plan to initiate regulatory enabling tox studies later on this year. And so it gives you a sense that we feel that the program is what we call in late research phases as part of that.
We have actually published some data in rodents, of course, and which shows the ability of this antibody guide pair to provide a survival advantage. That is, both in the context of enabling engraftment by essentially being a single dose of antibodies before the engraftment takes hold, as well as enabling a progressive additional engraftment that the antibody enables. Because basically, the edited cells are completely stealthy to the antibody. So what you can envisage is a situation also post-initial engraftment. You can dose the antibody to allow even additional engraftment of edited cells over unedited cells because of the survival advantage. So the data has been shown in rodents, and we are progressing some non-human primate studies as well, in collaboration with the...
You know, in part, the NIH and Fred Hutchinson as part of that. The kind of things we want to look at is in the context of different doses of the antibody, what it looks like, what are the kinetics of engraftment in this particular context. As you can imagine, busulfan is a very harsh initial regimen. It's one that essentially kills all of the cells, and then you do an engraftment. The antibody is a more very precise opportunity to actually go to the relevant cells, the long-term stem cells, as you need to do. And so the dynamics of that engraftment and the kinetics are expected to be slightly different from busulfan. And so we want to understand, in all of those pharmacological studies, what is the behavior as part of that, so.
But the fact that we are, you know, guiding towards the initiation of designing the enabling studies would hopefully provide you some confidence that we see that path coming forward. Now, the important thing is that. So we've selected essentially the antibody. We selected the guide, even though, you know, there are backups in places as you would normally do with any program. The important thing is also that there is a path forward where it's useful to and possible to essentially take the antibody into human healthy volunteer studies to determine the PK/PD, and that would eventually allow us to introduce the antibody into the sickle cell context at a later date. And so we feel that that is potentially a very efficient way of introducing the antibody in the longer term in sickle cell studies.
So let's talk a little bit about positioning, with the current generation of technology, recognizing that ESCAPE could potentially change a lot of these variables down the road.
Sure.
How do you think about positioning versus the approved products, gene editing and gene therapy, by Vertex, CRISPR, and Bluebird, respectively, and showing what you describe as sort of a best-in-class profile in sickle? And where does that show up in terms of something that can be on a label? you can negotiate with payers with, something that sort of has some commercial heft?
Yes. And it is an absolutely an important point and one that we also are very keen to emphasize, is that we do see a multi-billion dollar opportunity, even in the context of busulfan with the current technologies. If you think about it, you know, there is already, as you've seen with Vertex and Bluebird, an opportunity to price those products in $2-$3 million per product. And if you just look at the allogeneic number of transplant or individuals that aspire to have an allogeneic transplant in the U.S. alone every year, it is typically about 1,000 people. Now, of those 1,000 people, only 20% have access to an acceptable donor. But in the case of an autologous process, you don't have that issue. So...
If you just, you know, think about 1,000 patients now with a $2 million-$3 million product, you can see how that is already a multi-billion-dollar product. Now, the important thing about the differentiation aspects and what we would like to see in order to determine the best in class is essentially a deeper resolution of all those parameters that ultimately contribute to sickle cell disease. That is essentially a series of events that occur in the body that cause an inflammatory milieu in general, that ultimately leads to progressive organ damage, which is what kills prematurely the patients of sickle cell disease. Those things are things like ongoing lysis of cells.
You know, a healthy human, the half-life of cells in the blood are typically about 120 days. In a sickle cell patient, it is only a few days, three to four days. And you can imagine that your bone marrow now needs to pump out, you know, several cells on an ongoing basis, which not only causes inflammation by virtue of the fact that cells are lysing, releasing all sorts of cytokines and chemokines, but also now creates an even higher opportunity for leukemia and myeloproliferative diseases. So what we want to see is that deeper resolution of hemolysis. And if you look at the Vertex or even Bluebird data, they've made an important strides in towards that, but they've not got to the normality. So if you look at reticulocyte counts, for instance, they're not normal.
The other aspect that you would want to see is the ability of generating hemoglobin to level that would fix anemia. And if you look again at the hemoglobin level, particularly in male individuals who are higher than females, the Vertex profile has not yet reached normality. The VOCs, which are the vaso-occlusive crisis, which are actually an acceptable endpoint, so far, even in that context, as you looked at the broader patient data set that Vertex has done, that resolution from the high 90s is now in the 80s. And so you can see that the, you know, Vertex has made a lot of progress, and clearly is a drug that will make a difference, very significant to these patients.
But it's got not quite got to the point where, you know, you would really achieve that resolution that you would wish to be. And there, there is a residual component that still contributes to the inflammatory milieu. Our preclinical data would suggest that we should expect to see a deeper resolution of all of those parameters. And importantly, in the data we generated, if reproduced in human, would essentially establish that 60/40 ratio between the healthy protein, in this case hemoglobin F, as well as the hemoglobin S, the 40% that causes disease. The 60/40 ratio is what you normally see in sickle trait individuals. You know, these are heterozygotes who don't typically have the disease.
Again, if you look at some of the Vertex data, the hemoglobin S is about 50%-55% still, and hemoglobin F is about, excuse me, 40%. So they've improved it, but not quite to that ideal setup that we want to see. And that's really what we are expecting to see and demonstrate as our best-in-class product profile.
Let's talk a little bit about the path to that profile. Obviously, showing differentiation on durability of VOC benefit, like any durability endpoint, takes time. A one year endpoint can't be achieved in less than one year, a two year endpoint can't be achieved in less than two years, et cetera, sort of. Let's talk about. So how long of a follow-up period do you need or would you need to potentially show differentiation on each of these key points? VOC, durable VOC benefit, on anemia, et cetera. These places where you think you have an edge, and you think you see a clear path to a superior profile, how long do those studies have to be, or how large? In some cases, in terms of powering at least, size can make up for duration.
Yeah, the design that we are pursuing is basically, in terms of numbers and the fact that the study that we are conducting, we expect to be pivotal in nature, is very similar to what you see on Vertex. We are expecting, estimating about 45 patients to be enrolled in that. And the number of individuals that you need in order to support a BLA filing, again, will be very similar to the ones that we've seen with Vertex. So in that sense, it's good not to be the first, because you have a certain certainty about those regulatory interactions. There's a range, of course, of timeliness that you would need to demonstrate the different benefits, all the way to ultimately clinical benefit on eliminating the progressive organ damage.
That, of course, will only come later on. But, with the exception of VOC, which I say even the FDA was contemplating an earlier readout of VOC 9 as opposed to VOC 12, which is ultimately the endpoint. The other ones are really relatively fast in being able to demonstrate the resolution of hemolysis could potentially be—if we achieve the depth that we are contemplating, should occur within weeks, maybe a few months, but not years. The same would be true for hemoglobin levels, for example. The same would be true for sustained levels of hemoglobin S, F, and reduction of hemoglobin S. So all of those parameters could actually be demonstrated in a relatively short period of time.
Of course, we will need to discuss and agree with the regulators and the FDA all of those parameters in there. But I think there is certainly in my reading of conversation with many experts in the field the realization that VOCs are important, but they're also not everything linked to the sickle cell disease. And there is a willingness, even from regulators in my view, to understand that the clinical picture is more complex than VOCs alone. And so that, obviously, barring the—we will need to have, of course, the conversations to confirm that. But I think we have a greater opportunity to demonstrate the clinical picture that is much more deeply resolving of the sickle condition.
So that makes sense to me. In terms of a lot of the feedback we've gotten in our sickle cell physician survey or our key opinion leader expert calls, et cetera, we've spilled an ocean of ink on this topic, that VOCs are actually not microvascular and organ damage. They are two separate phenomena, both of which are particularly tragic for patients in different ways.
Of course.
But when you talk about the microvascular damage that really leads to early mortality, stroke, kidney failure, et cetera, poor, poor bone marrow health and bone marrow failure, those tend to be longer term. You can't measure those necessarily in nine months or 12 months in most patients. So do you see those data points as potentially supplemental filings after an approval? 'Cause those are moving the opposite direction of a VOC 12 to a VOC 9.
Sure, but hemolysis, you can potentially demonstrate or lack of, very quickly.
That's true.
Hemoglobin levels, you can demonstrate pretty quickly. So this is the important thing, and the good news about sickle cell disease is that it is managed by experts in the field. So, it's not a small number, but it's a handful of specialized centers that really manage the majority of the patients. So, these experts, as you pointed out, they do understand the clinical picture being more complicating and complex than just one parameter or the other. So what we expect is that there is a reasonable opportunity to demonstrate differentiation in the short period of time, and then eventually to complement and strengthen, if you will, those claims over the time that it takes to demonstrate the clinical benefit that comes into that. So it's a... I would say it's a short-term opportunity that then can be, you know, further strengthened over time.
I don't want to spend all of our time on sickle. I want to talk about another program where there's obviously a lot of excitement and debate because a lot of different technologies are approaching this, this issue, which is Alpha-1 Antitrypsin. Obviously, it's become a little more crowded of a development landscape, but certainly not in terms of approved therapies. Talk to me a little bit about how you see your technology fitting in, in a world of potentially hypothetically available RNAi therapies, other, other, other editing approaches, et cetera. And, you know, what is your-- where do you land in terms of what's your, your killer app in terms of patient population?
Yeah. So, Alpha-1 Antitrypsin, as you mentioned, is a very high medical need disease, and it's a complicated disease because essentially impacts both the liver, typically, and the lung. But in all those cases, particularly in the severe population of the patients, it's always caused by the single point mutation. The same single point mutation occurs in about 100,000, we estimate, patients in U.S. alone, is this E342K mutation. As a consequence of that single point mutation, the protein misfolds. The protein is normally made in the liver, and it accumulates in the liver as a consequence of those misfolding, causing toxicity in the liver. But importantly, preventing this protein from being secreted from the liver and going into the lung, where it does its job of protecting the lung from elastase.
To my knowledge, what we are doing with base editing is the only treatment that would actually go into the liver and correct the single point mutation, so that we can restore the appropriate and correct folding of the protein, and we can restore the secretion of that protein into circulation and therefore protecting the lung at the same time. The only other approach that I'm aware of that could do that is actually RNA editing. However, the difference is that in our case, we can have the opportunity to be a once-and-done treatment because we correct the mutation at the DNA level versus an RNA editing that will require antisense oligos, for example, to be dosed chronically throughout one lifetime in order to essentially recruit endogenous ADARs, you know, RNA editors, in order to make that correction.
The potential additional advantage of correcting the mutation at the DNA level is also the fact that that gene will remain under the control of the endogenous promoter. And, in this, in alpha-1, is actually an important factor to consider because the regulation of the expression of alpha-1 is regulated by the inflammatory or infection conditions that you may be under. And in fact, that during that infection, you will want to have alpha-1 to be upregulated in order to have better protection. Even in the case of the RNA editor, that upregulation may or may not be...
I guess the efficacy, I would say, and the dosing level of the antisense oligos would have to be determined whether if there is a higher production of RNA, messenger RNA, as a consequence of that upregulation, whether, you know, you still have to, you know, to be able to see. But in general, I would say, RNA editing is potentially doing the same correction. In the case of other strategies where siRNA, for instance, the potential issue there is that you may fix the liver issue, but to some extent, if anything, you probably exacerbate the lung condition because you're now eliminating even low level of production of that alpha-1 protein. And then you need to rely to some type of protein replacement in order to provide you the benefit for the lung.
Obviously, we know that the current standard of care, which is protein replacement therapy, is not curative in nature, and in fact, because of that, is not even approved or reimbursed in Europe, because the benefit is, at least over there, is not considered to be relevant. So, you know, whether that can be curative as an approach, we don't know. And then there are other opportunities in which the protein replacement could potentially be done through a viral delivery. But now you have an extremely complex drug product, where you have a combination of siRNA, viral for the template, and then, you know, potentially also an LNP delivery of the editor. So-...
I think the elegance of a single approach, this is a messenger RNA plus guide in an LNP formulation, dosed IV, potentially as a single dose that will go and cure that single point mutation and restore essentially the clinically relevant levels of Alpha-1, I would say is potentially a killer.
One of the questions that I get around, not just this approach, but around genetic medicines that have a curative intent or a one-and-done intent, curative or not, versus chronic but infrequently dosed therapies, which many oligos fall into that category- Dosed many weeks apart, months apart, once a year, et cetera, is the bar for safety for an irreversible therapy. How do we think about the bar for safety for a irreversible base editing approach to Alpha-1 Antitrypsin versus how you—what you've qualified as sort of a key competitor technology in ADAR RNA editing? Like, how do you see that in terms of where receptivity by clinicians, receptivity by physicians, regulatory bodies, which I know U.S. and EU, for example, have a very different bar for tolerance in that regard?
Yeah, I would say actually, regulators, there was probably more of a difference between European and U.S. regulators. But I think you probably have seen with the recent acceptance of the IND from Intellia, for instance, from Verve, that there is definitely an understanding of the path forward that is viable, and that clearly the benefit-to-risk ratio is one that is acceptable in under those circumstances. We certainly believe that that's the case. One thing I would say is, yes, there is a theoretical risk. In the acute phase of the risk, the RNA editing versus DNA editing will be frankly identical. If there is something acute that you are causing as part of that, you will see it at the same time.
In the longer term, of course, the risk could potentially be different, but the advantage that we have is that the assays that are there to measure the potential risk profile are really very sophisticated and very sensitive at the moment, to the point that it's possible to... While there is never an opportunity to say the risk is zero, but we can essentially define the risk to be within those ranges of editing that you would see typically your genome to undergo on a routine basis. You see, you know, unfortunately, our genome is not static. In all of our somatic cells, we see hundreds of mutations occurring every single day of our life, and that's when we are not exposing ourselves to X-rays or anything else.
So we have the sensitivity to be able to say that we are really in ranges that are at or below, significantly below that kind of range of mutation. So, and on the other hand, you have the opportunity to provide a curative or semi-curative, you know, to the extent that essentially you have fixed the problem that was causing that, which is the other side of that risk-benefit ratio. So I think all in all, all in all, we are in a reasonable spot for this high unmet medical need. In fact, I've developed many drugs of different types, including small molecules and biologics. What I would say is I wish that I had the degree of control that I have now in genetic medicines, in estimating the toxicity of small molecules, to be honest.
We can now go precisely to the level of a single nucleotide, and we can do it with a variety of different assays that are complementing each other so that it gives you a broader picture of the risk that you may incur. Of course, if you find something that is not acceptable, you stop it, you don't progress.
Great. We are coming up to the bottom of the half hour. Thank you so much for your time. Obviously, looking forward to a lot of data over the next year or two from you guys.