Good morning, thank you for joining the Fifth Annual Guggenheim Genomic Medicine and Rare Disease Conference. I am Debjit, my pleasure to have John Evans, the Chief Executive Officer of Beam Therapeutics. Great to be here. Awesome. Let's, maybe, you know, help people understand base editing and more because I think a lot of people don't understand what Beam stands for. That's right. Yeah, it's actually, a joke we tell that Beam stands for base editing and more, and we're always looking for what the and more is. I think we've figured a lot of things out actually that fit into that bucket. Beam is a next generation gene-editing company. We work on CRISPR, but it's a new form of CRISPR. We're using CRISPR for what we think of as its best feature, which is its targeting ability. You have a CRISPR protein, you load in a guide RNA that has the address in it, where you're gonna go target within the genome. Once we get there, we do something very different. Rather than cutting, which is what the earlier CRISPR technologies do, we make a single base change. Using a deaminase that is attached to the CRISPR, to make a much more precise edit to your gene sequence and not cut, not disrupt the sequence or the chromosomes. That gives a lot more control and precision over the edits that we're making, and we're exploiting that in a wide range of different applications. We have pillars in hematology, immunology, and oncology, and liver, ex vivo and in vivo, all to try to bring this next generation technology to as many patients as we can. Regulatory headwinds has been something everybody's talked about over the last year or so. The Intellia IND clearance, what does it mean for base editors? Yeah. Or it means nothing? Well, no, it's good news. I think it's expected from our perspective. Yeah, people have been kind of trying to figure out where the FDA stands on novel technologies for forever, right? This is an old game. Every new technology has its own path through the FDA because the FDA doesn't understand it. They have to answer a certain set of questions, "How do we characterize the risk and benefit of your investigational product?" The company is the one who knows the technology, so it's a dialogue between the two sides to teach the FDA about the science, then help them answer the questions they need to answer. With, you know, gene therapy, this happened with RNAi, this happened with editing. It's been happening. We've obviously come a long way, now we have, you know, ex vivo programs and blood cells where we have open INDs. In fact, CRISPR and Vertex have now filed for an approval on one of those, which is really exciting. We have CAR-T products which are highly edited. We have one of our own in the clinic now. The, you know, the moving threshold frontier has been in vivo, that's the next version of this. Seeing Intellia now get open in the U.S. is great news. At the end of the day, the FDA's, on the in vivo products, is asking a set of pretty simple questions. They're basically saying, "Okay, if you're gonna just administer it in vivo rather than ex vivo setting where you can isolate a single cell that you're editing, here in vivo, you know, it's a little more of an open-ended experiment, and so make sure you've done the work on biodistribution. Where are you going in the body, right? And depending on where you go, make sure you've characterized your off-target potential in those tissues." I think that is a reasonable set of questions. They're asking for a lot of data, so it's a fairly thorough package that they're looking for, but it is not insurmountable, and it's something that obviously Intellia has done and that we are prepared to do as well. To take a slight tangent, CRISPR-Cas systems have been around for a little bit longer than base editors, right? In terms of the comfort level, where is base editing versus, say, CRISPR-Cas systems? Yeah. CRISPR-Cas was discovered about 10 years ago, and base editors about five. We're sort of, you know, halfway on the path that the CRISPR-Cas companies have been on as well. I think that there's no question that over 10 years we've learned a lot about the CRISPR-Cas systems. You know, the step one there was, how do we use them therapeutically, right? If you're gonna chop up the DNA, you've gotta really think about where am I gonna do that carefully so that I have a therapeutic effect, and I think that took a little while to figure out. There have been some good applications that have resulted from that, which is great. The other questions are things like off-target, how you deliver them, what the regulatory package needs to be, and those are all things that I think the companies have made a lot of progress in doing. I think there is a certain amount of comfort growing with the editing field in general, with CRISPR more specifically and with that kind of editing. Base editing is newer, but it's really on its own sort of similar path. The good news for us is, you know, we're in what I like to say is sort of a fast follower position. We get to build on all of what's going on with gen one and hopefully then do it faster and get there sooner. Then there's a little bit that's new with us. Base editing have slightly different off-target profile, a slightly different edit, which has a lot of advantages, and so we have to characterize that and help people understand that. The CRISPR is the same, the guide RNA is the same. Lipid nanoparticle delivery or ex vivo transplant is the same. There's an awful lot that actually is similar to and builds on the comfort that has been growing on the CRISPR technology, even as we bring something new to the table. Got it. For every new technology from a validation perspective. I t's usually going after one low-hanging fruit, r ight? As you mature, how do you think, you know, which direction would you take the pipeline to? I think low-hanging fruit is really what it means is it's about risk, technical risk, right? What we wanna do is we wanna have clinical programs that take as few technical risks as possible, so that you have a chance to validate your new technology and then learn about it, and then build on that next more complicated application, right? For us, we chose very carefully. We're doing a very broad and somewhat ambitious plan. Unlike some of the other companies in the space, we went after all of the different delivery modalities in parallel. We're doing ex vivo in blood. We're doing CAR-Ts in T cells. We're doing LNPs to the liver. We actually have an eye program using AAV, just like LUXTURNA. It's a lot to do at the same time, but in every single one of those places, there is clinical data that we can point to that shows that delivering a complex medicine in that way is possible. In fact, there are even approved products that look kind of like that. They're not editing products, but they have some of those principles. In our minds, what we were doing is we were taking out as much uncertainty as possible on the delivery, manufacturing, regulatory side, and let just the novelty be the editor. We've chosen sickle cell disease in hematology, where we really know exactly who to treat and how to treat them. It's just that what's new is our more precise editor. With CAR-T, we're going after T-cell leukemia, so the antigen is CD7. These are patients who were left behind by the CAR-T revolution, but we know CD7 is a validated antigen. It should work. What's novel is the way in which we edit those cells, right? In vivo, our two programs, BEAM-301 and BEAM-302, for glycogen storage disease and alpha-1 antitrypsin deficiency. In both cases, patients have a single point mutation that is misspelled in their gene, and we have a drug that should convert that one letter back to normal. Again, not a lot of uncertainty biologically. If we can get to the liver in enough cells, change the gene back to normal in enough of those alleles, the patient should do very well. The delivery is an LNP. We've seen this before. You know, that's the point about low-hanging fruit. You're trying to take as many variables out of the equation as possible. Now, once those work, you can then build on that and do a lot more. In each of those verticals, we have a whole portfolio strategy to go build on that and go farther. In the case of hematology, we're working on next generation versions that could potentially change the way we condition patients in transplant and get that to many more patients without the need for chemo. Not just the most severe sickle cell patients could then opt for this therapy, but many, many more. In CAR-T, we're working on allogeneic cells. Like, how do we really make cells allogeneic? It's gonna take more than one or two edits, we believe. That's the next generation thing that we're working on. In vivo, lots of different liver targets that we could potentially go after, moving into more common diseases, as well, and then even thinking about delivery beyond the liver. Those would, you know, be the things that build on the first gen low-hanging fruit programs as they move forward and give us a lot of optionality and diversification within the portfolio. We started this by saying Vertex CRISPR just filed a BLA for sickle cell. Yeah. From your perspective, BEAM-101, what can you do now to expedite the program, both at a patient level and a CMC level, which is where Vertex really stepped in for CRISPR? Absolutely. Yeah. We've been hoping for this for a while, you know. Bluebird obviously was the first-gen path here, and they had to change manufacturing midstream, right? They went to the suspension formulation for manufacturing and, you know, I don't know the science too well, but it may have been very important to do. It was, the FDA said, "Okay, you have a new product," you had to sort of run a different trial, and the pivotal ended up being a, you know, kinda different trial. From my perspective and the way we think about all of our programs at Beam, you know, we want these all to be what I call precision medicines. We know who to treat. We know exactly what mutation they have. We have a drug that ought to fix what's wrong with them. You shouldn't be doing phase I, phase II, phase III development, right? If at all possible, you should do one trial that's been very well designed. Obviously, there's an expansion phase of some kind. You generate a package of data that should be enough to file, right? In the case of sickle cell disease, I think that is what's happening if you do it right, and that's what CRISPR and Vertex are showing. One trial, about 45 patients, eradication of vaso-occlusive crises, that's clear clinical benefit, and the statistics is not debatable. You know, these patients have them, and then they stop having them. We've been building on that for a while. The BEACON trial for BEAM-101 was always designed with that intent, that if possible, we'd like to do the sentinel patients, there's three of them to start, and then an expansion phase, and then get to that same 45 number, follow them for a certain amount of time, and then file. I'd say over the last year, as the CRISPR-Vertex path has become even clearer that it was happening, we have then even farther ramped up the things we've been doing to then commit to that path for BEAM-101. Those things include, we've basically done some changes to the protocol to accelerate enrollment in the trial. We're doing patient 1one now. Patients two and three will follow in, you know, the second half of the year, but they'll be more in parallel. We're actually doing some of that overlapping, then we even hope to be able to initiate enrollment of expansion patients by the end of this year as well, which is great 'cause then you're open enrollment until you can get to that 45. We're also, you noted, manufacturing. We're doing investments now that are required to basically lock down your process. That's a big part of a BLA package. We wanna do all of that now so that by the time, you know, many of those expansion patients will be then put onto our final commercial process from an FDA validation perspective. Operationally, a third piece is most of those, we anticipate, will also be done in our facility out of North Carolina. Currently using an external partner, which is great, but we have a big manufacturing facility in North Carolina that we have built. We think that'll be GMP operational by the end of the year, and we expect the majority of those expansion patients to be done out of North Carolina, and that facility can bridge from both clinical to commercial as well. We're building in everything we need to now to go as fast as possible in the clinic, and then to have continuity into the commercial phase for that BEAM-101 product. Got it. Is the threshold gonna be from a clinical efficacy perspective? Are we talking about fetal hemoglobin levels, or does it all of that doesn't matter, it's about the hard endpoints? Well, I mean, ultimately, it is about the hard endpoints. I think that's, I think that's fair. you know, initially, the approvable endpoint will be, vaso-occlusive crises elimination. you know, time and VOC free, things like that. clearly, there's a, you know, high bar being set by the other, you know, parties in this field, bluebird bio and CRISPR, which is you basically can't have VOCs, right? You have to eradicate those. Our goal will be to do the same. We're not gonna beat them on that endpoint. It is awfully nice to, I would say, to have an endpoint that is known to be tractable, that is gonna be validated by the FDA, that is full clinical benefit. We're not talking about accelerated approval, and we can then build the trial towards that. That's all good. We like that. Where differentiation will come from is, though, you know, on other sort of attributes over time. You know, up front, to your point, there are a lot of things to like about the editing product for BEAM-101. We have a higher level of editing than anyone else. We're at 90%, 95% editing. That means more cells are edited, fewer sickle cells left behind. The edits we make are more precise. They're right in the on/off switch of the fetal hemoglobin genes, so we're more direct, and it's a more pure and consistent product, where every allele's getting the same point changes instead of a random mix of insertions and deletions. We get a very consistent profile and a higher dynamic response. We got higher levels of F overall than anyone else. We're up over 60% in our preclinical models. That, by the way, that 60% good hemoglobin and about 40% sickle globin is the same ratio that a carrier has, like a trait patient, and they are normal, right? We think we wanna get all the way to that point. Obviously, also non-cutting, right? We don't have any genotoxic stress, risk of chromosomal aberrations, non-viral, so we're not doing random insertion. with the bluebird bio product, I think a lot to like there. Longer term, how will that show up? I think we'll be looking at everything from blood parameters, resolution of hemolysis, you know, more normalization of how the blood works. We wanna see less inflammation. That, of course, could also lead to less organ damage over time, which we know, of course, is what kills patients with sickle cell disease. It's not the vaso-occlusive crisis, it's the general systemic, smoldering challenge that this disease presents. Bottom line is we wanna just deliver a deeper cure, and we think that'll show up over the medium and long-term outcomes. Over the near term, sort of everybody's going after the severe 25,000-ish kind of patients, right? Yep. You've had a lot of time and effort behind the ESCAPE program. Yes. Yes. Which I believe is in lead optimization right now. What needs to be done so you could leapfrog into the bigger opportunity? Yeah. Our wave one product that I've been describing, you know, we will obviously enter several years after Vertex and CRISPR, but we think it's a best-in-class option. It's a better editor. We believe it'll be a better cell product. We're gonna compete for that. We think that is a meaningful market. Every year, a certain number of patients who are severe will opt for that market, and, you know, that will be, you know, something that is both commercially and therapeutically quite impactful. Nonetheless, you know, we are not done if we have only treated those severe patients, right? There's a lot of other patients with sickle cell disease, both here and around the world, that we need to think about. Our goal with this next-generation technology is to fix the biggest problem, which will keep more people from opting for a cure, and that's the chemo that gets used, right? The way this works is you edit the cells outside of the body. Before you put them back in, you've got to get rid of the rest of the old cells. You're using chemo, usually busulfan, to do that. For a severe sickle cell patient, this is a good trade. This is, of course, it's standard of care in transplant, so it's not anything novel. There's a reason we don't use transplants every day in medicine, because it's a fairly intensive procedure. What we're doing with this next-generation product, which could really dramatically expand the access to these sorts of things, both for sickle cell disease and beyond, we call the ESCAPE platform. Basically, using the elegance of base editing, we're just adding a second edit. Literally just one more guide into the mix. Might be the exact same editor as 101, for instance. Everything we know about that would still apply. The second edit basically changes on the surface of the cell a single amino acid, okay, which is where an antibody will bind, okay, and will block that binding event. Now we can use an antibody to clear blood cells to make room for your graft, but it will ignore your new edited cells because it can't bind anymore. Okay? This is a really elegant way to use base editing, and it takes advantage of the precision and non-cutting nature of base editing, because if you were to use a nuclease, you just would blow up that receptor, and your cell wouldn't function without it. In our case, we can literally just not change the function of the receptor at all, just change the surface of it in enough way that the antibody no longer binds. Now we can basically select in the body for new cells at the expense of old cells. We think that this will finally bring about the future that a lot of people have been dreaming about, which is to use precise antibodies to condition rather than chemo, which is kind of just carpet bombing your marrow and has a lot of side effects. there have been some challenges with CD117. How are you sort of thinking as a company to go around those? Yeah. I think that, you know, those challenges, I mean, there's been one, you know, obviously outcome with Magenta, where they had some toxicity there. You know, there's so much nuance to that. I mean, they were using a very potent payload, I would say. One reason that companies are doing that is because if they can't discriminate between old and new cells, they end up having to go in before the graft arrives. You need a really deep eradication of cells, and then you need to get out of there again before the graft arrives, otherwise you'll just kill the graft. You end up using these very hot payloads, which are quite toxic, and I think that may be something behind what happened there. We don't view KIT as, you know, as a class problem here. I think that there are gonna be lots of ways to do this, and the beauty, again, of our KIT technology is we can have the conditioning agent present alongside our graft, right? 'Cause the graft will just ignore the conditioning agent 'cause of that edit. Now we can dose higher, we can dose longer, we can use different kinds of payloads. I think it gives us a lot more flexibility than other companies have had, and that's the game changer to this technology. If it works, it will, I think, revolutionize the way we think about transplant both for sickle patients and beyond. It'll bring base editing to many, many more patients around the world, and it'll be a very significant technology advantage that Beam has because you really need base editing to actually do that concept at all. Got it. base editing more and more brings me to Orbital Therapeutics. What's the vision behind that, and where do you see that in two years from now? Yeah. Beam at the end more, you know, Beam takes a very, I think, creative and somewhat unusual business strategy. We've thought from the beginning that we needed to create this under-one-roof integration of all the editing you would wanna have, with base editing being the lead, delivery, every kind of delivery that's gonna work, and then of course, manufacturing, and put that all together. We've been accumulating a lot of technology and a lot of things under one roof. Okay. Once you've done that, it's gonna be way too much to exploit all on our own. We knew that as well. Furthermore, there's gonna be some things that we wanna get access to that we can't quite afford to do ourselves, but we'd still like to, you know, get access to stay on the cutting edge. We've done a series of deals that I almost characterize as innovator relationships, where it's not with a pharma. We've done some of those too, Pfizer and Apellis. Where we are trying to trade, you know, something that we have in return for something that they can bring us, right? In the process, unlock value from this, from this engine that we've built. We did a deal early with Verve, right? Verve is in the cardiovascular editing space. We gave them our editing technology. They're running with it and doing a great job, and in return, we have some opt-in rights to their programs. We did it with Prime Medicine, where we again sort of helped start the company and put a bunch of, you know, delivery and other technologies in, and in return, we have exclusive access to prime editing technology in fields that are interesting to our portfolio, which, you know, could be a big advantage at some point. With Orbital, the latest one, so we're again, we're putting in a bunch of delivery and mRNA technologies that we have. We think they can be exploited for things like mRNA vaccines, mRNA gene therapy, maybe even in vivo CAR-T, things like that, you know, that are maybe a little next gen and we're not working on them today, particularly, you know, some of those aspects are not things that are gonna fit easily in our portfolio, but we think can help patients. We put that in, we end up owning a part of the company, so we have about a 20% ownership stake in this new startup we've created. They've raised money, and then they will invest that money in the next generation of RNA technology. That RNA technology might be longer lasting, might be more potent, might be able to be delivered to different tissues. We get access to that IP in our core fields, gene editing and cell therapy and things like that. You know, it's a way basically to both unlock value again for these applications from stuff we've already built and benefit from investment in the cutting edge of an area that is important to us, which is RNA, but where we're not gonna put 50 or 100 people on it internally. I think it's a really clever win-win sort of sort of model, and I, you know, it won't be the last of these that we do, but I think it's an important one. I wanna talk a little bit about extrahepatic indications. Yeah. I just wanna ask you, do you guys have rights to David Liu's latest spinal muscular atrophy program that just got published in Science last week? Yes. We don't yet have rights to everything and, you know, there's sort of always something new that you can license. Yes, I mean, the spinal muscular atrophy program that he's working on obviously uses base editing, uses all of the same constructs that we have platform-level licenses from his lab, Harvard Broad, on. That would be squarely within the scope of what we're working on under that technology. I think, you know, that is an interesting target. I think we're, you know, we're certainly intrigued by that so, you know, we obviously have some of our own stuff, but if there's incrementally helpful things from David, that would be licensable for us as well. From a extrahepatic indication perspective, where are the investments right now? Yeah. I know from a delivery perspective, you already probably have that in-house. Yeah. How are you thinking about it down the road? Yeah. This, on that in vivo pillar, this is the growth, right? This is where it goes, you know, kind of two directions. One is we know liver is a check. We know we can deliver to the liver. Obviously, there's more potency to be had and more optimization to do, but it's on the way, okay? One aspect of planning is, okay, what are the next liver targets we're doing? We have a bunch of those that are, that are cooking now, coming behind 301, 302. That includes more rare diseases, but it also includes more common diseases, you know? You know, we've talked about hepatitis B. Millions of people around the world have chronic infection there. Can we silence that with base editors? You know, things like Verve is doing heart disease, metabolic disorders. You know, there's a lot to do there, just in the liver. That's one path. The other path is trying to get to new organs. We have this technology to take LNPs there, and that's the Guide Therapeutics technology we bought a couple years ago, where we do have some evidence of that being possible. Our probably next focus there is actually blood cells. If you think about the synergy with the sickle portfolio, where if you could do an in vivo delivery to the blood system, that would cut the whole transplant out altogether. Immune cells is another very interesting area for us. CNS, muscle, lung, heart, those are all sort of focus areas. I think it's known that in the, you know, the Pfizer and Apellis deals, there are a couple of CNS focus areas there. Pfizer's got a muscle focus. Apellis has an eye focus. So there's definitely some real efforts in some of those areas from a delivery perspective and from an editing perspective, trying to push that next boundary and open up, you know, whole new territory for delivering editors. Why don't we finish with alpha-1 antitrypsin. Mm-hmm. Going back to liver- Yep. That's your most mature asset outside of the ones that you talked about already. Yeah. Yes. Alpha-1, you know, it's such a, it's such an exciting target. It's such an elegant demonstration of the power-based editing. This is, you know, 60,000 patients in the U.S. have a single letter misspelling in this gene that creates this alpha-1 antitrypsin protein that causes two problems. It's a mutant form of the protein that builds up in your liver as a toxic attack on the liver. You end up having liver problems. Also because it's building up in the liver, it's not secreting to your bloodstream, where it's the second most common protein in your blood. It's supposed to be all around the body, and especially in the lungs, protecting you from protease degradation of tissues. You end up with this emphysema or lung degradation phenotype, and people end up on double lung transplants, and, you know, it's a really horrible disease. You know, people have tried for a long time to get something that can help. You know, you can knock things down in the liver, but you're making the lung worse. You know, gene therapy doesn't work 'cause you need so much of the protein. It needs to be regulated normally. Really, what you want to do is edit. You want to fix the gene. For every single gene we fix, we are no longer creating toxic protein. We are secreting normal protein, so you're going to help both the liver and the lung. It's a single letter misspelling that is correctable with an A-base editor back to normal, and that's what we do. It's a very elegant approach. You know, obviously very excited about this. That'll be a regulatory filing in early 2024. You know, I think has all of those great precision medicine features I mentioned. We know who to treat. We know there's a lot of demand for a better cure for them and, you know, very large population of people suffering, and I think that, you know, base editing in an LNP deliver is the right path in our minds. Let's finish with, catalyst for 2023. Yep. Obviously the lead programs across the board are moving fast. BEAM-101 getting, you know, to probably the big sort of moment that will be disclosable will be sometime towards, you know, second half into the year where we've got all the sentinel patients on trial and we're beginning to enroll the expansion cohort. That would be a milestone that I'm looking to achieve operationally. Obviously, that would imply that patient one has gone well and that we're on track there. Data out of that trial will be in 2024, 'cause we wanna give an update on multiple patients with some reasonable follow-up around six months. Second, BEAM-201 is the cancer product. We wanna be treating patients mid-year. Again, that'll be the first quad edited cell in the industry that I'm aware of. That will be obviously a very exciting milestone both for that product as well as for the future of multiplex editing and T-cells, which is a big franchise for us. Third and fourth would be the liver programs. Obviously, the 301 glycogen storage disease will be a regulatory filing either at the end of this year or early next. We are gonna file that most likely both U.S. and ex-U.S., really the timeline is just dependent on how much of those FDA satisfying studies are required as we go through all that data. BEAM-302, the alpha-1 program is right on the heels of that's an early 2024 filing. That one probably is ex-U.S. only to start, for a different reason. We wanna avoid the use of protein replacement therapy, which is common in the U.S. They get a nice clean background to see upregulation of the protein. Certainly come back to the U.S. at some point, midstream there. That's the lead assets. I'd say in addition to that, you know, continued progress on the ESCAPE platform will be critical, in particular sort of deciding exactly how are we gonna do this. Is it antibody? Is it ADC? et cetera. I think progress on the allo platform, for CAR-Ts, you know, there's no guidance, but I think if that were to start to work, that would be very exciting and a, and a nice upside, franchise for us. New liver targets, as well for sure, will be something that is in focus. As always, you know, potential for business development and, you know, other strategic activities. Awesome. Congrats and on the progress, and good luck for the rest of the year. Thank you very much. Great to see you. Thank you. you. Thank you for being here.