Beam Therapeutics Inc. ($BEAM)

Capital Market. Today is a 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?

Great. Yes. 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-stranded 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, Risto-cel, is moving towards market, and we'll talk a little bit about that. I'm sure we'll 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 BEAM-302. 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 on to that and building on that platform will be a variety of other liver programs. We have BEAM-301 for glycogen storage disease Ia, that we'll have data this year. And then we're just going to be filing an IND this year for our third liver program targeting PKU, editing some of the mutations there and another sort of major opportunity. And so we're thrilled with the early progress. I think the data has been very much confirmatory 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 the liver and effectively, you can do that again and again for different programs. So 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.

Got you. Got you. That's super helpful overview. Maybe let's double-click on alpha-1 antitrypsin. Maybe just remind us what data you have seen so far? And then maybe just if you can talk about dosing. It's, again, my understanding that you guys have tried to go a little bit higher than the 60 milligram, either by doing a 75 milligram or a 60 plus 60. I think that experiment maybe didn't pan out the way you were hoping for, but maybe what are the lessons learned from kind of going higher and then we can go from there.

Yes. So I think -- so the first data we showed a year ago was after 3 dose cohorts. So we went from a low to a medium to a sort of medium high dose, and that was 60 milligrams. And as you recall, that was shown to be a potential functional cure, like we had reached the threshold of efficacy we were looking to get to. So at 60 milligrams, we achieved over 11 micromolar of alpha-1. 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 have 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 2 doses and doing more 60s just to confirm where are we on the curve in terms of our maximum 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 2x 60 didn't add much either and the second dose was not as powerful 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 in excess of what a carrier would have, an MZ person. And Z had been reduced by 84%, okay? 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 -- these patients in a position where they shouldn't have any progressive disease going forward.

Got you. Got you. That's actually super helpful. I think you already alluded to it, but I think this is important for kind of the broader field of gene editing. Why was the 60 plus 60 like the second time around, maybe not as well tolerated as the first time around? Obviously, you dosed the two, I believe, I think it was 8 weeks apart from each other. So you would have thought that the first kind of lipid nanoparticle will be kind of completely washed out from the system. Like why was that maybe not as well tolerated as first dose?

Yes. It's hard to know. I think certainly, that's true by the preclinical data, 8 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 non-normal livers. I mean this is alpha-1. So alpha-1 livers are different in terms of their physiology, they're kind of -- 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 showstoppers. I mean we saw higher infusion-related reactions, so more like grade 2s where you're giving a Motrin to handle some soreness. And then we had basically one patient who gone to a grade 3/4 AST/ALT. But it was asymptomatic. They never went to the hospital. There was no bilirubin and it resolved very quickly, right? So 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 pharmacokinetic outcome, there's no reason to pursue it. But I think for the field, nobody should draw from that conclusion that re-dosing LNPs is not possible. It clearly is. Moderna does it all the time. Intellia has re-dosed 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 have received subtherapeutic doses and will need to get the full dose at some point soon.

But in that case, you're not going to go higher than whatever is the 75 milligram? Or is that to receive like 60 you're going to get 15 or is that...

No. Usually, what you do is you -- 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. We wouldn't...

Go higher than that. Okay. That makes sense. Maybe one last one on safety, if I may. I think this is super important for the broader field here given that you're obviously pioneering in 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 have seen there? And how are those kinetics of the ALT and AST elevations compare between patients that have liver involvement versus patients that don't have liver involvement. Obviously, it's a complex indication. There's a liver manifestations, there's a lung manifestation and so on. So just maybe walk us through the kinetics and how the two -- the magnitude of the elevations compare between the two buckets.

Yes, it's a great point. So -- and I want to make sure people understand. So we're all learning about LNPs in real time. So there has been this concern from a couple of the programs or one of the programs that Intellia 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 Intellia has spoken to it. That's a specific issue related to their editing and that target, which I do not think is LNP related broadly. Pretty much every other LFT signal that I can think of, including this one, classic LNP signals 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. The key is you want to see them 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, et cetera. And that's exactly what we saw, right, in this case. So I think nothing out of the ordinary, just a sign that the liver was still sensitive, I think of it and not fully [indiscernible].

Sure. Okay. That's helpful. Maybe let's talk about bystander editing. That's something comes up in every conversations we have with investors. Maybe 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. Maybe just remind us what kind of work you've done there?

For sure. So with base editing, you can, in some cases, get an additional edit in addition to our target edit if there's a second, in this case, A, within the editing window. With alpha-1, we know that can happen in the most common such outcome in addition to the pure correction of the Z mutation back to M, which is the main thing we're trying to do is sort of a neighboring change, which basically we get a mixture. You'll get some just M and you get some of this what we call M variant. But we -- this is 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 is secreted normally. It is functional. We've done structural biology showing that it folds and that its structure is the same as the normal. It turns out that variant position is actually commonly varied in the human population. There are 6, 7, 8 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 variant. So that shows you that the M variant is clearly functional and contributing to the total functionality we have. 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 -- using the serum from these patients, direct inhibition of human neutrophil elastase, very dramatic drop, very quick by this alpha-1 sort of mixture that we're creating. And so again, showing you it's clearly functional.

And I forget, have you disclosed the ratio between the variant and the wild type? Or is it...

It's comparable to what we see in preclinical models. So you see some amount of M and some amount of M variant.

Okay. Okay. 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 the higher is the alpha-1 at baseline, the higher is kind of the boost. And I appreciate at the end of the day, you need to have as many patients as you possibly can about this level micromolar. So can you enrich the study in some capacity to kind of stack the odds in your favor and try to maybe enroll or maybe exclude patients that have baseline level below certain thresholds? Or how should we think about that part?

I think -- yes, it's a great point. And I think you're probably thinking about this correctly. I don't know exactly how hard and fast to rule it is. But generally, my read of our data is that, yes, there is a spread. And it's true even at the baseline, Z patients live anywhere from 4 to 6 or 3 to 7, it's kind of a range. And if you were low on that range, then you get edited, you're probably low on the resulting range. And if you were high in that range, you're probably high in the resulting range. And that's just, I think, physiology, patient to patient. The key for us 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? Now could you game that? Yes, of course, you probably could. And we're certainly not excluding any patients on the basis of their AAT levels. So we take them all. I think, especially for small N 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. That's definitely important. Where we're at, we've now treated 29 patients total and counting. So your ability to play those games goes away with larger N. I mean we've already converged on what I would consider to be a typical average baseline, and we're going to treat another 50 patients, that will only continue to happen.

Got you. Got you. Super helpful. You guys came forward early this year about alignment with the FDA and a path to accelerated approval. Again, you guys have talked about biomarkers and maybe you haven't offered the specifics, but we can all think about like total alpha-1 and M and Z and the whole nine yards. How do you feel about that, especially in the context of the never-ending headlines around the FDA? Is your alignment? We've seen the companies obviously complaining about moving the goalposts and whatnot. How do you feel that the FDA is fully on board, everybody is 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 accelerated approval?

It's a great question, and it's something we're all obviously watching. I think that -- I think the outgoing leadership 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. 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 -- hopefully, that stabilizes, and I expect it will. I think the good news in a way for alpha-1, it's true of sickle as well is we're not doing anything unusual here. right? So we're -- so our alpha-1 path is not reliant on the plausible mechanism pathway, right? Nor I think hopefully, will I have to worry that somebody is 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 sickle program, by the way, very stable review team, and they're doing a great job, very constructive. So 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 approval 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. 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.

Got you. Got you. That's helpful. What's the -- I think one of the components here for the accelerated approval is like, yes, I'm going to drive level of alpha-1 above certain thresholds. However, there's a little bit of debate around augmentation therapy now with this data with Inhibrx and Sanofi, they 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 achieved. So I do feel that as you try to advocate for accelerated 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 endpoints that you're now doing? Obviously, biopsy will be invasive, as it will be difficult to enroll patients and whatnot, at least for now. But what are you measuring to actually prove in addition to emphysema type of potential benefits you also have a liver benefit?

Oh, for sure. So I think -- so first of all, on the Inhibrx program, so yes, they do achieve these high levels. Of course, as you know, 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 as good as it's going to be when you really need it when you're sick, right? So 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 equally, right, the Inhibrx is not a natural protein. It is an FC-bound set of AAT proteins. What is the bio-distribution 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 in some of these ways. All that said, then, yes, on the liver, we definitely believe there will be clinical benefit here as well. 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 been -- have tolerated the drug the same as Part A. 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. So -- but in the Part B, we are doing biopsies before and then 6 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.

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

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

And the primary point of that Takeda Arrowhead trial is biopsy, right? So it kind of makes sense. 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 payers appreciate the longer-term pharmaco-economic value of doing one and done or they will rather pay less for something that I got to pay for 1 year like I guess like because I'm assuming that you're going to ultimately price higher than what's the price of augmentation therapy for 1 year, given it's one and done. So like will the payers get it?

Yes. It's a great question. There's no question we will price higher than the 1 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 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 $5 million, $10 million given all the expensive medicines and the loss of productivity and of course, the hospitalizations. And even ICER, [ institute of cost-effectiveness ], which is a fairly conservative body said over $2 million price in sickle made sense. And as far as I know, there have been no reductions on price in the sickle market. So we're on speeding up authorizations and things like that. But ultimately, that's the 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 the lifetime cost for an alpha-1 patient can be anywhere from -- depending on their course, kind of the $4 million to $5 million to $8 million over time. So certainly, we think that's suggestive of 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 of what we're doing and the value to patients. And of course, relative to augmentation, we would have more sources of value as well, right, not just the one and done, but obviously the liver plus the lung, more of a deep resolution of the situation. So bottom line is, I think it's definitely a good value story, and we're very eager to bring it forward.

Got you. Super helpful. I know we're unfortunately almost out of time here. Maybe a quick update on sickle cell disease. Tell us what's next for this program. And then we've seen headlines from Tessera or other companies that are kind of working in vivo and there's a broader enthusiasm around in vivo more broadly in oncology, we're seeing a lot of transactions that went on there. So like I guess, give us an update on your ex vivo approach. And what's the latest thinking to pivot to in vivo?

For sure. So as our ex vivo, Risto-cel, 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 4 months, which means we can treat patients quickly and with high predictability. Part of that is base editing, part of it is 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 multibillion dollar a year opportunity to bring an exciting product forward, and that's what Risto-cel 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 getting the T cells pretty well. We think HSCs are coming. And now will it work as well as our ex vivo at first? We'll see, right? It just depends on the translation. I will say that with LNPs, remember, it matters what dose you're giving, right? So in preclinical studies, it's always important to see that they disclose the dose. And if they didn't, you have to sort of see how close to the finish line they really are. But I think it's going to happen. I mean we're quite active there, of course. We have the ex vivo capability of Risto-cel. But of course, Beam is also an LNP 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.

Got you. And on that note, I have a lot more questions but over 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, Luca.