Welcome to another session here at the Jefferies Global London Healthcare Conference. I'm Michael Yee, one of the biotech analysts, and I'm up here on the stage with the CEO of Beam Therapeutics, John Evans. I was chatting with John about how exciting things are these days because there were some recent data with your technology recently reported in phase one clinical efficacy and safety, and that was reported this weekend at AHA. So we'll talk about that. But also, obviously, Beam has been embarking on their own phase I in sickle cell. So maybe if I could just take a step back, I'd love to have John maybe just talk about where Beam is today with your lead program, with a little bit of your pipeline, and also obviously some data recently. Maybe you could summarize for us about how you're thinking about Beam today and going into 2024. Yeah. Thank you. So it's great to be here. You know, this is a tremendously exciting time in the field of medicine, where we're really seeing gene editing become a reality. It's something that we've long dreamt about, but now it's really happening. We've got CRISPR and Vertex taking the first what's called a nuclease, sort of the first-generation version of gene editing, to the FDA for approval in sickle cell disease. That's right. They had a, you know, great advisory c ommittee. We expect that to get approved in December. That's imminent. Right. Beam, of course, represents a next-generation version of gene editing and using CRISPR called base editing, where we use the same CRISPR tool to target within the genome, but instead of making the cut, we make a single base change within the DNA, so more precise, more efficient, and you have more control over the edit that you make. And so this was invented several years after the original CRISPR, but now it's making great progress. We have the platform approach, so we've been moving that technology into many different indications, for ourselves, sickle cell disease as well. We think we have a better way to do it than what CRISPR and Vertex are doing, higher levels of editing, higher levels of F, overall deeper cure. That's an ex vivo product. We're also doing work in the liver, using LNPs to deliver a lead program there as alpha-1 antitrypsin deficiency, where, between 60 and 100,000 patients in the U.S., every patient has the same point letter misspelling in their liver, and we can potentially turn that back to normal with a single base edit. So that's a program that'll be filed into the clinic early next year. In parallel, as you noted, we have a very active business development strategy, and so that includes Verve. So we ended up putting our technology in their hands for three cardiovascular targets. We're trying to lower cholesterol permanently to create a permanent change in the risk profile for heart attack, which is still one of the leading causes of death in the world. So they have moved that into the clinic, and they just showed some phase one data, and it showed that base editing works. You know, it indeed has dose-responsive knockdown of the target protein, and that program has a path forward. We just entered into a really exciting transaction with Lilly where they were quite enthusiastic about that approach. And so we had some opt-in rights to the Verve programs. We've then transacted those, so now Lilly takes those over, and so Lilly will partner with Verve going forward. We received $250 million upfront and $350 million in development milestones. We're also partnered with Pfizer and Apellis, so it's been a really active phase, you know, both for Beam, getting the platform up and running, doing these business development deals, moving our own pipeline forward, sickle, alpha-1 antitrypsin deficiency, and for the field. You know, base editing, kind of that next-generation technology moving quickly. But on the background of just general, everything seems to be working in editing, and we just see incredible promise for the years ahead. Mm-hmm. Absolutely. So, you know, again, excluding equity stock market conditions... you have been generally executing on the plan. You are in the phase I for sickle cell, and your partner has been on track and reported the data. That would have been Verve with the PCSK9 data last weekend. Yep. So, maybe just talk about your own clinical program that you're embarking on in sickle cell. Yep. I believe the guidance is that you are about to infuse the patient shortly. Maybe you could tell us if you have. But that you are obviously on track to treat and treat more patients and report out some data for your phase one in sickle cell. After we have watched CRISPR with CRISPR-Cas9 finish their pivotal program, you are doing this with base editing. So tell us where you are with that, and tell us about the progress of that trial. Yeah, great. So BEAM-101 is our, is our program for sickle cell disease. So again, we're using the base editor to rather than cut the DNA, which CRISPR Vertex sort of cuts at the BCL11A site, which represses fetal hemoglobin, and so if you scramble that sequence, the fetal hemoglobin turns on, it protects the cells. Because we can make single-base changes, we can be a little more precise and thoughtful about where we're gonna make that edit. So we go straight to the fetal hemoglobin genes themselves, and we've literally chosen the single letter in the genetic code that if you change it, you get the biggest bang for your buck in terms of turning on that gene, and every cell we edit gets the same change. So you get a very consistent, very high level of correction, and again, we think preclinically, when you do the head-to-head, it looks superior to the Vertex edit. Not to say the Vertex edit isn't working, it is, but we think that we're- Yeah, we're talking about editing efficiency- Exactly, editing efficiency- ... in vitro. Yep. Biological response of the edit. Okay. So we're starting up a trial called the BEACON trial. We've got many sites open, and at this point, many patients on trial. As you noted, this is a long process to get each patient ready. You have to collect their cells, manufacture, and then do a transplant. It's about a six plus month process, but with the beauty of the trial right now is we can do many patients in parallel. Okay. So we have many patients moving through. The first one will be dosed by the end of the year, and then we have others in manufacturing and mobilization as we speak, which would follow shortly thereafter. This all sets up for a data release from us in 2024, probably the second half of 2024 where our goal is to not just give, you know, one patient with a couple of data points, but really a robust picture, multiple patients, long-term follow-up. Of course, we'll be dosing all throughout the year, so we will have lots of patients really on study by the time we give that first data set. That should really give you a picture of what BEAM-101 can do.... That's all on the path to what we think could be a registrational data set. You know, so the beauty of Beam, right, we're not doing dose escalation or, or you know, we're going straight in with what we think could be an efficacious dose, and we think about 45 patients on that trial will be sufficient to create a data package that the FDA could look at for potential approval. And we benefit from having just seen the advisory committee of Vertex and CRISPR, so we know exactly the package that, that they took to the FDA, and, and indeed, you know, the Beam trial looks like it, it does get us the kind of data set that, that they were looking at. At the same time, we see from that advisory committee the places where we think BEAM-101 could be better. Okay, tell us about that. Right, so, you know, the Vertex CRISPR program, again, large scale improvement for patients, absolutely no question about it. You know, hemoglobins are not quite back to normal. Hemolysis, not quite back to normal, sort of borderline on a couple of markers and retic counts clearly still high. You still have vaso-occlusive crises in some patients, that are sort of breaking through. So, you know, we think overall, even on those kind of near-term markers, let alone longer term aspects of organ damage, you know, we think there's role for a deeper cure, a better edit, to have a role to play in that market. Since this is a long-term market, the idea that someone is filing for approval, you believe that over the time—by the time you execute and get all of this data, that over a longer-term time frame, that your drug would be best in class, and therefore, you know, that you should have majority market share? Yes. Yeah, that's a great point. It's a great point. So there are probably some genetic diseases where they're small enough that if a product comes along that is good enough it could treat everybody before you have a chance to get them. Right? And that would be amazing for, for patients. In, in this case, that's not the case, right? Right. So there's 100,000 sickle patients in the U.S. alone, and because we are doing this in a complicated transplant, because it involves chemo, not every patient is going to sign up for these products. We think of it more as it'll be kind of a slow burn, annual number of patients who sign up for the therapy, and, and then we will be competing for share out of that total, and it will go on for some time. It'll also take a little while to operationalize this. It'll be more complicated commercially than your average product. The first few years since Vertex was here yesterday, talking about the launch would be gradual. Yep. You know, and so it's gonna take time, and by the way, comparable products, including gene therapy have started off, and it's gonna be the early days and the early years. That's right. And that kind of, you know, cross-sections where you become p art of it. That's right. So we have time. So I think we're not, this market's not gonna go away overnight. It's not gonna cure everybody. But even if it cures, you know, a 1,000 patients a year or something like that, you know, the prices that we're talking about in the U.S. of $multi-million, that's a big category, you know? And, you know, it. I think a healthy drug category never has just one drug. Right? So I think there's a good competition. The competition will help patients, and we do see, you know, a real market opportunity for BEAM-101. So two things, talking about clinical efficacy, you are about to infuse the first patient. Two questions: one is, is there any situation where it's actually not the right dose, that you would use it to be higher? Is that even possible? And then when you get the data, you're gonna look at it. This is how you're gonna determine that it's right, but presumably, you think it's right. What, what exactly are you looking for in the first two, three, four, five, six patients that you'd put out, and how would we compare that to CRISPR's product? Yeah. So I think I'm, we don't see a scenario where we would need a different dose. Right. I think, I think the field has really learned a lot over the last really decade of knowing, you know, how many cells you need to put in, how you characterize those cells. Right. So we have a very good feel for that. Of course, we will have to look at the data. You know I'd never say never, but I think, you know, we don't have anything anticipated. Every patient will get what is intended to be a curative dose. And then in terms of markers, it's sort of the things I said, it would be, and it, all of this is very visible in the competitor data sets. Yeah E specially now, post AdC om. It's all been presented. We've seen it now. Multiple presentations. There was a while when we weren't seeing all this data, but now we've seen it. But basically, it would be editing rates. So, you know, we show 90%-95% editing of cells rather than the 80% that you see with the Vertex product pre-clinically. Okay. It's the F levels, that's the gene we're trying to turn on. We get 60%-65%, versus Vertex's 35%. We probably would also show kind of the mix across all cells, how consistent is that, is that F level? Okay. I think that's gonna be an important story. The S levels, the sickle protein that causes the disease, have we how far do we drive it down? Okay. Right. We generally get to the sort of 60/40 ratio of normal to sickle, which is the same that a carrier would have, a trait patient, and they don't have the disease. That's not where Vertex gets to. We would then show hemoglobin. Okay. We would show hemolysis. Yep. We would show these other markers, I think, with you know, are all signs of how deeply did you go, how much cure have you achieved, and is the marrow back in a state that looks you know, sustainable? Okay. Of course, vaso-occlusive crises, I showed. VOC, hopefully there aren't any VOC. Yep. So one of the things in 2024 that will dictate how much data you have is sort of how fast you can enroll. Now, one of the things, to be fair, it has taken some time to finally get to enrolling and treating this first patient, but you think that is really going to gain some momentum because of some changes in the design. I mean, I don't know how many patients you will treat and report on, but can you sort of explain what the changes were and how much line of sight you have to three, five, six,eight, 10 patients? Yeah, totally. So we have changed the protocol, so you know, Again, the complication of the process, you have to go through many steps: screening and transfusions, mobilization. That's the long phase where you're gathering cells from the patient over multiple rounds. That's variable, and then once you have enough cells, then you go to manufacturing, release and then conditioning and transplant. So the challenge has been, you know, what's gated on what, right? Do you have to wait as you get these trials going before doing patient number two, before patient number three? At this point, we've removed almost all the gates with the FDA. The FDA has worked with us on this, and it's, again, a sign of the field maturing, I think. So at this point, the only gates we really have at this point are the actual transplant itself. So we're gonna have to transplant one patient now, check for engraftment over the course of 40 days. Then we can transplant a second patient, and again, their cells are already in process, check for engraftment, third patient, check for engraftment, then you're off to the races, and then you can do as many as you want. Okay. So in terms of momentum, I can, you know, I think you'll have to just see this as the news and progress comes out, but we really feel we already have momentum. Okay. So we have, you know, many, many sites open. We've got patients on trial. They're moving through, the manufacturing process is going well. So we certainly are very confident in that data package being robust. Okay. Now, presumably when you get this data towards the end of the year, and maybe Jefferies thinks it's gonna be ASH 2024, but when you get this data, how fast and how many patients? Is this basically a mimic of the CRISPR regulatory program? And I don't recall how many exact patients that was, but this should be a speedy process after that, and this should be, you know, literally the key catalyst once this data comes out. Yeah, I think that it's the key catalyst in that, you know, so far, once you - if you give a mature enough data set you know, again, not just one patient, a couple dots, but mature enough data set, that has tended to be consistent from there to the end of these trials. Yeah. You're not seeing a lot of variability, which is good. It shows again, that editing in general is predictable, and robust, and repeatable, which is great. So I would think that readout should give you a good feel for what the product looks like, right? Okay. Competitive differentiation, and are we helping patients, which is, of course, the goal. Really from there, it's just a numbers game. Okay. Right? It's just it's just getting to that 45th patient enrolled and dosed. 45 yeah. We haven't guided how long that will take, but, you know, certainly that's a kind of 24-25 story. Okay. Then there's a certain amount of follow-up that we have to do, looks like about a year, you know? Okay. And then you have a package that you can start the FDA about. One of the things maybe you could shed some light on is that, although Vertex said yesterday that it's gonna be a gradual launch, people look at 2024 and 2025, they looked at gene therapy that launch has been slow as well, and they wonder, "Hey, you know, John, do you think that this is a market that can sustain either two products, but quite frankly, is gonna take off? Yeah. Do you see that as an issue? Would you be surprised to see that it is a slow launch, and maybe, "Hey, don't worry," because that's gonna impact people's perceptions of what Beam is doing. Well, I think- What would you say to that? Yeah, I think for me, the main answer is, I do think we should be cautious on our expectations for how fast the launch goes in year one. I have to say, Vertex seems very bullish, which is great to see. Albeit- Long-term maybe- Albeit maybe- ... they're trying to talk it down. Trying to manage expectations as well. Yeah, yeah. You know, I mean, this is operationally complicated. It's a new paradigm, transplant-based. I think we have to be patient with the market for sure. We'll be watching along with everybody. I mean, that's gonna be very interesting to see. Maybe the one thing I guess I would just add to that is we are playing the long game as well. Right? So we—as you know, we have next gen versions- ... of our products. Talk about that, conditioning. Exactly. Yeah. So the next one is called this ESCAPE program, and it's a really beautiful variation on BEAM-101. It takes the BEAM-101 edit, but now it adds a second edit, which gives us the ability to create a custom antibody that can clear the patient's old cells and make room for the graft without touching the graft. Basically, the graft is ignored by the antibody, and this can only be done with base editing, and it's a beautiful illustration of our technology because we make such a subtle change on the surface of the cell. So if that works, it allows us to do everything I described in sickle, but now without the chemo. Okay. Okay, and I would say if there's any reason that that first market falls a little short in terms of how big it gets and how fast it goes, it would be the chemo. Right? It would be the patients look at it, and they say, "Gosh, that looks like, like a hassle. I know this is a fatal disease, but I-- maybe not yet," right? Well, we could fix that, right? And so when we do the sort of modeling of that program, that's a program that, first of all, would have a kind of, you know, incredible competitive advantage. You would take the whole market. B ecause nobody would choose chemo if they could avoid it. And secondly, it grows the market. There, we're very confident you have patients coming off the sidelines, and now you start to dip more into the prevalent pool more quickly for the market. Yeah, right. So number one, big differentiator, for the initial population. N umber two, opens up the market for people who may be less severe a nd would actually consider it. Exactly. Exactly. When would be, like, the first data set on that technology? Yeah, so it's a few years apart. Yeah. You know, it's coming along, but we're in late lead optimization on the conditioning agent. You know, that's a biologics. You have a sort of normal biologic time frame as soon as we get a development candidate nominated. Okay. But, you know, everything we're doing with 101 just lays the groundwork for that next program. Okay. So for us, it's really a lifecycle strategy, and we see a kind of a long-term franchise in the space. Okay. So we're watching that. The second part I'm really excited about is all of the other applications you could apply this to. Specifically, Wall Street is quite familiar with AAT, another area Vertex is working on. Yeah. But you have a potential to really transform it as well with the correction of the actual, gene mutation to totally correct the misfolded AAT. The other piece of information that's come out is, Verve had cleared the IND for their in vivo. Yep. So, FDA, I think that's the first. Yes. Well, technically the second with Intellia case. Second with Intellia case, yes, I agree. That gene edit, and so now there's been two U.S. IND clearances for in vivo gene edits. Yeah. Two questions. One is, how do you interpret, you know, the Verve data that come out and the clearance of it? Obviously, the FDA have looked at that data and blessed it, I guess, to clear it. So regardless of the stock reaction of what's happened over the last week, make a comment about that and what the FDA has seen. And then to that, talk about AAT and what you're trying to do, 'cause that's an IND, so we should pay attention to that, 'cause that's the next program. Yeah. So I think our kind of core pillars, we have the hematology story I just told you, and then in vivo to liver will be kind of the next big story. To the liver, yep. In that franchise, we have a couple programs disclosed, but the big one is alpha-1. That'll be the lead program. And it's long been a really attractive place for us to go. It is 60,000-100,000 patients in the U.S. Everybody has the same point mutation, as I said. It's called the Z allele. You have a ZZ phenotype or genotype. We have a base editor that turns that one letter misspelling back to normal, right? Very simple. If you fix that in the liver, you will do two things: one is you'll stop creating toxic protein in the liver, which causes liver toxicity, and you'll start creating normal protein that will raise your alpha-1 levels in your blood. That will protect your lungs from degradation. These patients get lifelong emphysema, COPD, and ultimately, lung transplants. The good news is, one thing is people have been excited about AAT. Yes. Because, again, Vertex has sort of pre-prepped everyone for how big this market could be. There's also an existing unfortunate weekly infusion, so there is a market of these people already on a drug that is very inconvenient. Yeah. But also that Verve, with a liver-targeted LNP has already proven last week that it does get to the liver, it does make corrections, and they are having high editing efficiency which drove a pretty good therapeutic effect. Talk about what that means to you and what, like, why that you think it's even better for AAT. I wanted people to understand s ort of the importance of the alpha-1 program. There's really three things that have de-risked that program recently Yeah. So, one is potency. We've been working on potency. We just published a set of data in September showing a full pharmacology workup, showing that we can get, you know, corrective levels of editing that would be clearly therapeutic under 1 mg per kg, right? So we think potency really matters. This is like preclinical. Preclinical, yep. In vitro assays. Yep, in vivo. E nsuring high efficiency. Yep. Okay. That's step one. One. Step two has been the overhang that the FDA has had on INDs and gene editing, and as I have told people all year, we think that will get resolved. Okay. It's just kind of the new thing. The FDA tends to be a little more conservative, but if you work with them, eventually they get there, and indeed, they've opened up Intellia's phase III. Verve's IND is open. So we see a clear path forward there. And then the third is Verve's data, right? And so that is now, you know, human proof of concept for base editing in the clinic, which looks great, and, and I, I think, you know, it's clearly efficacious, it's dose responsive. And the, just the editing rates that they achieved, you know, because the bar is lower on alpha-1 and glycogen storage disease- Explain that, though. 'Cause what we're doing- Explain why, why do you think the bar is lower? What we're doing with our products, with these programs is we're literally correcting a broken gene, right? You do not have to correct 100%. Now, we may. We're gonna push to as high as we can go, but the bar for clinical effect is much, much lower than that. We generally think about 20%-25% editing in the liver for alpha-1 would start to be therapeutic. About 10% editing for glycogen storage disease would be therapeutic. What is that based on? There's a calculation that 20% editing will lead to this much amount of correction? Yeah, it's based on that. It's based on our pharmacology models. Okay. It's also based on clinical genetics, right? Okay. I mean, clearly, a carrier of 50% activity is normal. I see. Okay. You have some intermediate genotypes you can look at. And so the bottom line is when we look at the Verve data set, you know, for us, we get very encouraged because it clearly shows LNP delivery of base editing can work, and if we were to reproduce those kinds of editing rates, we would easily clear the hurdle for efficacy in these important diseases. So I think all of these different things are coming together make us very excited about moving those programs forward, and they're liver programs, so unlike sickle, they do move faster. Just clarifying one point, so the filing strategies. So Alpha-1 actually will start as a CTA. Okay. It's gonna start ex- U.S. Start outside the U.S. That'll be a Q1 filing. We will come back to the U.S. relatively quickly in development. You know, we'll clarify exactly when. Okay. But it's a, you know, 3 + 3 dose escalation design. Here you are starting at a lower dose that is expected to be plausibly efficacious, but still, you know, margin of safety. Plausibly efficacious, okay. All right. Then you escalate from there. I think the dose ranges we will look at are comparable to what the, you know, Verve and Intellia have explored as well. I see. But, you know, we feel some confidence that based on all of our preclinical data, that we will be in efficacious ranges well within that- Yeah, so Verve... Sub 1 mg per kg range. Verve had done four different doses. Well, they got very high efficacy, very good efficacy on the top two. Yep. There was some efficacy in the bottom two. You have a lower threshold for editing that would give you therapeutic efficacy, so you could see efficacy earlier. How fast after the CTA in first quarter could you be dosing someone, and where, where, which geography is this? Yeah, so it'll be ex- U.S., you know, it'll... You know, I won't disclose the specific countries, but it'd be classical. New Zealand? You know, those sorts of places. Yeah. Yes. So I think we will. I won't give you guidance on dosing, but I do think that, you know, this is probably, you know, if we're lucky, this is a, you know, a year later, plus or minus kind of data set, so early 2025. But right, it's just gonna be like for like. We're not doing the first cohort. You would probably wanna dose a bunch in different things and then give us a full data set. That's right. I might push you, but Wall Street might push you for, "Hey, I mean, come on, John, if there's therapeutic efficacy with the lower one, get it out there," but... You can always go faster, but I think- Okay I think it's a 25 data event. Okay, 25 data. But I think it's a pretty exciting one, and again, there's only, you know, three, four cohorts to test, and I think we'll have a sense of what the drug's doing. Okay, and just to close out in the last minute. You did a, I'd say, pretty beautiful transaction with Lilly. They came to you. They gave you $250 million just for an option to go ahead and of course, the data is now out for Verve. Yep. So Lilly has sort of blessed their interest in this technology through the Verve transaction by giving you a bunch of money, and, so where are you with cash? Yeah. How much does that take you? It's expensive. Yep, it is expensive, but, you know, we actually have a-- we've already made a lot of investments, so now it's just moving these through. So, you know, we've been very successful with BD. I do think base editing is a kind of next-generation technology that gets pharma really excited. We've done the Apellis deal for $75 million, Pfizer deal for $300 million- Pfizer deal, yep. ... and now the Lilly deal for $250 million plus $350 million. So, I think you can see the scarcity value and the attraction of the platform leaves us pro forma with, I think, $1.25 billion, and that carries us to at least, late 2026. Yep. So well past all the data events that I've just described in the pipeline, and, you know, feel very, very excited about that. Fantastic. John, thank you very much. Looking forward to a great 2024 with you. Thank you. Thank you.