Conference Transcript - BEAM 2026-05-20

Luca Issi, Analyst — RBC Capital Markets

The Capital Market, today's our great privilege to have Beam as part of our 2026 Global Healthcare Conference. Representing the company, we have John Evans, Chief Executive Officer. John, thanks so much for joining us. How are you doing today? Doing very well. Thank you, Luca. Great. Long list of questions here, but maybe before we go into specifics, it would be great if you can maybe start a little bit, big picture about what progress has the organization made recently and kind of what's ahead here for Beam?

John Evans, CEO

Great. Yeah, so it's great to see you all. So Beam Therapeutics is a next generation gene editing company. We're working on a new form of CRISPR called base editing. And so this allows us to make single letter changes in genes on a permanent basis without needing to make a double strain and break. This lets us make many more kinds of edits, more therapeutic edits, more precise edits, including doing things like correcting mutations back to normal rather than just knocking things out. We are pursuing this in a variety of different places, ex vivo and in hematology for the treatment of sickle cell disease. Our lead program, Ristocell, is moving towards market, and we'll talk a little bit about that. I'm sure we will have a BLA filing as soon as the end of this year, followed by a research effort to move sickle cure in vivo using some of our LNP capabilities. On the liver side, our second major focus area, we have a variety of different programs. The lead program there is alpha-1 antitrypsin deficiency. This is BEAM302. And here we are correcting the single letter misspelling in the alpha-1 gene back to normal. And this is the first time actually that anyone has been able to do that. We're really thrilled about that. Huge population, incredible level of unmet need really due for better therapy. Following onto that and building on that platform will be a variety of other liver programs. We have 301 for collective storage disease 1a that'll have data this year uh and then we're just going to be filing an ind this year for our third liver program targeting pku uh editing uh some of the mutations there um and uh another sort of major opportunity and so um you know we're thrilled with the early progress like the data has been very much confirmatory of of the way we think base editing should work and then the beautiful thing about this platform is it's very predictable right so once it begins working in the clinic there's every reason to believe it will continue to work in exactly the same way whether that be the fact that the editing once it's in the cell can edit the dna predictably or the fact that an lnp once you've delivered it safely to deliver

Luca Issi, Analyst — RBC Capital Markets

and effectively you can do that again and again for different programs so so in you know in many ways in some ways we've made a lot of progress in other ways i feel like we're just at the starting line of our vision because now we get to take that flywheel that has been built and apply it in more and more places with increasing amounts of confidence gotcha gotcha that's super helpful overview uh maybe let's uh double click on alpha one and that trips in maybe just remind us what data you have seen so far um and then maybe just if you can't talk about dozing it's again my understanding that you guys have tried to go a little bit higher than the 60 milligram either by doing the 75 milligram or the 60 plus 60 i think that experiment maybe didn't pan out the way you were you were hoping for but maybe what are the lessons learned from kind of going higher and then we can go from there.

John Evans, CEO

Yeah. So I think, I think the, so the first data we showed a year ago was after three dose cohorts. So we went from a low to a medium to a sort of medium high dose, and that was 60 milligrams. Uh, and as you recall, that was, that was shown to be a potential, you know, functional cure. Like we had reached the threshold of efficacy we were looking to get to. So at 60 milligrams, we achieved, um, over 11 micromolar of alpha one. That's the sort of magic threshold people talk about. Because basically, anyone who is a carrier or better, a carrier is someone who only has one copy of the mutant gene, and they don't have the disease, they live above that line. And anyone who has the disease, who has progressive lung and liver damage, generally live below that line. They're in the single digits. So we had gotten all of our patients up there. So then the subsequent experiment, as you're referring to, I just consider it to be good drug development. You really have to get your dose right, right? And you have one shot at that. And so what we basically said is, okay, 60 is clearly a possible dose. And then we want to do some experimentation around that, sort of pushing the dose higher, trying two doses, and doing more 60s just to confirm, you know, where are we on the curve in terms of our maximal PD effect. And the bottom line is somewhat as we sort of anticipated, we clearly have sort of saturated the pharmacodynamic effect here for the drug already at 60. So 75 didn't add much of anything. It was still well-tolerated, which was great. The two times 60 didn't add much either. And the second dose was not as well-tolerated as the first dose. So clearly that's not getting anything. So the bottom line is we confirmed that 60 was where we want to be. That larger data set showed 60 milligrams to deliver an average alpha-1 level at 16. And that's very consistent with what a carrier would have. We had a percentage of M, the normal protein in the body, up around 90 plus percent, which is an excess of what a carrier would have, an MZ person. And Z had been reduced by 84 percent. So we had clearly and dramatically changed the disease physiology to at least a carrier physiology, someone who would not have the disease. And that's the basis from our confidence that we think we've put these positions, these patients in a position where they shouldn't have any progressive disease going forward.

Luca Issi, Analyst — RBC Capital Markets

Gotcha. Gotcha. That's actually super helpful. I think you already alluded to it, but I think this is important for kind of a broader field of gene editing. Why was the 60 plus 60 like the second time around, maybe not as well tolerated at the first time around? obviously, you know, you dosed the two, I believe, I think was eight weeks apart from each other. So you would have thought that the first kind of lipid on a particle be kind of completely, completely washed out from the system. Like, why was that maybe not as well tolerated as first dose?

John Evans, CEO

Yeah, you know, it's hard to know. I think certainly it's true by the preclinical data, eight weeks should have been enough to have kind of a clear background, right? And yet we did see a little bit of response. That said, these are not normal livers. I mean, this is alpha one. So So, you know, alpha-1 livers are different in terms of their physiology, their macrophage biology is different. There's all sorts of things that may have sort of retained some sensitivity given that time period. I don't have data on this, but I feel fairly confident that just a longer time period would probably resolve that. Also, just to note that the things we saw were not, you know, showstoppers. I mean, we saw higher infusion-related reactions. So more like grade twos, where you're giving a Motrin to handle some soreness. And then we had basically one patient who'd gone to a grade three, four ASEALT. But it was asymptomatic. They never went to the hospital. There was no bilirubin. And it resolved very quickly, right? So, you know, again, a sign that those livers weren't quite back to normal. Back to my first comment, obviously, given that we didn't see a dramatic change in the pharmacologic outcome, there's no reason to pursue it. But I think for the field, nobody should draw from that conclusion that redosing LNPs is not possible. It clearly is. Moderna does it all the time. Intelia has redosed patients successfully. I expect we will as well. So in fact, we still intend to go back and redose the patients in our trial at the 15 and 30 milligram level who received sub-therapeutic doses and will need to get the full dose at some point soon.

Luca Issi, Analyst — RBC Capital Markets

But in that case, you're not going to go higher than whatever is the 75 milligram? or is that the idea? So the patient that received like 60 are going to get 15 or is that?

John Evans, CEO

No, usually what you do is you say once you sort of settled on the final dose, in this case, it would be 60, then at some point you would go back and just give them 60. 60, okay. We wouldn't go higher than that.

Luca Issi, Analyst — RBC Capital Markets

Okay, that makes sense. Maybe one last one on safety, if I may. I just think this is super important for the broader field here, given that you're obviously pioneering this space. So what can you tell us about the kinetics of the kind of liver elevations? Obviously, it's kind of somewhat physiological to see some of the liver elevations with LNP. What can you tell us about what you've seen there? And how are those kinetics of the ALT and AST elevations compared between patients that have liver involvement versus patients that don't have liver involvement? Obviously, this is a complex indication. There's a liver manifestation. There's a lung manifestation. So, just walk us through the kinetics and how the magnitude of the elevations compare between the two buckets.

John Evans, CEO

Yeah, it's a great point. And I want to make sure people understand. And so we're all learning about LNPs in real time. So there has been this concern from a couple of the programs, or really one of the programs that Intelia has been running, the TTR program, where you saw an unusual LFT signature that was maybe late appearing, right, around day 28. Okay, so that, as far as I know, that's the only time that's been seen. I think Intelia has spoken to it. You know, that's a specific issue related to their editing and that target, which I do not think is LNP-related broadly. um pretty much every other lft signal that i can think of including this one um classic lmp signal is just it goes up fast and then it comes down fast right it's really the kind of mass action of putting a lot of lipid into the liver all at once and the liver gets inflamed um the the key is you want to see the you know within days coming down rapidly and you want to see no bilirubin change right because that shows you the liver function has not been affected it's still processing bilirubin etc and that's exactly what we saw right in this case so i think nothing out of the ordinary um just just a sign that the liver was still sensitive i think of it you know and not fully reset sure sure okay that's helpful um maybe let's talk about by standard editing that something comes up in every conversations we have with investors maybe uh remind us what kind of work you have done to really make sure that not only you have this like level that are above this magic number of 11 micromolar but the fact that the actual protein is functional let me just remind us what kind of work you've done there for sure so so with base editing you can in in some cases uh get uh you know an additional edit in addition to our target edit if there's a second in this case a within the editing window um with alpha one we know that can happen and the the most common such outcome in addition to the pure correction uh of the the z mutation back to m which is the the main thing we're trying to do is sort of a neighboring change um which basically we get a mixture you'll get some just m and you get some of this what we call m variant um but we this is the the fingerprint of the drug we've known this for a long time so we've had plenty of time to really characterize that variant and show that it is normal and comparable to the m so it secreted normally it is functional um it we've done structural biology showing that it folds and that its structure is is the same as the normal um it turns out that variant position is actually commonly varied in the human population there are you know six seven eight different variants you can find in people the one that we're making is found in people and not associated in disease. And it's just a permissive sort of surface residue on the protein. I think the most important data we have shown is that when we showed the functional data, we showed that we had very high levels of functional data consistent with what you would expect to see if it was just the M and ours was the mixture of M and M variant. So that shows you that the M variant is clearly functional and contributing to the total functionality we have um we just gave an encore of our top line data and there's a nice chart in there you can see where we're showing direct you know using the serum for these patients direct inhibition of human neutrophil elastase very dramatic drop um very quick uh you know by by this um this alpha one um sort of um mixture that we're creating and and so again showing you that it's clearly functional And I forget, have you disclosed the ratio between the variant and the wild type?

Luca Issi, Analyst — RBC Capital Markets

It's comparable to what you see in preclinical models.

John Evans, CEO

So you'll see some amount of M and some amount of M variant.

Luca Issi, Analyst — RBC Capital Markets

Okay, that's helpful. Maybe let's talk about going forward, the pivotal trial. It feels to me that the level of alpha-1 that you get in the serum is a little bit of a function of the baseline characteristics and you know the higher is the alpha one at baseline the higher is kind of the boost and appreciate it at the end of the day you you need to have as many patients you possibly can about this level micromolar so can you enrich this study in some capacity to kind of stack the odds in your favor and try to maybe enroll or maybe exclude patients to have baseline level below certain threshold or how should you think about that part i think yeah it's a great point and i think you're probably thinking about this correctly um i don't know exactly how hard and fast to rule it is but generally my my read of our data is that yes you know there is a spread and it's true even at the

John Evans, CEO

baseline right z patients live anywhere from you know four to six or three to seven it's kind of a range and and you know if you were low on that range then you get edited you're probably low on the resulting range and if you were high on that range you're probably high on the resulting range um and that's just i think physiology patient to patient um the the key for us you know is to make sure that every patient regardless of where they are gets above the therapeutic threshold is in the teens looks like a carrier right because i want to be able to say every patient has been functionally cured and the great news is that is what we're seeing right um now could you could you game that yes of course you probably could uh and we're certainly not excluding any patients on the basis of their aet levels so we take them all um i think especially for small n you know like early data sets you certainly want to look at the baselines and understand that a patient start from a high place and go to a high place you know that's that's definitely important where we're at we've now treated 29 patients total and counting so you know your ability to play those games goes away with larger i mean you know we've already converged on um what i would consider to be a typical typical average baseline and that you know we're going to treat another 50 patients, that will only continue to happen.

Luca Issi, Analyst — RBC Capital Markets

Gotcha. Gotcha. Super helpful. You guys came forward early this year about, you know, alignment with the FDA and a path of accelerated approval. Again, you guys have talked about biomarkers and, you know, maybe you haven't offered the specifics, but we can all think about like total alpha one and, you know, M and Z and the whole nine yard. How do you feel about that, especially in the context of the, you know, never ending headlines around the FDA are, you know, is your alignment, we've seen the companies obviously complaining about them moving to go post and whatnot. How do you feel that the FDA is fully on board? Everybody's on board, both the reviewers are on board, and the top of the house are on board and not like top of the house changes, like, walk us through your level of confidence around this, etc. approval.

John Evans, CEO

It's a great question. And it's something we're all obviously watching. You know, I think that I think the outgoing leadership, you know, actually had some really good ideas about modernizing the FDA and some specific policies like the plausible mechanism pathway that I think are actually quite helpful to beam and to base editing. Of course, some of those were also a continuation of work that was done under the Biden administration by Peter Marks. You know, so it's actually bipartisan kind of where that's going. So we're obviously eager to see how this goes. I know there's been a lot of anxiety over some of the late flip decisions that have happened and impacted some folks. So that's, you know, hopefully that stabilizes, and I expect it will. I think the good news, in a way, for AlphaOne, and it's true of Sickle as well, is we're not doing anything unusual here, right? So our AlphaOne path is not reliant on the plausible mechanism pathway, right? You know, nor I think hopefully we'll have to worry that somebody's going to rug pull us at the end, right? I mean, I think it's just this is a classic accelerated approval, and the review team that we're working with is not the folks who have left. It's professional FDA reviewers. They've been there for years. We've worked with them consistently over the last several years. That's also true in our SICL program, by the way, very stable review team, and they're doing a great job, very constructive. So, you know, I think not too much worry here, but of course I want the whole situation to stabilize. In the case of alpha-1, as I said, classic accelerated pulmonary pathway, you have all sorts of biomarkers that tell us that we are likely having a curative benefit for these patients, right, that you would predict. That's the whole point. And that includes the alpha-1 levels, the total, getting up into the carrier range, the M, the M percentage that we're creating, the reduction in Z, the fact that it's functional, the fact that it's inducible. all of that together shows you that you've basically recapitulated the physiology of a carrier versus a patient. And we know that carriers are stable. So that should be enough for an accelerated approval. The FDA has seemed very amenable to that. The main pushback they pushed towards us was to have 12 months of follow-up because they know that alpha-1 levels can bounce around. They want to make sure they have a good longitudinal series, perfectly reasonable. So we'll enroll 50 patients, follow them for a year, and then bring it in. Gotcha.

Luca Issi, Analyst — RBC Capital Markets

Gotcha. That's helpful. I think one of the components here for the accelerator approval is like, yep, I'm going to drive level of alpha one above sort of thresholds. However, there's a little bit of debate around augmentation therapy now with this data with inhibrics and Sanofi that kind of a little bit of raising the bar on like the total level that can drive in the serum. And so there's a debate around like trough versus what you achieve. So I do feel that as you try to advocate for excessive approval, it will be important for you to show that this liver benefit is not just theoretical, but it's actually there. So can you maybe speak about some of the endpoint that you're not doing? Obviously, biopsy will be invasive. It would be difficult to enroll patients and whatnot, at least for now. But what are you, what are you measuring to actually prove that in addition to emphysema type of potential benefits, you also have a liver benefit?

John Evans, CEO

So I think, so, so first of all, on the, on the, on the inhibitor program. So yes, they do achieve these high levels. Of course, as you note, because it's a chronic therapy, you have to worry about the trough level. And then it's also not inducible, right? So that trough is, is, is as good as it's going to be when you really need it when you're sick, right? Right. So, you know, we, our trough is different. It's really a floor. And when you're sick, you get more. Right. And so it's a very different kind of dynamic way of looking at the numbers. And so I think, and I, you know, equally, right, the inhibitor is not a natural protein. It is an FC bound set of AAT proteins. You know, what is the biodistribution of that? Does it show up in the right places? Is it fully active? I think there are probably a lot more questions there. Right. For us, everything about our situation, you can rely on the MZ genetics to tell you what that should be. So I think we have just a higher background credence and probably less to prove on some of these ways. All that said, then, yes, on the liver, we definitely believe there will be clinical benefit here as well. And I think it's a key differentiator for our class of drugs, right? We're going to simultaneously help the lung and the liver. With the liver, we're trying to drop the Z protein and relieve the liver as much as possible. and we're clearly doing that. We're getting Z levels down to or below what an MZ carrier might have. And again, they don't generally have progressive liver disease of any kind. How will we show that? So we are doing biopsies in the Part B patients. As a reminder, the great news of Part B was that so far all the Part B patients have tolerated the drug the same as Part day. So that despite having livers that are advanced in their disease, doing the LNP dose didn't change the safety or efficacy, which is great news. It means that our cohort C is going to be an all-comer cohort where everybody comes together. But in the part B, we are doing biopsies before and then six months and 12 months. So we should be able to measure, are there resolution of aggregates? Are we seeing any fibrosis change over time? I think over the long-term, those are endpoints we may be able to develop. And of course, there is about 10% of the population in alpha-1 who are liver-only, that for whatever environmental reason, their liver got sick before their lungs. That's the group we don't have in our registrational cohort. So we'd have to go back and do something like that for them anyway.

Luca Issi, Analyst — RBC Capital Markets

Can you also do MRIs or is biopsy kind of the go-to? Or maybe the trials are too short to actually show a benefit. Yeah.

John Evans, CEO

It's an emerging field. This is, this has been pioneered a little bit by Takeda with the RNAi drugs, which of course liver only in their, in their benefit potentially. Um, but that end point work will be, will be applicable here. You can do some imaging, there's fiber scan, there's other things there. Um, but I, I think biopsies end up being important to kind of directly measure fibrosis as well.

Luca Issi, Analyst — RBC Capital Markets

And the primary point of that Takeda Arrowhead's trial is a biopsy, right? So it kind of makes sense to me. So maybe just quickly, early days, but kind of fun to start talking about approval and maybe pricing. You have obviously a very interesting model, which is one and done. Obviously, augmentation therapy is a comp to a certain degree out there. Maybe big picture, how you're thinking about pricing and will payer appreciate the longer term pharmacoeconomic value of doing one and done or they will rather pay less for something that I got to pay for one year? I guess, because I'm assuming that you're going to ultimately price higher than what's the price of augmentation therapy for one year, given it's one and done. So will the payers get it?

John Evans, CEO

Yeah, it's a great question. There's no question we will price higher than the one year of augmentation, right? I mean, the whole one and done model has to do that. Payers are very sophisticated. They want to deliver cures and great medicines to their patients. and they do the math, right? I mean, that's kind of what the business is. They're really good at math. And so, you know, when we generally, when we bring them a great value story with strong pharmacoeconomic argument, they can understand it and they will get behind it. And we've actually seen this play out in sickle, right? So in sickle cell disease, you know that the lifetime cost of a patient is five, $10 million, given all the expensive medicines and the lost productivity and of course the hospitalizations. And, you know, even ICER, Institute of Cost-Effectiveness, which is a fairly conservative body, said, you know, over $2 million price in sickle made sense. And as far as I know, there have been no rejections on price in the sickle market. So, you know, we're kind of speeding up authorizations and things like that. But ultimately, that's a price that the payers have said they're willing to pay. And that includes CMS and Medicaid, right? So this is a broad consensus. Alpha-1 is basically similar, right? And we've published some data showing that lifetime costs for an Alpha-1 patient can be anywhere from, depending on their course, kind of the four to five million to eight million over time. So certainly we think that's, that's suggestive of, of, you know, genetic medicine pricing. Of course, it's too early to talk specifically about that, but I do think that we feel strongly about the pharmacoeconomic value, what we're doing and the value to patients. And of course, relative augmentation, we would have more sources of value as well, right?

Luca Issi, Analyst — RBC Capital Markets

Not just the one and done, but obviously the liver plus the lung, you know, more of a, more of a deep resolution of the of the situation so um you know bottom line is i think it's a it's a definitely um you know a good value story and we're very eager to bring it forward gotcha super helpful i know we're unfortunately almost out of time here maybe quick update on sickle cell disease tell us what's next for this program and then you know we've seen headlines from the sera or other companies that are kind of working in vivo and there's a broader enthusiasm around in vivo you know more broadly in oncology we see a lot of transactions and whatnot there so like I guess give us an update on your Xvivo approach and what's the latest I'm thinking to pivot to InVivo.

John Evans, CEO

For sure. So Xvivo, Ristacell, you know, BLA as early as the end of this year. We think we have a really incredible manufacturing process, which is what the market is really looking for and asking for. That's been a struggle so far with some of the early rollout of some of the other agents. We know our vein-to-vein time is just over four months, which means we can treat patients quickly and with high predictability. Part of that's base editing, part of it's the manufacturing. So we're very enthusiastic about what that can do for patients. Of course, that is to treat the severe patients, right? There's about 10,000, we think, maybe more, maybe less, who are eager to get that kind of therapy. And that's a, you know, multi-billion dollar a year opportunity to bring an exciting product forward. And that's what Ristocel will be. Nonetheless, of course, we're very eager to go treat the other 90,000 patients with sickle cell disease, who for a variety of reasons are just not quite in that bucket where they will choose the transplant-based option, but they'd be a great fit for something that is in vivo and more scalable. And so we're also working on that, of course. And there have been data out there. We've seen some of that. We have some of our own. It's obviously a bigger challenge to get to hematopoietic stem cells in the body with an LNP than it is initially in the liver, of course. And now people are also getting the T cells pretty well. We think HSEs are coming. Now, will it work as well as our ex vivo at first? We'll see. It just depends on the translation. I will say that with LMPs, remember, it matters what dose you're giving. With preclinical studies, it's all as important to see, did they disclose the dose? If they didn't, you have to see how close to the finish line they really are. I think it's going to happen. We're quite active there, of course. We have the Xvivo capability with Ristocell, but of course, Beam is also an L&P company. We're an in vivo company. Everything else we're doing is in vivo. So I think we've got a lot of tools in the toolkit for that one. And certainly, our commitment to the sickle community is long-term, and we expect to be bringing waves of programs forward to try to cure everyone on a global basis over the long term.

Luca Issi, Analyst — RBC Capital Markets

And on that note, I have a lot more questions, but no more time. John, I appreciate you joining us. Thanks, everyone, for joining us here at RBC Conference, and we'll talk soon. All the best. Thank you.