Ladies and gentlemen, the program is about to begin. Reminder that you can submit questions at any time via the Ask Questions tab on the webcast page. At this time, it is my pleasure to turn the program over to your host, Greg Harrison. Hi, welcome to the Bank of America Smith Biotech Virtual Conference. I'm Greg Harrison, one of the biotech analysts here at B of A. Today I'm happy to introduce Beam Therapeutics, represented by John Evans, CEO, and Giuseppe Ciaramella, President and Chief Scientific Officer. Thanks for joining us, everyone. For those of you out there watching, if you wanna send me questions, I'm happy to ask them on your behalf. John, if you'd like to start off with some opening remarks, that'd be great, and then we can jump into Q&A. Sounds good. It's great to be here, Greg, and thanks for having us. Beam, as people may be familiar, is a next-generation gene editing technology company. We are pursuing a technology called base editing, which is a newer version of CRISPR. We can use the same targeting power of CRISPR, but we make much more precise single base changes in the genome. As one-time treatments, we don't need to go through a double strand of break to do that, so we don't ever have some of the consequences of cutting the DNA in the process. It's a very versatile system, and it gives us a lot of different advantages, both near term and long term, that we're exploiting in a very broad pipeline. Our strategy has been to pursue all of the different kinds of delivery in parallel. That has generated a lot of product opportunity, and we've shaped that into really three different, we call pillars within the portfolio. Hematology, where we're editing blood cells. That leads us to, in the near term, sickle cell disease, where BEAM-101 is moving forward really quickly now in the clinic, towards treating patients, which we think can be really competitive and potential best-in-class product. Longer term, we're using base editing to go further than that and even potentially change the conditioning that we use to get transplants done in patients, and make this a lower genotoxic procedure, which could then, of course, rapidly expand the patient population. In immunology, our second pillar, you know, lead program is BEAM-201. That's a quad-edited product, taking advantage of the fact that because base editors don't cut, we can make as many edits as we want in T-cells and stack them on top of each other for more engineering and more function. That is now off clinical hold, moving into phase 1. Longer term, our ambition here is to use that ability to make many edits to create cells that are truly allogeneic. You know, this is more like four, five, six edits each cell. That's research work that's ongoing now and could lead to a really significant franchise opportunity in allogeneic cell therapy. Finally, the third pillar in vivo, with which liver is the lead. Here we have BEAM-301 for Glycogen Storage Disease, now in IND-enabling studies. Now recently nominated BEAM-302, our first development candidate for alpha-1 antitrypsin deficiency, both correcting the causative point mutation in those two diseases back to normal. Both now we report quickly. Longer term, very excited, of course, about many different targets in the liver and the ability to potentially expand delivery using lipid nanoparticles, for instance, non-viral delivery to other tissues across the body. Very broad set of opportunities, very diversified portfolio with a lot of different profiles in terms of how we use the editors, how we deliver them, and what kinds of really significant franchise opportunities they can potentially create over the long term. Great. That's a great overview and, you know, tons of exciting stuff that you're working on. Maybe if we could just start with, you know, an overview of how your base editing works, you know, to make these edits and, you know, how that's different from other strategies like traditional CRISPR editing. CRISPR uses a guide RNA to target the DNA. What's beautiful about that is if you change the guide RNA, you have a new medicine. You know, you can just retarget it to a different part of the genome. That's why CRISPR has been so successful. Base editing builds directly on that. We use the exact same targeting approaches as CRISPR. We think that's the, you know, really its best feature. What's different is when the CRISPR gets there, it makes a double-stranded break, and that has a lot of consequences. It's a genotoxic event to the cell. You get cell damage responses come up. The cell can put the pieces back together again in the wrong order. If you have multiple breaks, that can create chromosomal rearrangements. You can also get large unintended deletions and changes at the on-target site. Finally, just remember that, you know, when you say, you know, we have 80% indels, which is often what people talk about with nucleases, well, that's actually a constellation of a variety of different random changes, right? It's all the different insertions and deletions. You're getting, you know, hundreds of different alleles at the target site. You really can't control the sequence you get. Some of those alleles may be more or less productive. They're certainly uncharacterized. With base editing, we really address all of those latter issues. We have the ability to basically land and open the DNA. We don't make the double-stranded break, so we don't have any of those chromosomal problems or genotoxic stress problems. Instead, we're making a single base change using a deaminase, which is a chemical enzyme that we've tethered to the CRISPR that is tuned to just make, you know, one kind of change at that target site. That change is permanent. It's efficient. It's biochemistry basically on the, on the genome. We, you know, are intending at very high efficiency levels, and we don't care about the cell state, dividing, non-dividing. You know, it generally just will work the same in any kind of cell. You know, it's really the, the high efficiency, the specificity with which we can make the edit, the lack of double strand of breaks and the effects on the cell, and then the control, ultimately, of the sequence that results, where we know exactly what allele will result. We can fully characterize that allele that lets us predict its function and really, I think, be now editing with a lot more rational intent. Great. Your lead program, as you mentioned, is BEAM-101 in sickle cell. Maybe you could just, you know, give us an overview where you're at with that. You'll, I think, be treating the first patient soon. You know, the timeline, what we can expect in terms of the data readout. First patient is enrolled as was our goal for this year, so that we've now started back in November. That's very exciting. As we've said, it's about a six-month process to get the first patient dose. That's the extent of time for a transplant. You're going through transfusions, you know, several rounds, mobilization, several rounds, manufacturing, conditioning, and then transplant. That could be a, you know, Q2 kind of mid-year event for next year. What we're working on now is making sure that subsequent patients can be as compressed as possible. It is a sentinel cohort. We have to do one patient at a time, there may be ways, and we're working on doing this to do some amount of that work in parallel, where you're going to the ability to go from patient one to patient two, patient three, and then on into expansion, which is of course the real ultimate goal. That is ongoing. You know, ultimately over the next year, I think we'd like to really make decent progress through those sorts of enrollment challenges and goals and, you know, with an eye towards the time to BLA filing, which is really our goal here, particularly as Vertex looks like they're validating a filing pathway for a single trial, which we'll know more about next year as they bring that in for filing. In terms of data, you know, I think that, you know, we'll obviously be looking to, you know, probably target a medical meeting. That's tended to be our pattern. You know, we haven't made a decision yet in terms of exactly, you know, how many patients we'd want to publish on. But we do wanna make sure we bring forward a, you know, reasonably robust, you know, set of information that helps you understand the drug and gets the community excited about it. I think, you know, I think we see a clear path for one oh one, and we think that the market for a busulfan-based regimen like this is actually meaningful. Notwithstanding the fact that everyone would agree that if we can then fix the busulfan part and get rid of, you know, that impediment, more patients will definitely choose this and the market would be even larger. We're quite motivated to get 101 forward as a best-in-class agent, even for this initial wave of the sickle market. Mm-hmm. Great. You mentioned CRISPR and Vertex and your goal to be best in class. How do we tell, you know, at these earlier stages when you have your data mid-next year or so, you know, what should we be looking for that would indicate whether your product really is differentiated, just given that the bar is pretty high here in this indication? Maybe I'll have Pino answer that. I mean, just to lay out the timeline, I think if we're dosing middle of next year, I don't think we'd have data middle of next year. Okay. You know, we could follow that patient. Obviously, again, it comes back to would we publish on just one patient or wait for several, and I think we may, you know, we may do the latter. We'll see. We'll see how it goes. At some point, yes, we will have a data set that should be pretty instructive. You know, Pino, if you wanna talk a little bit maybe about the differentiating points of the product and what we'll be looking for in the clinic. Yeah, absolutely. Obviously, VOCs as you know is something that is very impactful to the quality of life of the patient. You know, these are excruciating pain crises that they undergo. It seems both from the bluebird data, from Vertex data and even from the one patient from Editas, that this is actually a relatively easy thing to fix when you get, you know, a certain level of editing efficiency. The reality is that the disease of sickle cell disease is much more complex than VOCs alone. In fact, really what kills the patients ultimately is the progressive organ damage, which is not just caused by VOCs, but it's caused by, you know, many other factor that are contributing factor of sickle cell disease. In particular, the very short half-life of these cells causes these cells to lyse all the time. You have a frequent hemolysis, you have a release of cytokine and chemokines that contribute to inflammation. The viscosity of the blood is thicker. There are many parameters that actually are not necessarily fixed just by fixing the VOC. What we have seen pre-clinically is that by achieving the highest level of F upregulation that anybody has reported, we get in excess of 60%. Importantly, what we also see is the concomitant decline of hemoglobin S to levels of 40% or less, which are actually similar to ones that you see in sickle trait individuals. These are individuals who are heterozygotes and do not typically have symptoms. When you look at the data from Vertex, but even this one patient from Editas now, they still have levels of hemoglobin S at about 55%, which is not quite where the sickle trait is. It remains to be seen how deeply they actually resolve the progressive organ damage, which I think is ultimately what a curative approach needs to do. We will clearly monitor, of course, the organ damage aspects, and we will focus on kidney, on the brain as well as the lung. There are many of these parameters that are actually early signs of efficacy, if you will, that you can monitor. We will monitor, first of all, of course, the editing efficiency, the high upregulation of F and the decline of S will all be things that we monitor. The quality of the rheology of the blood, the viscosity, the improvement of the half-life of the B-cells. We will look at the inflammatory milieu that these patients have, the oxygen binding capabilities. All of these parameters are able to provide a clinical, essentially picture that could show how much more deeply we have resolved basically the sickle cell complications. Great. Yeah, that's helpful. Your next program within sickle cell is BEAM-102, where you're actually changing, you know, to a variant, and fixing the gene, you know, directly. You know, where do you see this as, you know, fitting in down the road? It definitely seems like a more elegant approach than what people have been doing in the past. Where does this program stand? I know you've made some changes to the prioritization recently, and where do you see the potential here? I think, I mean, it is, it is a very elegant approach which we've always liked. You know, I think the key point is the reason for the prioritization change is it's not totally clear how it will beat one oh one, right? I think for all the reasons Pino said, we're pretty sure that one oh one is gonna fully do the job. Rather than create another busulfan-based regimen, which is what one oh two really represented, and wait for that to get into the clinic, then compare them and then think about what would go forward, we made the decision that at least in wave one for the busulfan market, speed matters, one oh one's there. Let's go, let's put all the patients there, minimize that time to BLA filing and compete with whoever's there. Maybe it's, maybe it's Vertex, maybe it's others by then. In the meantime, we think that the, you know, the next best use of our energy and resources is really to climb this ladder away from busulfan towards a non-G toxic conditioning regimen and/or AAV delivery. Those are our waves two and waves three. There the delta for value is much greater for patients and obviously from a commercial perspective. That's the priority. We made that pivot. The Makassar edit is still with us, obviously. We'll actually be publishing at ASH, abstracts on what we call the ESCAPE technology, where we're doing this extra edit, so we can make a selective conditioning where we can condition old disease cells but leave alone your new engrafting cells and do that alongside each other, which is something that no one else would have the potential to do. We show data on both ESCAPE-1 and ESCAPE-2. ESCAPE-1 is what references that conditioning trick alongside the F of regulation edit. ESCAPE-2 is that conditioning trick alongside the Makassar edit. Both are available to us for these future waves and, you know, definitely remain excited about it. The key point is we see more bang for the buck in terms of, you know, fixing the regimen, with the ESCAPE technology as our, as our next play. Got it. Now this is something a lot of people are working on, right? The trying to get rid of the busulfan. You know, I guess you have your own approach. What do you think wins in the end? Is there a common approach that could be shared or do you think it's going to come down to, you know, who comes up with the best proprietary approach to use with their product? I mean, the more efforts the better, 'cause we think this is a priority for patients. Of course, if anybody starts to fix this, it'll be a huge rising tide for the entire field, and we'd be very excited about it. You know, it doesn't have to be a proprietary approach. We're actually, you know, partnered with Magenta. You know, they're making good progress. We're hopeful for that program to make it. There are others out there. The trick is none of those programs have the advantage that our ESCAPE technology would give us, right? What they all have to do is, you know, fundamental question with the conditioning is you have to go deep enough initially to get, you know, to create a niche and space for graftment that is as good as a normal transplant, right? As good as busulfan. You've got to get out of the body in time so that you don't kill the graft, okay? That is a tightrope to walk. I think the key point is that as far as we know, that our technology is the only one that has the potential to really change the odds of that working, right? 'Cause now we can have the conditioning agent alongside the graft, high dose, redose, you know, continue to titrate, continue to shift chimerism over time in favor of our graft. I think that is a pretty powerful idea. That would be, of course, a proprietary technology. It would support our programs. It would have to be customized with our program, so it wouldn't be usable by others. I should note that actually that principle could be then extended, if it works, to many other settings. You know, we view for that technology sickle as the entry point, but we could then think about many other transplant settings, you know, making the transplant better. That would be an interesting business opportunity, and then revolutionary for patients, as well as tip the balance on many other types of diseases in hematology and beyond that could be treatable with transplant that isn't currently, you know, doesn't make sense from a risk-benefit perspective to do the busulfan transplant. sort of a beachhead to a potentially large franchise opportunity in hematology if it works. Okay. Yeah, very exciting opportunity there. Now BEAM-201, you had your hold lifted recently. Maybe you could give an update on, you know, where does that program stand? What, you know, what does it look like as far as getting that in the clinic and, you know, what do you see as the potential for this program? Yeah. Pino, do you wanna cover that? Yeah. We're obviously now in the process of opening several sites in the U.S. to start with and, you know, with a view hopefully to start dosing in the next year. The, you know, the program basically is targeting CD7 positive T-ALL. It's the first quadruple edited cell CAR-T cell that anybody has produced and we're excited about targeting a patient population that, frankly, it's been underserved in the past because of this phenomenon of fratricide. The antigen that is on the malignant cells is also expressed on the T cells. Unless you remove it, you end up, you know, T cells killing each other. The need for removing that increases the number of edits that you need to make, and that's why in the past, basically, it's been a challenge for developing CAR-T programs of this kind. We have taken the opportunity with base editing to do the multiplex editing, so we remove CD7, we remove obviously the endogenous TCR, but we also remove PD-1. Indeed, in this particular approach, our allogeneic strategy is similar to the allogeneic strategy, where we are removing CD52, and then we can use this antibody known as Campath to actually create the lymphodepletion. In addition to ALL, we're also to do an expansion eventually to CD7 positive AML, which represents about 10%-15% of the AML patient population. Got it. How do you think about this indication, you know, with... I mean, you mentioned, an expansion there into AML, you know. How do you think about moving into some of the larger CAR-T indications and balancing, you know, the looking for areas of unmet need and where you can be differentiated versus, you know, larger markets which may be, you know, more crowded right now? Yeah. I think for a additional indication, frankly for the bigger indication, our belief is that you really do need a better allogeneic strategy than the field has managed to produce so far. Unfortunately, as you can see, the persistence of all of the allogeneic strategies that are in the clinic right now seems not to be to the level that is needed to achieve the equivalent efficacy that autologous CAR-T approaches are actually having. We think that basically it's because the edits that are being made in those approaches are not yet sufficient to evade the immune system in a manner that gives you the adequate persistence. What we have decided to do is to... before we actually go into an additional CAR-T approach, is to actually deploy some of our research strategies and ideas in order to generate a much more allogeneic, a much more stealthy T-cell to the immune system. We're really not convinced that the current strategy, which is a beta-globin gene knockout or even the HLA E overexpression, are sufficient to adequately I guess cloak the T cells from both the T cells and the NK cell compartment. We have some ideas that we're deploying. The key point here is that there will be several edits that are needed. That's why we think that base editing is extremely well placed to actually do that. There will be four to six edits probably will be required in order to have that biological modulation as part of that. Of course, we're in research. We can't guarantee that that is gonna be successful, but we think that it's better to take that approach, and if we can do that, then frankly, it would open huge opportunities for that. If we can't, then, you know, we'll pivot away from this as one of the options. Makes sense. What is the registrational path for BEAM-201, you know, given that it's in a smaller patient population, you know, how quickly do you think you could get to the finish line here? Probably similar to, you know, what we've seen with the other CAR-Ts. I mean, remember, you know, one of the nice things about this from a development perspective is, you know, it, you know, you have the B-cell ALL field, right? That was where all the CAR-Ts went initially. This is just the T-cell component to that, right? It's a very similar disease, and we would expect, you know, similar kinds of strategies could be used to get to an approval. Obviously it is smaller, I think it is, it is a, it is a more niche population than the, than the B-cell population, but still a meaningful one to pursue and a very high unmet need, right? B-cell ALL has been transformed by CAR-T, you know, the therapies and really this T-cell population has been left behind. Of course, the reason they have been is because, you know, if you have a T-cell CAR targeting a T-cell, you have the problem of fratricidal killing, which is your T-cells kill each other before they get to the tumor. That's, you know, one of those four edits that Pino mentioned was required. I'd say increasingly, looking at a couple of autologous, a couple of academic programs that are out there on CD7, we think CD7 is a validated target biologically, which is attractive and rare in this field. It's actually reasonably, you know, open, I think, and we can hopefully, you know, get there first. Again, you know, we're looking for high CR rates, deep CRs, patients getting transplant. These are patients who don't have a lot of other options, in front of them if they've hit the refractory stage of this disease. We're quite hopeful it'll make an impact on their lives. Mm-hmm. Great. Then the other area where you're in is liver. BEAM-301 has been progressing. What does it look like in terms of the, you know, time to the clinic there and how are you thinking about that, you know, as an indication? Yeah. I mean, you're basically looking to... I mean, we're in our enabling studies now, which is, which is exciting. You know, it's, this is a biologic, so from developing candidate to, you know, you have to do a lot of manufacturing, then you can get started on the enabling studies. Once you've done that, you can obviously write and file, your regulatory filing. We see, you know, a good path forward for BEAM-301 now. You know, haven't guided on exact timing. It's generally a kind of 12 to 18 month process, you know, to get to the finish line here. But, you know, very compelling program. We think a low bar for editing liver target. These are patients who cannot handle fasting, and they really desperately need better options. This should be a one-time, you know, in vivo correction of a mutation, which I think is the first in the industry for something like that. We're, you know, obviously, you know, very excited about it. You know, again, smaller population, but, you know, something like 900 patients in the U.S., you know, that's still a meaningful opportunity and a lot of good that we can do. Then really would set the foundation for many others to follow Alpha-1 and many others. Okay. I guess one, you know, broader question, you know, how do you think patients think about something like a base editor or gene editing even at this point? You know, what tips the scale to where, you know, maybe some of the fear goes away and they become more broadly accepted over time? That's a good question. Pino, you wanna take a crack at that? Yeah, of course. You know, it's about generating good efficacy data without safety complication. I mean, there is no substitution to that. I would say that, you know, we talk a lot directly with patients. You know, we have a lot of patient outreach, particularly even for the GSDIa. We recently had several of those patients actually coming to visit us and talk to them. You know, there are some that are really looking for the opportunity to finally have a life that is independent of having, you know, to carry this complex starch. They have a, you know, a safety kit there. Everything that they do, they need to, you know, be. Every three hours, they need to basically use this thing. It really is so impactful in their lives that it creates really the opportunity for them wanting to explore this as a, as a solution. We will do a lot of work on educating essentially the patient population of, you know, why we think that actually the risk is appropriate here, in particularly in some of the indication with the. It will take some time, undoubtedly, but I think the outreach to the patient will certainly help understand it and put it in the right context, the risk that the technology carries. Yeah. Maybe I'll build on that just to say, I think, you know, we haven't talked as much about this. We're, we're not at commercial phase yet. You know, I really think there are gonna be tailwinds, you know, for this eventually, right? I mean, so there's that comfort building, the data generation Pino mentioned. Then, you know, ultimately, this is a, you know, one-time therapy that patients can kind of focus on, get done, and then hopefully have a lifetime of benefit, you know, if we're able to deliver on the promise. You know, you're really creating value, I think, for the healthcare system. Obviously, the pricing will need to be high. There's a lot to work through there as a challenfe. You know, you're displacing a lifetime of medical care to follow and risk. You're treating patients in the prime of their lives who have productive years ahead, or kids. The pharmacoeconomics, I think, can be positive. You're often displacing expensive chronic pharmaceutical or biotech products, right? Which is another cost to the system. I, you know, I really believe there's a strong value story here if we can, if we can deliver on the potential of this product profile. Yeah, that makes sense. One minute left. I'm gonna ask a question that you could probably talk for hours about, but we gotta keep it tight. Where do you go next with this platform, and how do you even narrow down all the opportunities to, you know, the areas that you decide to invest in? Yeah. It is a constant debate. Pino and I and the whole team talk about this constantly. Breadth versus focus, right? You know, obviously, our strategy is reflective of the fact that we are playing offense. We think we have something really compelling here that has a tremendous amount of applicability. I think we've designed a portfolio that has deliberately not just shots on goal, which people think about, but really are asking different questions of the technology in different ways, so that when we get those answers, not only we de-risk a product to move forward to patients, but we've also got information that tells us, "Okay, this is working. We can do more of this," right? We're gonna sort of tune our portfolio over time based on that. Then I think I'd go back to where I opened, you know. The sort of the pillars conversation already reflects some of that, where we've sort of shaped it now to say, "Okay, you know, there's a big hematology story, there's an immunology story, there's an in vivo, let's say, liver story, and beyond." In each case, we've got these lead assets, which are very exciting and we could create revenue and make an impact on patients. At the same time, they may open doors to these very big sustainable opportunities. At least so far, you know, changing transplant, you know, changing the way that we do, you know, hematologic treatment, you know, allogeneic therapy, cell therapy broadly with high levels of multiplex editing, in vivo delivery, plug and play to liver and to other organs. I mean, these are gigantic opportunities for us. There are other ways to even use base editing as well. We continue to have other opportunities that are always on the horizon and we have a lot of skunk works ongoing too that could generate, you know, future seeds for growth even beyond that. I agree with you. It's a lot of opportunity. We're prosecuting it as smartly as we can, even while we focus on executing at the front of the pipeline. Great. Yeah. Super exciting and can't wait to see where you guys go with it. With that, we're out of time here. I'd like to thank Beam for joining us today and everyone out there for watching, and take care, everyone. Thank you very much. Thank you.