Hi everyone, my name is Maury Raycroft. I'm one of the biotech analysts, Jefferies. It's with great pleasure that I'd like to welcome the Beam Management Team. We've got Giuseppe Ciaramella, President of Beam Therapeutics, and also the CFO, Sravan Emany, CFO from Beam. Thanks so much for joining us today. Pleasure. For those who are new to the story, maybe if you can give a one-minute intro to Beam Therapeutics. Yeah, so first of all, thank you for the opportunity. Beam Therapeutics uses a technology called base editing, which is a next-generation editing technology that uses the Cas9 protein as its targeting domain, using this amazing ability of the Cas9 protein to land on different spots of DNA just by changing a small stretch of RNA called the guide RNA. We modified it in two important ways. First of all, we eliminated the opportunity for this protein to make a double-stranded break, which can lead to some unwanted genotoxic effects. The other one, we fused to that Cas9 protein an additional human protein called the deaminase, which is capable of converting one nucleobase to another directly on the gene. Depending on which deaminase we use, we can either change its C to a T or an A to a G. As you know, depending on whether we are the top strand or the bottom strand, those base pairs will exist in any base pair that you need. The good news about that technology is that it turns out to be very versatile and also very efficient in many different cell types. Of course, we can make point mutation corrections like we are doing with some of our programs. You can also use that single nucleotide change to do other things like introducing stop codons or changing actually active sites of proteins or binding pockets of receptors, which we all use in a variety of different strategies for editing. It has proven to be very beneficial in that setting. Got it. Yeah, it's a great intro. Maybe starting with your AATD 302 asset, for the data update at early 2026, can you provide specifics on the scope of the data you're going to share? What can you say about the durability and safety so far? Yeah, as we've guided, we plan to give you a more fulsome update on the program early in 2026. It won't be at JPM, just to be clear. As you know, we are in a phase one/two dose escalation trial, which has been investigated in a variety of different doses: 15, 30, 60, and 75 milligrams, as well as 60 milligrams given twice. We plan to essentially share data, particularly on the higher-level cohorts of six people, six patients at the 60 milligram, six patients in the 75. There will be a handful of patients that would have received the 60 times two. In addition to that, we have also started what we call the part B of the program. In this case, there are patients whose liver is more impacted compared to the part A, which is focused on the lung only. We hope to have a couple of patients in the initial cohort as well. We have started in that case at 30 milligrams, benefiting actually from the great tolerability that we have seen with the LNP. We did not have to go back all the way to 15. Also importantly, we hope to be able to give you some guidance on what is going to be the approvable path of this program, because fundamentally, we believe that the data that we have already shared on the 60 milligram cohort, which shows a median of 12.4 micromolar total AAT, of which more than 90% is actually AAT protein and the functional protein, is already therapeutically relevant. We plan to move the program as quickly through approval phases. The 75 and 60 times two is a way to accelerate and basically discover in parallel whether there is a little bit more pharmacodynamics to be obtained. Fundamentally, we believe that we have a drug and therefore our intent is to move it as quickly as possible. Got it. Okay, and maybe a couple of clarification questions. For the 75 meg and the 60 meg multi-dose cohorts, how much follow-up are you going to have for those? 75 is going to be a few months, I think. Obviously, six times two will be less because there is an eight-week window between the first dose and the second dose. We'll probably have a little bit less. If you see the data that we've generated so far, actually, you can get a perspective relatively quickly. After two weeks, we already start to see pretty much a peak. Certainly, within three or four weeks, you can see a stable steady-state level. Within that time frame, you'll be able to sort of infer a significant amount of sort of confidence in the data that you see or not. Got it. For part B, are you going to have any liver biopsy data? Not at the time of the early 2026, because it will take some time. Typically, you may want to have some wait before you see any benefit in spite of that. We will obviously share that data as soon as it's practical to do so. Got it. Just wondering, have you seen any patients with acute phase response in your study? It's a great question. We're collecting the data, I guess. We just want to be in a situation where we have robust data to be able to show you. There is, frankly, every expectation that we will see that. The promoter is exactly the endogenous promoter. We just change it directly on that. The promoter is essentially, it has evolved to respond to an acute phase as part of that. We have put in place also some clinical operations such that, for instance, if someone doesn't feel well, we can send a nurse home rather than having the patient come into the hospital. We've created every opportunity to be able to monitor that. We're also monitoring C-reactive protein, which is a biomarker of inflammation, which is obviously typically associated with some of those things. Whether it's going to be part of the early 2026, I'm not sure. But we're poised to be able to collect a robust data set to show that. Got it. Okay. Just in terms of development plan for 302, you mentioned part of this update is going to be on the regulatory front as well. Can you just talk about your interactions with FDA, latest interactions since the RMAT designation? What can you share about just the amount of data, or is the amount of data that you have in early 2026, is that sufficient for pivotal planning? Yeah, so we don't go into the details of every single meeting that actually we make from the FDA, as you can imagine, is also a competitive set. Suffice to say that the RMAT designation does give us the opportunity to have more frequent interactions with them. Whether the data that we have is sufficient, obviously will depend on that conversation we'll have. We'll provide you more guidance, if you will, early in 2026. We do believe that the data set that we already mentioned is essentially therapeutic. If you think about it, there is, to our knowledge, no one that has 11 micromolar functional AAT expressed in the blood and has progressive disease. In that sense, basically the phenotype and genotype that we have reestablished is one similar to heterozygous, call it SZ or MZ. These are individuals that unless they've got real sort of strong additional insults, they do not develop a progressive disease. That is already our base case. That is good enough. We'll see whether we can squeeze a little bit more out of the system. Got it. What are your base case or maybe bookend scenarios for what the next step development path could look like and what the regulatory update could be? Yeah, our base case and sort of the approach that we certainly intend to discuss with the FDA will be an accelerated approvable path on the basis of biomarker data. The reason why we think that that is certainly the base case that we believe in is because with the first time that we are able to demonstrate the restoration of the functionality of the gene with actually independent orthologous genes. Not only can we show total AAT, of course, which is an established sort of biomarker, but we can show that that total AAT is functional. Importantly, we can demonstrate that that total AAT has been generated as a consequence of converting Z to M. We have shown with our initial data set that we reduced Z by more than 80%. We achieved this 90 to 10 ratio, which is already improved over the MZ heterozygous as part of that. We think that actually is a compelling set of data that altogether will demonstrate that the cause of the disease has actually been eliminated. As a consequence of that, we think that we have probably the strongest scientific argument to be made for at least an accelerated approval. We shall see if the FDA agrees. Should they not agree, I guess the other bookend would be a clinical endpoint type of study that would look at the ability to essentially stop the progressive damage to the lung and also see maybe some benefit to the liver with the biopsies. The good news is that even in that case, particularly if you use CT densitometry, you are able to demonstrate basically a clinical benefit within certainly 100+ individuals over a period of two to three years maximum. This is not going to be a thousands of people type of study. CT densitometry, just to recognize the fact that the FDA has not yet accepted it as an approval endpoint, but their official statement is that they are evaluating the data and they are working with a variety of different patient advocacy groups to come to a consensus and analyze that. Worst case scenario is that you generate FEV1 as well as CT densitometry and basically together should be able to demonstrate the benefit in this individual. We feel confident that this program has the opportunity to move relatively quickly. The bookend will be an accelerated approval. The other one will be a clinical endpoint. Either way is a relatively easy path for approval and launch. Got it. Maybe a couple of clarification questions there for the biomarker. Do you think it's going to be both biomarkers with the normal AAT and then the reduction of the Z- AAT? Yeah, our plan is actually to generate as compelling a set of data. We will provide both the alpha-1 antitrypsin total as well as functional. We think that those are probably the more relevant initial thing. We will also measure M. We will measure reduction of Z. We will measure the amount of Z that's left, if any. All of that is really a complete package of information that shows almost independently of each other that the function of the gene has been restored. To our knowledge, actually, that's the first time in humankind that anybody has been able to go and find a mutation that causes disease and fix it. Right. Yeah. I guess just focusing on the biomarkers, which FDA may do, is there an analog that's out there just to help define what the thresholds should be? Yeah, I mean, often it's been talked about, the 11 micromolar, but the 11 micromolar has been talked about in the context of enzyme replacement therapy, which actually has been used to approve the original enzyme replacement therapy. That is, I would argue, there seems to be that in that context of ERT, it may not necessarily be sufficient because there are other aspects to be determined. I believe that with the Inhibrx, Sanofi program, the FDA wanted to see more than 11 micromolar. For us, it's a very different paradigm. I don't believe that that actually translates to where we are. First of all, in enzyme replacement therapy, you're not eliminating the offending Z from the liver. You're also not eliminating the offending Z from the lung, which is also very important. When you have five, six micromolar left of Z, that individually is already contributing to lung inflammation in addition to being a marker of the fact that the liver is making a significant amount of that. The quality of the basically phenotype that we're generating is a very different paradigm from enzyme replacement. We're at 90% M. Even at 12.4, more than 11 micromolar are actually totally functional. We're already at the situation, as I mentioned before, which is similar to heterozygous. We do not have progressive disease. We think that the conversation we have is about reassuring the FDA and ultimately patients and physicians that what we've done is restored the functionality of the gene and therefore eliminated the cause of the disease. Got it. You mentioned the potential size of a functional endpoint-based study. For an accelerated approval study, I guess what could the size of that be and the timeline as well? Yeah, so obviously, we'll provide some guidance and it's difficult. What I can provide you is some speculation right now, but the speculation will be substantiated potentially from what we've seen with sickle cell disease, where, for instance, the pivotal trial for CASGEVY and LYFGENIA was about 50 patients. I would argue that maybe alpha-1 is a little bit more, but it shouldn't be hundreds of patients, right? If our estimate is somewhere between 50 and 100, it might be actually a reasonable spot for an accelerated approval. If that's the case, then maybe a confirmatory trial with, again, in the 100+, particularly with CT densitometry, should be sufficient to provide the package that you need. Our understanding is that if you manage to get the accelerated approval, that should be enough actually to support uptake of the drug as well as reimbursement. Got it. Anything on what the timeline of the study could be just based on the kinetics of the biomarker changes? The kinetics actually are pretty quick. As I mentioned earlier, and you can look at the data we generated within, frankly, four weeks, you already should have a pretty strong sense that we've got a robust and durable. Probably in the context of an accelerated approval would be several months. One would stimulate maybe three to six months. Some of that kind of follow-up should be sufficient to be able to demonstrate durability. That should be enough. Even within a couple of weeks, you already see from the data we generated that you start to get close to the peak of benefit. Got it. If you get the alignment for the accelerated approval study, you would likely have to have some sort of a confirmatory study as well. Would that accelerated approval study basically expand into the confirmatory study? Maybe you could expand the phase 1/2 study to become actually accelerated. We will see exactly what we do. There is an example of both for a variety of different strategies there. Those are the kind of things that we hopefully will be able to give you a little bit more clarity on early in 2026. Okay. Okay. Kind of further away, but maybe if you could just talk about how you'd anticipate pricing could look, assuming you get accelerated approval path and get approved, what could that look like just based on the value proposition of this drug? Yeah, we haven't given guidance on pricing yet, but I think at this point in time, I believe that it would be consistent with other gene therapies. Okay. That's fair. Just wanted to check too on just with the gene editing space, with the overhang with the patient death, I guess thoughts on that. Does it impact how you do safety monitoring or mitigation protocols? There's no impact on our protocols, nor on any additional demand from the FDA on how we monitor sort of safety. It's obviously a very sad situation, particularly for the patient and his family, I believe it was he. We don't believe that there is any repercussion on us. Obviously, there's going to be more data that I think Intellia will generate and hopefully share with the community at some point. Our sort of analysis of that is that it's very much linked to the combination of nuclease use and the particular edit that they were making at the TTR sequence. More data needs to come out. We'll see. To us, no repercussions. Okay. Yeah. Yeah, I think a lot of unknowns with that. We barely know anything about this patient or the situation. We will find out more. We'll find out more. Okay. Shifting gears to sickle cell disease. You're going to have data at ASH coming up pretty soon. The study has 26 patients in it. Data in the abstract looks in line with what you showed at EHA. Are you going to have data with a later cut at ASH? What else is going to be included in the poster that's not in the abstract? Yeah, you'll probably see data on a few additional patients over and above that. You'll see a little bit longer duration. You're absolutely right. The data that we already sort of described in the poster and that you will see described is really a continuation of the data you've already seen, which we feel already demonstrates a very differentiated profile. Certainly from a clinical point of view, where we got the highest level of F upregulation and the lowest level of hemoglobin S that has been achieved so far. That's really important because essentially it reproduces the heterozygous individual genotype and phenotype that do not have any symptoms. In addition, we show very rapid resolution and full resolution of anemia across the board. Also, we show that all the hemolysis parameters are normalizing. Importantly, the neutrophil engraftment as well as the platelet engraftment is the fastest that anybody's done. Neutrophil engraftment is really very important because that's the time that it takes for you to stay in the hospital. It's at least 10 days less than CASGEVY, for instance. For platelet, there's a label warning in both LYFGENIA and CASGEVY that there may be delayed platelet engraftment. For us, it's within 20+ days. All the hematological parameters are really indicative of a much deeper resolution of sickle cell, which is great to see. We also have taken the opportunity, frankly, to optimize both the manufacturing process and the way we release that. Also, the median number of mobilization cycles, which is a pretty labor-intensive and time-consuming process, for us is one, as opposed to the competition, which was about 2.3-2.5. Those are meaningful. Every mobilization cycle is at least a month before that comes to play. We feel that at least on the basis of our clinical evidence, we have the opportunity to at least double the output given a certain capacity that exists in the system, but also an opportunity, frankly, to build upon that even more so. In fact, what was encouraging, you may have seen the data from CASGEVY, they've actually almost doubled the number of patient starts compared to last time. The issue that they seem to be facing is that they're not dosing the same number. Our understanding is that a lot of those patients are actually caught up in several rounds of mobilization because they have a relatively high failure rate, as we understand. Obviously, they're in the commercial setting, but even in the clinical setting, they were seeing a longer period than what we are actually experiencing. We think that we will have a differentiated product, not just from a clinical point of view, but also from a process and, frankly, patient journey and also capacity in the hospital setting, all of which has the opportunity to ensure that this is the chosen brand to pick once all of these things will be launched on the market. Okay. Yeah, that's helpful perspective. For the neutrophil and platelet engraftment times, I guess what explains how those are faster? Yeah, it's possibly a variety of different factors that are contributing to that. Perhaps the one that we believe is the more influential process is the fact that we don't make a double-stranded break. In fact, if you look at our time of engraftment, it's very similar to an allogeneic cell where the cell has actually never been edited. We, by not making a double-stranded break, believe that the cell basically doesn't even recognize the fact that it's been edited. We call it, and that's also true in the fact that we have a bigger, greater yield at the very beginning following isolation so that we don't need to generate more mobilization cycles. We've also optimized, frankly, the manufacturing process really extensively. Ours is fully automated as opposed to many manual steps that we believe CASGEVY and LYFGENIA are requiring. Got it. When it comes to the fetal hemoglobin, what are your thoughts on that? Could a higher fetal hemoglobin translate to better VOC results? It's possible. Obviously, we'll continue to monitor it. So far, we have seen no VOCs, but it's early days, and that's good, and we will see. Yes, in theory, it's a deeper resolution of that, right? It's not only the higher level, which is obviously important to reduce hemoglobin S, but it's also, as you've seen some of the publication that has been done, is the greater consistency of high level per cell that we achieve compared to a nuclease-based approach. In the nuclease, and this has been published, you can see that there is a big spread of hemoglobin F level. Some cases, you can have cells with very high F. On average, you see the 45% or so that they do. Actually, the spread, there is a significant number of cells with much low F. In some stressful circumstances, those cells may retain the propensity to sickle. In fact, there seems to be some breakthroughs coming up in the real world that it has gone a little bit lower than the high 90%. It is still transformational for sure in that case, but I think there is at least a theoretical possibility to see a benefit in VOC, even though the bar is very high, of course. Yeah. Yeah. When thinking about comparing across different programs, at some point, will you share the vein-to-vein time for 101? Given the fewer mobilization cycles and rapid engraftment, is it possible to quantify how many hospital day reductions 101 can deliver versus? What do you see in the BEACON study? Yeah, we're still in the clinical setting compared to a commercial setting. Obviously, there is a big caveat there, and we will see where it is. Even sort of clinical to clinical comparison, we seem to be able to do that in roughly half the time that has been reported. Whether that will continue, we have got hope for it, but greater number of ends will only tell. Got it. For the registrational path here, it's probably similar to CASGEVY, I'm assuming. Yeah. That's basically our assumption is that a similar package will be sufficient for approval. Got it. Okay. Yeah, anything else that you've learned from the CASGEVY launch that you can apply for 101? There's a variety of different things, including how the launch and the sites have been updated, the apheresis. There is also how we actually do the plerixafor mobilization. There is a poster actually that we present on at ASH where we've optimized the way utilization of that. There is a variety of optionality, but including the fact that we have a very automated process all the way from manufacturing to release. The other point which is important is, I believe CASGEVY needs to, once the cells have been isolated, needs to go all the way to drug product production and release. We don't have to do that. We have the ability to actually freeze the cells post-collection. We pull them together, and when we've known the number, they give us a likely dose. And then we manufacture only once and QC only once. That is also a consequence of the fact that we have direct control of the manufacturing because we have our own manufacturing facility where we also do QC release. Got it. Briefly, I wanted to ask about your ESCAPE study too with the anti-CD117 antibody dosed to the first patient there. I guess could we see some clinical data from that program? Just to make sure that it's clear, we've dosed the first healthy volunteer. This is basically the antibody only where we are doing a PKPD study to demonstrate what is the dose that we expect to generate that niche that we need to be able to do that. This is potentially a really important alternative to bisulfa, which can be used not only ex vivo but also potentially in in vivo. We're making good progress actually with targeted LNP for in vivo delivery to HSCs. You're not guiding to timelines for that? Not yet, but we'll probably during the course of next year, likely to see some data from that. Okay. For the next gen sickle cell, the in vivo sickle cell disease program, any status update on that? Not yet. We're in what I would call lead discovery still phase, but you probably have seen recently there's been a sister company that we co-founded, and I was the interim CEO called Orbital Therapeutics that was acquired by BMS They use basically the LNP technology and targeting domain that we have developed with Beam. We work very closely to understand various aspects of targeted LNP that are essentially transferable from one to another. We're now focusing on finding the right targeting domain for the HSCs, but everything else, all the manufacturing release criteria and so on, has been optimized and has been shared basically between the two companies. Got it. Okay. Sravan, maybe you want to comment on just cash position and runway? Sure. As of the end of the third quarter, we had $1.1 billion cash. That's cash into 2028. We also have the proceeds from the Orbital sale, but we'll give full runway guidance in a few months in January or so at the JPMorgan Conference. Got it. Okay. Thank you both for joining us today. Thank you.