Beam Therapeutics Inc Aktie

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.

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review top line clinical data from the Phase I/II trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency. You can access slides for today's call by going to the Investors section of our website, beamtx.com.

With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Jeff Teckman from St. Louis University; and Dr. Giuseppe Pino Ciaramella, our President.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date.

Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.

With that, I will turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. We believe base editing uniquely positions us to fulfill that vision through onetime durable genetic medicines that correct disease at its root cause while delivering predictable and reproducible outcomes.

One year ago, we established clinical proof of concept for our onetime in vivo base editing therapy BEAM-302 in alpha-1 antitrypsin deficiency or AATD, and accomplished an incredible milestone for the field of genetic medicine, delivering to our knowledge, the first ever genetic correction of a disease-causing mutation in DNA.

Today, we're excited to share a compelling and robust data set from 29 AATD patients treated with BEAM-302 in the ongoing Phase I/II study. These updated data further strengthen our belief in the best-in-class and first-in-class potential of this onetime therapy and pave the way for the advancement of BEAM-302 into pivotal development.

Beam was founded on a simple but powerful idea that making precise, single base changes in DNA could fundamentally change how we treat many serious genetic diseases. Base editing allows us to correct mutations without creating double-strand DNA breaks. Our goal is to translate that capability into onetime genetic medicines that durably and predictably restore normal gene function.

We believe that predictability is not just a scientific advantage. It's a strategic one. Predictable outcomes can streamline R&D, reduce development risk, support regulatory efficiency and ultimately build confidence among physicians, patients and payers. Over time, we believe that impact can ripple across the entire health care ecosystem. That same predictability also allows us to build a scalable platform for developing multiple genetic medicines.

Many of the core components of these therapies can be reused across programs, so that once we demonstrate success in one setting, we can apply those capabilities to additional diseases with greater efficiency. In that way, we're not simply advancing a single therapy. We're building a repeatable engine for developing multiple genetic medicines over time.

Our liver-targeted in vivo portfolio is a clear example of this platform in action. Now with 3 core programs that are in or nearing clinical development, BEAM-302 in AATD, the focus of today's discussion, as well as BEAM-301 for glycogen storage disease Ia and BEAM-304 for phenylketonuria, all leverage our LNP delivery capabilities, enabling us to apply the same core technologies across multiple programs and moving them forward efficiently through emerging regulatory pathways.

Today's data further underscores the strength of our industry-leading in vivo liver-targeted precision gene editing technology and our ability to efficiently and rapidly execute to advance to pivotal development for BEAM-302.

Before turning the call over to Amy to walk through the results in detail, I'd like to briefly highlight a few key takeaways from the data set we are reporting this morning.

First, treatment with BEAM-302 continues to demonstrate robust and durable efficacy with more patients at higher doses and longer follow-up. In the single-dose 60-milligram cohort where patients have follow-up out to 12 months, we observed meaningful increases in both total and functional AAT, achieving steady-state mean levels of 16 micromolar and once again, with all patients above the 11 micromolar protective threshold that is associated with lung health.

In addition, treatment resulted in substantial reductions of approximately 84% in mutant Z-AAT, the toxic protein responsible for the liver manifestations of the disease and that in circulation can also contribute to lung disease. Most importantly, these patients now produce corrected M-AAT for the first time as seen in a clear shift in circulating AAT protein composition to approximately 94% corrected M-AAT, consistent with correction of the underlying genetic mutation. All of these findings are consistent with AAT profiles seen in MZ genotype carriers, people who do not have severe AATD nor progressive disease and are not at elevated risk for lung or liver disease without secondary factors like smoking or obesity.

Second, we now have strong evidence that AAT production is inducible following BEAM-302 treatment during periods of inflammation when it is most needed as expected from BEAM-302's mechanism of action. In one patient, AAT levels increased to approximately 30 micromolar during a respiratory infection and critically retained the corrected AAT composition of approximately 95% M-AAT, suggesting the edited gene does indeed function under normal physiologic regulation following treatment with BEAM-302. This is the strongest induction result yet observed after a genetic treatment in AATD showing that treatment with BEAM-302, not only elevates basal AAT levels to a new floor similar to carrier levels, it further provides a dynamic capacity in the body to generate even more AAT whenever it is most needed. Restoring the AAT acute phase response in these treated patients offers a fundamentally different treatment profile from that seen with augmentation therapies and shows the power of precision-based editing to correct all aspects of this disease.

Third, BEAM-302 continues to demonstrate a well-tolerated safety profile across the single dose cohorts with Grade 1 transaminase elevations being the most common adverse event. Based on the strength of both the safety and efficacy data, we have selected 60 milligrams as the optimal biological dose for our pivotal cohort, which we plan to initiate in the second half of this year.

Taken together, we believe these findings reinforce the potential for BEAM-302 as a best-in-class and first-in-class onetime treatment for AATD.

With that, I'll turn the call over to Amy to go through these BEAM-302 findings in more detail.

Thanks, John. Alpha-1 antitrypsin deficiency, or AATD, is a serious genetic disorder caused by mutations in the SERPINA1 gene, which affects the production of alpha-1 antitrypsin, or AAT, a protein made in the liver that is secreted into the bloodstream to protect the lung from inflammation and damage.

The most common severe form of AATD results for mutations in the Z allele, known as PiZ, which is caused by a single G to A point mutation in the SERPINA1 gene. This results in the extraction of a pathogenic variance of AAT known as Z-AAT that misfolds and aggregates in the liver leading to liver damage and disease such as cirrhosis, and you'll hear more about this from Dr. Teckman shortly.

The Z-AAT made in the liver is poorly secreted into the circulation and less effective in inhibiting neutrophil elastase, leading to total circulating levels of AAT that are 10% to 15% of normal in homozygous PiZZ individuals. As a consequence, the lung is left unprotected from neutrophil elastases and other damaging proteases that can cause progressive lung destruction, resulting in early onset emphysema. So in this disease, it is caused by too much abnormal AAT that gets stuck in the liver and too little AAT that gets out in the circulation.

The current standard of care for AATD for patients with lung disease primarily consists of treatment for emphysema, such things as bronchodilators, inhaled steroids, oxygen therapy and with severe cases requiring lung transplantation.

The only approved treatment today, plasma-derived AAT or augmentation therapy requires weekly intravenous infusions to achieve static levels of AAT, lacking the natural upregulation of AAT, so important during infection and inflammatory processes such as respiratory infections.

While augmentation has been shown to slow lung disease progression, it does not stop it, nor does it prevent ongoing liver damage and has no impact on the Z-AAT aggregates in the liver or circulation.

Treatment for liver disease is limited to supportive care as there are currently no approved therapies. In severe cases, liver transplantation remains the only option. The PiZZ genotype accounts for over 95% of severe AATD cases. And despite affecting more than 100,000 individuals in the U.S., only about 10% of people living with this disease have been diagnosed.

As shown in Slide 12, clinical genetics provides critical information on a wide range of AAT levels and highlights why reaching the protective threshold of greater than 11 micromolar for AAT in circulation is critical for decreasing disease risk related to AATD. Patients with the severe PiZZ genotype have 2 copies of the disease-causing mutation, leading to a high risk of developing both emphysema and liver disease. These patients have very low levels of AAT between 3 to 7 micromolars shown in orange. All of their AAT is in the mutant Z-AAT form, which is much less effective and can form polymers in circulation, leading to lung inflammation and injury.

In the middle are individuals with just 1 mutant PiZ copy referred to as MZ or SZ individuals. And in this case, the majority of these individuals had AAT levels above 11 micromolar.

On the right-hand side of the slide, you can see how these genotypes correspond to lifetime risk for emphysema and liver disease. People with the PiZZ genotype are greater than 30x more likely to develop emphysema, and greater than 20x more likely to develop liver fibrosis or cirrhosis. Conversely, an SZ or MZ individual's risk is only marginally greater than a person with no mutation, and disease in these individuals requires the presence of additional risk factors, such as smoking or obesity.

These genotype characteristics are important as they help define what the critical goal posts are for efficacious AATD treatment. Any treatment that can achieve carrier range or better levels of AAT greater that 11 micromolar protective threshold along with further upregulation of the gene during inflammation would eliminate risk of progressive disease and would represent a functional cure of severe AATD.

Our base editor consists of 2 components, an mRNA encoding an adenine-based editor protein and a guide RNA that directs it to the precise location of a Z mutation in the SERPINA1 gene. Both are encapsulated in a lipid nanoparticle or LNP for delivery to the liver. Once in the liver cells or hepatocytes, the base editor precisely and directly corrects the misspelling, so it changes the A base into G base, converting the disease-causing PiZ mutation back to the normal functioning PiM form.

By correcting the root cause of AATD at the most proximal source, the DNA, we believe that BEAM-302 has the potential to deliver on the critical aspects of a onetime transformational genetic medicine.

First and foremost, our goal at BEAM-302 is to have a person make corrected and properly functioning M-AAT that gets into the circulation so that it is above the protective threshold of 11 micromolar, which as described earlier, is informed through genetics and was clinically accepted as the basis of augmentation approval.

Second, BEAM-302 aims to treat the full spectrum of AATD disease manifestations by significantly reducing mutant Z-AAT levels as much as possible to prevent aggregates in the liver and blood that can lead to ongoing organ damage.

Finally, AAT needs to be available in a dynamic manner, meaning that during periods of inflammation or infection, AAT levels need to be able to increase in order to combat lung destruction from unopposed proteases generated from inflammatory cells such as a neutrophil elastase protease. This is not possible with existing therapies like augmentation.

With those goals in mind, we designed a robust Phase I/II trial to assess early safety and efficacy of BEAM-302 and enable dose selection in patients across the spectrum of AATD.

The dose escalation base of the study is structured in 2 parts. Part A includes patients with lung disease to establish an understanding of the safety in patients without clinically evident liver disease, followed by Part B, which includes patients with mild-to-moderate liver disease with or without AATD-associated lung disease.

As of the February 10, 2026, data cutoff, we have treated a total of 29 patients across both Part A and Part B, representing a meaningful update from our proof-of-concept data last year where we presented data from 9 patients.

In Part A, we have completed a 15 mg cohort with 3 patients dosed for 12 to 18 months of follow-up, a 30 mg cohort with 3 patients, each with 12 months of follow-up, a 60 mg cohort with 6 patients followed for 5 to 12 months, a 75 mg cohort with 9 patients followed for 2 to 9 months and a multi-dose cohort evaluating 2 doses of 60 mg given 8 weeks apart, which included 3 patients followed for 84 days or 28 days after the second dose.

In Part B, we completed a 30 mg cohort with 3 patients followed for 4 to 5 months and dosed 2 patients in a 60 mg cohort. The first patient had 3 months of follow-up and the second patient was dosed after the February 10 data cut and is included in the safety data throughout the DLT period, but excluded from the efficacy data.

Turning to safety. Single-dose BEAM-302 demonstrated a well-tolerated safety profile at doses up to 75 mg. Importantly, the safety profile was consistent in patients across all single-dose Part A and Part B cohorts. In the 26 patients treated with single-dose BEAM-302 from 15 milligrams up to 75 milligrams, no serious adverse events, dose-limiting toxicities or Grade 3 or higher adverse events were observed. All treatment-emergent adverse events were mild to moderate.

Grade 1, asymptomatic transient elevations in ALT and AST were observed within the first 28 days in some patients. In addition, Grade 1 and Grade 2 infusion-related reactions were observed and all resolved within a day.

In the multi-dose cohort evaluating 2 doses of 60 milligrams in 3 patients, we observed a higher rate of events following the second dose of BEAM-302. One patient experienced Grade 4 ALT and Grade 3 AST increases within days of the second dose, which were asymptomatic and resolved without treatment.

The Grade 2 ALT increase occurred in another patient, which also resolved without treatment. No clinical signs of liver dysfunction or bilirubin increases were observed in any patient. Transient Grade 2 IRRs occurred in all patients.

Turning to efficacy. Treatment with BEAM-302 led to durable increases in total AAT into the MZ carrier range at single doses of 60 milligrams or greater. Here, we show steady-state mean total AAT levels by dose, which is the mean of each patients total AAT levels measured by an LC-MS assay from day 28 to the month 12 visit or until the patient's last visit is earlier than 12 months.

In the 60 mg cohort, where we have now just 6 patients with follow-up out to 12 months, we observed a steady-state total AAT mean of 16.1 micromolar. In addition, all patients consistently and durably demonstrated mean steady-state total AAT levels above the 11 micromolar protective threshold.

In the 75-milligram cohort with 9 patients and follow-up out to 9 months, we observed a steady-state total AAT mean of 14.4 micromolar. Increased total AAT in circulation was functional as demonstrated by a functional AAT assay based on neutrophil elastase inhibition.

The full change from baseline in total AAT was comparable between the 60 mg and 75 mg single dose cohorts, suggesting near saturation editing at doses greater than or equal to 60 mg.

BEAM-302 was designed to increase total AAT by inducing the expression of corrected M-AAT while at the same time, stopping the expression of mutant Z-AAT. As shown here, mutant Z-AAT was durably and significantly reduced by 80% at steady-state compared to baseline in the highest dose cohorts.

As a result, newly produced corrected M-AAT comprised the majority of total AATs in circulation with 94% M-AAT in the 16-mg cohort and 91% M-AAT in the 75 mg cohort. This exceeds the AAT profile seen in people with the MZ genotype with 80% M-AAT and 20% Z-AAT in circulation do not have disease unless there is a second injurious insult.

Moving to Part B, patients with AAT-related liver disease show similar efficacy trends as Part A patients without liver disease. In the 30 mg Part B cohort, 3 patients achieved a steady-state mean total AAT of 12.5 micromolar, of which 75% was newly produced M-AAT, representing a 51% reduction in mutant Z-AAT.

In the 60 mg Part B cohort, only 1 patient was efficacy evaluable at the time of the data cutoff. That patient achieved a steady-state mean total AAT of 17.2 micromolar and similar to the 60 mg part A cohort, 95% was newly produced M-AAT, driven by an 86% decrease in Z-AAT.

In the multi-dose cohort, we observed an efficacy profile consistent with a single-dose 60 mg cohort. The 3 multi-dose patients achieved a mean of 16.5 micromolar of total AAT at day 84, which was 28 days following the second dose of 60 mg of BEAM-302.

In addition, the mean Z-AAT reduction was 80% and the newly produced M-AAT was 93% of total AAT. Together, these early data suggest that a single dose of 60 mg BEAM-302 has achieved near saturation editing.

As I highlighted earlier, one of the goals of therapy with BEAM-302 is to restore the physiologic control of AAT during inflammation, which is when lungs require higher AAT levels to maintain protection against tissue-damaging proteases. Here, we show strong evidence of inducibility of AAT in a patient who experienced a respiratory infection roughly 8 months after treatment with BEAM-302. This patient was dosed with 60 milligrams of BEAM-302 in Part A and achieved steady-state mean total AAT of about 16 micromolar through month 6.

At an unscheduled visit around month 8, patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total AAT to approximately 30 micromolar. After the infection resolved, their total AAT levels trended back down along with their CRP values by their month 9 scheduled visit.

Importantly, the patient maintained consistent AAT composition of 94% M-AAT before, during and after the respiratory infection.

This case study shows clearly that there are 2 distinct assets at AAT protection offered by BEAM-302 treatment.

First, the achievement of a new basal AAT level above the protective threshold achieved within 28 days after treatment. Second, the ability to produce significantly more proactive M-AAT on demand during periods of inflammation or infection.

In summary, we are encouraged by these robust and comprehensive BEAM-302 clinical data now in 29 patients and follow-up out to 18 months. These data demonstrate that a single 60-milligram dose of BEAM-302 led to durable correction of a PiZ mutation, resulting in increases in total AAT to mean of 60 micromolar, above the therapeutic threshold of 11 micromolar and into the MZ range. Production of corrected functional M-AAT in circulation for the first time and significantly decreased mutant Z-AAT by approximately 80%.

Treatment with BEAM-302 enabled production of corrected and functional M-AAT that was under normal regulatory control as shown by the increase in AAT that occurred in response to inflammation in a patient with a respiratory tract infection, enabling the body to naturally regulate AAT as needed.

And importantly, BEAM-302 was well tolerated with an acceptable safety profile at all single doses tested to date in 26 patients. Based on the strength of safety and the efficacy profile of BEAM-302 in single-dose cohorts, 60 milligrams was chosen as the optimal biological dose for the pivotal trial, which we plan to initiate in the second half of this year.

Pino will provide more details about the next steps for pivotal development shortly. Taken together, we believe these data demonstrate the potential for BEAM-302 to be a transformative onetime treatment for AATD that could meaningfully impact both the lung and liver manifestations of the disease.

With that, I would like to turn the call over to Dr. Jeffrey Teckman. Dr. Teckman is a Professor of Pediatrics and Biochemistry at St. Louis University School of Medicine and a recognized world leader in alpha-1 antitrypsin deficiency. His over 30 years of research and clinical care has focused on the mechanisms of liver injury in AATD and improving the diagnosis and clinical management of patients across the disease spectrum. We're pleased to have him with us today to provide a clinical perspective on the disease, the needs of patients living with AATD today and how emerging genetic medicines could reshape the way this disease is treated in the future.

Dr. Teckman, over to you.

Thank you, Amy. It's a pleasure to be here. On a personal note, I've been working on alpha-1 antitrypsin deficiency for a long time. When I first started, we didn't even know how this disease worked in the liver, let alone, a concept that we would have cures on the horizon. And it's very exciting to see how much has happened. I think the question to first start with is why alpha-1 antitrypsin deficiency now?

There are a lot of conditions. There's a lot of interest in biologic treatments. Why this disease? Well, first of all, there's increased awareness in the liver disease and the hepatology field. There has been a lot of talk about "steatotic liver disease," our new word for fatty liver disease, steatotic liver disease. And there's a recognition that metabolic genetic liver disease like alpha-1 antitrypsin deficiency actually caused steatotic liver disease. And as more people with steatotic liver disease are being evaluated, there's more testing going on for specific causes like alpha antitrypsin deficiency.

The lung disease of alpha-1 is well known, but not -- the patients are not fully diagnosed. And the treatment options, while they exist are suboptimal, there is protein replacement as we'll talk about but it does not return people to wild type. It's very expensive and it's burdensome to patients.

What's also unique about alpha antitrypsin deficiency is the patient community is highly centralized. There is a very active foundation, the Alpha-1 Foundation. They have national meetings. They have a registry. They have a therapeutic development network, and they're a major mover in research and treatment and in lobbying for alpha antitrypsin deficiency. So these factors together really make this a great time to be developing treatments for alpha-1.

Next slide. So just as a background reminder, the alpha-1 gene, the SERPINA1 gene has hundreds of variants. M being the normal wild-type allele, which is MM is 96%, 98% of the population in the United States and Europe. The Z allele is by far responsible for 90% to 95% of disease. People sometimes also talk about the S allele, which is the intermediate disease allele, which also when present with Z especially, it could be related to disease. But really, the vast majority of disease are individuals who were ZZ.

Next slide. As you might recall, the liver disease in alpha-1 is a storage disease and the lung disease is a serum deficiency. That's why it's called alpha-1 antitrypsin deficiency because it was originally identified as a serum deficiency, but the liver has too much.

Next slide. So this is just a schematic of alpha-1 protein processing in the liver. On the left side, you see a normal wild-type MM individual. That's the endoplasmic reticulum of the hepatocyte, the little black wavy lines are nascent polypeptide chains of AAT protein, and it folds into its secretion-competent conformation. That's the little knot. And then it's secreted into the blood in huge quantities. So the adult liver makes 2 grams per day of alpha antitrypsin.

On the right side, a ZZ individual is still synthesizing the same number of nascent polypeptides, but they do not fold efficiently into the secretion-competent conformation. So only 15% of the peptides reach a secretion-competent conformation are secreted. The rest accumulate in the ER of the hepatocytes. Now most of those polypeptides are degraded by proteolysis pathways within the hepatocytes. But for reasons we're not totally sure, some accumulate and form these unusual, what we call polymers of protein, which are highly cytotoxic to the cell. And so again, you have the situation where the liver has too much, but the serum has too little.

Next slide. So these are photomicrographs of human ZZ liver. On the left side is H&E. On the right side is what we call Periodic Acid-Schiff with digestion or PAS with digestion. So the PAS stains glycogen and glycoproteins red purple and the digestion washes the stain out of glycogen. And so if you have an accumulation of glycoproteins in the cell, which is shown there by the inclusions, what we call globules. So that shows the accumulation. Sometimes those are what 100% made up of Z protein in the polymerized conformation. Sometimes those accumulations are larger than the nucleus. So it really is very toxic to the liver cell.

Next slide. So what's the risk of liver and lung disease? And it is complicated. So let me just walk you through the slide for a second. So if you look at the top and from left to right is the odds ratio, that's shown at the very bottom. And you see the line there on 1. So that's the same risk as MM individuals. So at the very top, you see MZ. And MZ individuals have a modest 1.7-ish odd ratio increase of liver disease and cirrhosis. We think of MZ being a genetic modifier of other liver diseases. Most of those people have other kinds of steatotic liver disease, NASH, other things like that.

The risk of lung disease in MZ, again, it shows there, it is between 1.5 and 2. But really, that's just smokers. Nonsmokers who are MZ appear to have no increased risk of lung disease. If you again, if you go down a little further on FZ, so the cirrhosis risk for lifetime for FZ might be odds ratio of 3 over MM individuals, so increased, and emphysema, again, between 1.5 and 2.

So at the bottom in ZZ, the risk of fibrosis cirrhosis lifetime, the odds ratio is more than 20%. So significantly increased over the general population. And likewise, with emphysema, somewhere between 30 and 40 odds ratio increased risk compared to MM individuals. So what's really interesting about the data is that we appear -- in this treatment, you appear to be able to make people at least MZ, if not better. So that would eliminate 95% of the risk, which is incredible and very exciting and something that we're anxious to see how it turns out with further study.

Next slide. So this just sort of says over time, over a lifetime, because what's interesting also about this disease is it affects different people, different ages differently. So on the vertical is the incidence of medically significant disease in the ZZ individual at a certain age and then you have age from left right across the bottom. So early in life, ZZ babies and children can develop liver disease. But it's only about 20% of ZZ individuals have enough disease to come to medical attention in childhood.

And then the risk of liver disease in young adulthood and new onset liver disease is very low, but it goes up later in adults and again, become significant as a lifelong risk.

With regard to lung disease, you do see an increased risk of childhood asthma but not emphysema in ZZ children. The lung disease really starts to become evident in the 30s and older. And then again, the lung function decline in alpha antitrypsin deficiency is greater than the MM individuals general population. No, not everyone has -- who's ZZ has accelerated lung function decline. But it is well known that it is higher. And really even if you're a nonsmoker.

Next slide. So I wanted to go back and touch on how the American Association of Liver Disease, AASLD, which is the worldwide leader in liver disease science. So just in the last couple of years, we've changed the way we look at "fatty liver disease." And it's not just a nomenclature change, but it's really a recognition change. So we call it steatotic liver disease overall. And this, again, is the official sort of scheme, which not only shows metabolic dysfunction associated with steatotic liver disease, so that's individuals with obesity, high lipids who then develop MASLD as well as alcohol, but it's also recognized that increasingly that monogenic diseases like alpha antitrypsin deficiency, you see in the red circle on the right, contributes to the steatotic liver disease group of patients.

And so this has really led to an increased focus on diagnosis because it's on clinical grounds to a hepatologist, just history, physical exam, basic lab tests, you can't differentiate alpha antitrypsin deficiency from MASLD or alcohol, you really need to test for it specifically. And that's being increasingly recognized, especially as treatments are rolled out, it's going to be tested for even more. And we've seen that in a lot of rare diseases where when there's no treatment, the testing is modest. But when new treatments are available, there's a huge spike in testing.

And we saw that actually in alpha antitrypsin deficiency in the late '80s and in the '90s when the protein replacement for the lung disease became available. There was a dramatic increase in diagnosis. And we went from just a few hundred people on replacement therapy to thousands and thousands on replacement therapy in just a decade as a result of more treatment.

Next slide. So as we said, the liver currently has no approved treatment to supportive care and liver transplant if liver failure becomes untreatable. And the lung disease does have the protein replacement, which is an intravenous product. It's fairly burdensome and it doesn't do anything for the liver, right, because the liver is a storage disease and the lung disease is a serum deficiency. So this really brings up how the patients are really ready for new treatment options.

And there seems to be significant interest among patients on IV replacement therapy to move to something more permanent such as a DNA-targeted treatment, which would be equal, if not better, to the protein replacement.

I think one of the key concepts which has been touched on is the alpha antitrypsin protein is an acute phase reactant. So it can increase 3 up to 5 fold in serum with inflammation. So -- and that seems to be very important in the pathology -- pathophysiology of preventing damage because if you get inflammation of the lung and pneumonia, then you make a lot more alpha antitrypsin to protect those tissues from injury. And that's part of the normal physiology. People on IV protein replacement don't infuse more when they're sick. They just have that same dose. So they don't get that boost.

And we see that in some of the data, that there is an acute phase reactant boost, which will probably be much more effective at protecting the lung. And not require weekly infusion. So there's -- there seem to be a lot of interest in patients for this kind of intervention.

Next slide. So again, just touching on the community, the Alpha-1 Foundation, their registry, their therapeutic development network, their funding of research and their support with government. I personally have been to the FDA a number of times as part of delegations from the Alpha-1 Foundation to discuss therapeutic development to discuss how these treatments should be evaluated and how important it is to treat both the liver and the lung. So these are very exciting developments. I think the community is going to be very excited about the data that we've been discussing. And I think we're very, very excited to see, not only improved treatment, but cures for this disease.

Next slide. So again, in summarizing our key takeaways, alpha antitrypsin deficiency has a wide range of presentations over a full lifetime, from infantile liver disease to emphysema in older adults. It's way underdiagnosed but increasingly being recognized, not only in lung disease, but also in liver disease as a result of increased focus on steatotic liver disease. There certainly is unmet need. Even though there are treatments, they're suboptimal. And these are very exciting developments. And we look forward to the next steps.

Thank you, Dr. Teckman. It's a pleasure to have you here with us today. As we disclosed in January, on the heels of significant regulatory engagement over the course of last year, we have reached alignment with the U.S. FDA on a potential accelerated approval pathway for BEAM-302.

To support the future BLA submission, we anticipate enrolling approximately 50 additional patients to be treated with BEAM-302 in an expansion of the ongoing Phase I/II study. The primary endpoint is expected to be based on AAT biomarkers evaluated over 12 months.

Continuing our track record for efficient and rapid execution, we're moving forward with multiple parallel efforts to maintain momentum in the ongoing Phase I/II trial in preparation for initiating the pivotal cohort, which we expect to do in the second half of 2026.

To start, now that we have selected 60 milligrams as our optimal biological dose, we plan to enroll additional patients in an expansion of Part A as well as continue to enroll patients in the 60-milligram cohort in Part B. This allows us to not only grow our safety database, but also to provide new sites in the U.S. with BEAM-302 experience prior to initiating the pivotal cohort.

At the same time, we're actively working to complete the pivotal protocol amendment. And recently, we completed site activation at multiple U.S. sites. This builds on our already extensive global site network spanning 12 sites and 6 countries.

At Beam, our commitment to lead in innovation for the AATD community extends far beyond one program. In addition to our focus on advancing BEAM-302 to patients as efficiently as possible, we continue internal R&D efforts for future life cycle management. We're also deeply involved in the advocacy and research communities and serve as a member of C-Path's CPA-1 consortium in collaboration with the FDA to accelerate AATD research by identifying clinical efficacy endpoints. And as a collaborator with Alpha-1 Foundation and Alpha-1 Europe alliance to educate about gene editing and obtain a critical input on clinical trial design and patient experience.

As we look ahead to the rest of the year, 2026 is shaping up to be a milestone-rich period for Beam, with multiple value-driven catalysts on the horizon across our growing clinical portfolio. First, we remain focused on advancing our lead programs, including progressing BEAM-302 towards pivotal development in the second half of this year, following the data that we shared today.

Second, we expect to continue advancing the pipeline with key development milestones across several programs that leverage the same platform capabilities.

And finally, we are doing this from a position of financial statement with a balance sheet that we believe supports the execution of our commercial, clinical and development plans over the coming years.

To close, at Beam, everything we do is driven by our commitment to patients. The promise of base editing is not just about innovation. It's about transforming lives and enabling people to live the lives that were meant to live. And we are deeply committed to our vision of developing onetime life-changing therapies for patients.

I'd like to thank the entire Beam team for their tireless efforts and exceptional teamwork in advancing this program from inception to today.

I'd also like to acknowledge that these findings today will not be possible, wherein not for the individuals whose lives we aim to change, people living with AATD.

We'd like to thank all of our partners, including the investigators, the clinical site staff, our clinical development and manufacturing partners, the Alpha-1 Foundation and other advocacy organizations around the world, and above all, each of the patients and caregivers who have taken part in our trials and made today possible.

Operator, please open the line for Q&A.

[Operator Instructions] Now first question in queue coming from the line of Cory Kasimov with Evercore ISI.

This is Adhi on for Cory. In the multi-dose cohort, how should we interpret the absorbed transaminase elevations? Are these events primarily a function of cumulative LNP exposure through repeat dosing? Or there is any residual concerns around the safety profile that could impact the future dosing strategies as well?

Yes. Thank you. Great question, and I'll pass that to Amy.

I think with one event such as that and the fact that it has very swift onset and a very rapid resolution along with some cytokine increases, we think it's likely driven by the inflammatory response to the second load lipids. However, given that I've mentioned, it's just a limited number of patients, we're not entirely sure. But I think what's important is the LFTs resolved very quickly back to normal, and there was no evidence, for example, that the patient had symptoms, required any intervention.

And in the end of the day, I think that this is something that we think we didn't see with the single dose, which is very reassuring. And we've now dosed, I want to remind people, 20 patients at the 60 mg and 75 mg doses with really just very consistent Grade 1 elevations in LFTs. And I also just want to note that seeing Grade 1 elevations of ALTs or even Grade 2 are not really predictive of more severe events in the future, such as things like DILI. So I think from that perspective, we feel very reassured at this point in time with our single-dose and our optimal biologic dose chosen of 60 mg times 1.

And our next question coming from the line of Maury Raycroft with Jefferies.

Congrats on the great data. Wondering if you can talk more about just explanations for why the AAT levels at 60 mg are higher than your last update, increasing from 12.4 to 16.1. Is it due to higher baseline AAT or dynamics with longer follow-up, maybe a combination of both.

And do you have a good understanding of the rate of AAT levels reaching steady-state after dosing. And do you think that could continue to improve with longer follow-up?

Sure. There's a lot in there. I mean I think maybe the first comment I'll make, and then I'll invite Amy to expand on it is, there's obviously a very significantly updated data set since last year. So we went from [ n of 3 to now n of 6 ] with much longer follow-up plus obviously expanding on the other dose areas as well.

So I think we commented last year, actually we felt that the few patients we had at 60 were probably a little on the low end and I think you've seen that sort of normalize here.

In terms of how the overall data set has matured, I mean, I think that we see a lot of stability in the levels that we're achieving and that is quite consistent with the mechanism of action of the drug.

Yes. I mean I do think that over time with more patients, we are seeing probably in the mean baselines that are more kind of what had been reported in the literature. So instead of having baselines of around 5, we're kind of up in the range of about 6 micromolar at this time. And I will say that once people hit day 28, they tend to kind of remain fairly stable from day 28, you can see all the way out now to as far as month 12.

What we don't know yet is will the people who are at the lower doses, let's say, the 15 or 30 mgs, which are not close to kind of editing saturation, will they continue to increase over time because of the potential theoretic survival advantage that the cells that have corrected M-AAT would have over those that still have Z-AAT.

But given the slow turnover in the liver of a T half-life of maybe 365 days, those drifts upwards over time in AAT levels may take a little time to see. In other words, 1 to 2 years, maybe kind of more along the line to what we need to see. But we're very pleased that we're seeing very strong steady-state levels and people maintaining those gains now in a durable manner.

Our next question coming from the line of Samantha Semenkow with Citi.

Congrats on all the great data and all the progress. I have a question for Dr. Teckman. Dr. Teckman, it would be great to just have your thoughts on what is most important here from an efficacy and safety standpoint in your view for a gene editing therapy specifically.

When you look at the emerging profile for BEAM-302, how compelling does that mean 16.1 micromolar in total AAT. There's a few other additional gene editing therapies in the pipeline, and I would love to get a sense on whether you think pushing that total AAT higher, if that's possible, would impact your view on the BEAM-302 profile as we see it thus far?

Dr. Teckman?

Yes, good question. And I think something that I've been thinking about and others have been thinking about. I mean certainly, there's some element of a continuum there. So more probably better. On the other hand, the curve of that line, it's not straight, right? I mean it's actually a curve. And as we talked about and at the level that we're seeing, it's at least MZ and that eliminates 95% of the risk. And plus, it's better than that because MZ people half the protein they're making is Z. And in this situation, we see that really almost everything in the liver at that dose is converted and then you have the acute phase reactant response preserved or restored.

So higher levels give some better protection? Possibly. But this seems pretty good. With regard to future treatment, hard to say, but this looks pretty exciting.

The -- it's commonly -- I mean we've discussed this at the FDA going back a decade, what should the target be and a lot of people have said, well, if you make people into carrier better that you've eliminated the vast majority of disease. So yes, I think it's pretty exciting.

Our next question in queue coming from the line of Eric Schmidt with Cantor Fitzgerald.

Some of the main values you've produced here are really impressive. So congrats on that. I guess I'm wondering if there are any patient-specific factors that either lead to better or lesser gene editing efficiencies or whether maybe there's limited variability?

And then as a follow-up, Pino mentioned that sites have already been activated in the Part C pivotal portion of the trial. I think some would probably claim that, that means the trial has already started, but what else are you guys waiting for to give us the green light on the go ahead there.

Sure. Maybe I'll take the first one and Pino can clarify on the second one. So I think the -- I don't think there's much to say yet on patient-specific factors. Generally, if anything, the results have been quite consistent across all types of patients and particularly now, not missing the point that the Part B and Part A patients, that's probably the biggest factor we were already controlling for in the trial, where a Part D patient has known significant liver burden. But as you've seen in the safety and efficacy of the 60-milligram dose has been comparable there, which is very exciting. So by and large, very consistent, frankly, across the full range of spectrum of patients in this disease. Pino, in terms of the site network and then the path to getting the trial open.

Yes. I invite Amy to comment as well. But fundamentally, we've made a protocol change, and we're in the process of the IRBs and the sites to review that and to improve it. Obviously, we submitted that to the FDA as well. And they don't necessarily need to provide the input, but it's obviously always helpful to provide a little bit of time for them to comment if they choose to do so.

So fundamentally, it's just the process of activating all the sites, making sure that we review this, we get the approval. In the meantime, we are continuing, as I mentioned, some additional Part A treatment as well as Part B, and I think that will provide basically almost like the training ground, if you will, for some of the U.S. sites. So they will be ready for the pivotal trial. Amy, anything else that I may have missed.

Yes. Just to clarify, just so people know the footprint that we're using is global, and that footprint is the exact same footprint we've used for the Phase I/II study. So when we talk about site activation for the pivotal, these sites have already been open for the Phase I/II study and now we'll just wind up conducting the pivotal with, as Pino mentioned, an amended protocol.

And so the good news there is a lot of these sites have already had experienced dosing people, kind of figuring out how to do the study, and this allows us to move superfast because we don't have to then go to new sites that haven't been familiar with BEAM-302 or that then we have to wait for sites to come on board and contract, et cetera. So I think we're going to be able to move very fast using our existing global site network.

Our next question coming from the line of Brian Cheng with JPMorgan.

Can you tell us a little bit more about how the additional 50 patients will be split across the lung and liver phenotypes in the expansion portion? And we know there's also a change in the way how you analyze total AAT here. Previously, you used turbidimetry and then here you use mass spec. Just curious if there's any potential influence in how we interpret total AAT levels.

So to answer your first question, I believe you wanted to know how the breakdown would be in the pivotal study for patients. And in that study, what we're requiring is that everybody have evidence of emphysema. So they don't necessarily have to have abnormal pulmonary function test, but they have to have at least CT scans and emphysema. They do not have to have liver disease, but they can have liver disease. And so what we're hoping here is we now have a pivotal cohort that is a spectrum of disease. So those with lung disease with and without as well liver disease.

So it won't be divided into a Part A, B or altogether. And we feel that our studies that we've done in Part A and B really assure us, to John's point, that the safety and efficacy should be the same, whether or not you have liver disease.

To get to the second point, we are using LC-MS because it's the preferred assay by the FDA to assess total AAT in circulation and enables us to test the AAT composition. So with turbidimetry, you can only just look at AAT. But with LC-MS, we can look at this composition of M-AAT, Z-AAT. And that's very important because it's not just the total AAT matters, but what is it made of?

And so from that perspective, that's why we're switching to this. Now in general, the values tend to be similar. But again, you would have to have each assay compared to each other. It's not enough to say like our LC-MS assay versus turbidimetry done at another hospital. So we have our own validated assays, and we tend to do our assay side by side, and turbidimetry will have a role because it's a very quick turnaround time. So we need that for things like eligibility and other things. But as far as endpoints go, it's going to all be LC-MS based.

Our next question coming from the line of Yanan Zhu with Wells Fargo Securities.

Congrats on the data. So I have a question for the doctor and a very quick follow-up regarding an earlier question for the company.

For the doctor, could you talk about what proportion of your AATD patients are candidates for this gene editing treatment? And how many of them do you think would be interested in proceeding if you prescribe?

For the company, the quick follow-up is on the Grade 4 liver enzyme question asked earlier. I was wondering, can you talk about the time course of this event? And how is it similar or different from the other Grade 4 liver enzyme elevations seen by gene editing peers?

Great. I'll start out. This is Jeff Teckman. Yes, I think there would be a lot of interest from patients. I think that like with a lot of new therapies, the use would expand over time. Most alpha-1 patients come to medical attention because of lung disease, at least in the past. And so there's a significant group of lung disease diagnosed patients. And as we said, there is treatment with protein replacement, but it's suboptimal and a lot of lung physicians don't even use it.

I talked to a patient last week who probably would benefit from it, but his doctor told them not to be on it because he didn't like it or something. So I think a new thing that's not going to be weekly infusions and burdensome, but is really going to return people to an excellent defense of the lung, I think people will be very interested in that. And I think there will be interest in people, especially as time goes on and it becomes more established, be interested in people from switching from infusions over to a one and done that really would be superior, at least that's our initial impression of the data.

With regard to the liver, I think that it's extensive and would -- more study would help us understand the impact. But there are a lot of people who are going to be diagnosed more frequently coming up. And again, if we have something to offer them, that is going to be powerful, and it's going to drive diagnosis.

I mean speaking to the liver doctor, I mean, we test just as an example, for Wilson's disease all the time, even though Wilson's is 10x more rare than alpha antitrypsin deficiency, but it has a treatment and if you can give it to people and save their life. So we send billions of Wilson's treatments for the 1 out of 1,000 that comes back positive. In this case, there will be way more people with alpha-1 that we would identify and then bring the treatment to bear. So I think it's patients, especially over time, as we establish better data, are going to be very interested.

In answer to the second part of the question about the time course for the Grade 4 LT elevation, this is very rapid. The LFT started to increase within 2 days. They probably peaked within 5 to 7 days and were within normal limits even by the next visit at month 4. And so this is a very rapid up-down. And as mentioned, the patients had no symptoms, was followed as an outpatient. There were no changes in bilirubin. And so again, I think this time course is more consistent with what one might see and what has been seen before with LNP dosing.

You asked about contrasting it a little bit to what's been seen, and I think you're referring to the Intellia data with some Grade 4 elevations. And from what we can tell from what's out in the public domain, it seems like those are occurring later in time and being picked up about 1 month post dosing or so. And so I think this is quite distinct from that.

I will point out as well that, as you can imagine, there's been no impact to efficacy either. So we don't think this is something that's like an antibody-mediated type of thing. We think this is more of a response by the body that you might see when you got a lipid load like after a COVID vaccine, et cetera, so more of an inflammatory response that's transient.

Our next question coming from the line of Mani Foroohar with Leerink Partners.

A couple of quick ones. One, we've seen a lot of dynamism in response to inflammatory insults, at least one patient you presented today. How should we think about what that might imply in terms of functional outcomes and clinical profile in a larger, longer pivotal study? And then I have a quick follow-up.

Well, I think -- I mean, just to clarify the question, I think -- I mean, clearly, we do think this is a dynamic mechanism. The gene is quite dynamic. It's one of the central parts of the acute phase response to inflammation. And I think you actually said it well in the question. I think we think it's a fundamental part of the value proposition of the mechanism of action of this drug to, I think as we said, not only get you to a new floor, but have you be able to respond over time.

We will know when there is an induction event because we're also monitoring CRP, right? So we're looking at inflammation in real time. So you can tell the difference between a patient who's giving you the read on their new basal level over the long term, which gives you a sense of what the levels have been changed to after therapy versus when someone is having an inflammatory event and the spike that happens as a result of that.

Maybe just one point of clarification. The 16 micromolar steady-state level importantly does not include the 30 micromolar spike that has been seen. So just to give you a sense, that 16 is really very much basal, a steady-state level measured over several months without incorporating the acute response.

Our next question coming from the line of Michael Yee with UBS.

This is Matt on for Mike. I wanted to ask one for the doctor, maybe an add-on to a prior question. And could you just talk about how you use IV augmentation therapy now, what the weekly burden looks like for patients. And I'm curious whether new or longer-acting recombinant augmentation could change that? And then just overall, how does that compare to a onetime therapy like gene editing from a patient perspective?

Sure. So I'll just say, I'm a liver doctor. I'm very familiar with the lung disease. So I don't prescribe -- personally prescribe protein replacement for alpha-1, but I'm very, very familiar with it. The -- until recently, it's all purified from human plasma. And yes, people have to have IV started or they have to get a port and it's disruptive to travel and things that people want to do. And again, I wouldn't underestimate what the problems with the therapy are.

Like I said, it helps people, but it doesn't return people to wild type and such that many people in the pulmonary field don't use it because they don't feel that the risk-benefit and cost ratio is even worth it. I don't agree with that, but that is a strong opinion among lung doctors -- some lung doctors.

With regard to the recombinant or long-acting, that might actually be a bad thing because as we've said, when you're sick, you need more alpha-1. It gets used up. So we didn't really talk about this the actual physiology. But -- so when alpha-1 antitrypsin protein does its job, which is to inactivate neutrophil proteases. So when neutrophils are moving through tissue as part of their attack against bacteria, they use proteases to open the pathways in the tissue. And alpha-1 is present in the fluid between cells and in serum to inactivate that so that, that effect doesn't spread as well as when neutrophils phagocytose, and there's some leakage of proteases. So again, alpha-1 is there so that it protects. So when you have an active infection, you use up and when alpha antitrypsin protein, its mechanism is it binds -- it's a suicide binding to a molecule of neutrophil elastase, for example, or other neutrophil proteases.

So you use it up. So if you have the long-acting, I mean, it's great that it has a long half-life in circulation. But if you get -- if you're getting infusions once a month instead of once a week and then you get an infection, your next infusions is for 3 weeks, you're suddenly unprotected because you used up all the alpha-1 that you've got.

So the acute phase reactant response and restoring that theoretically would be a major advance in lung protection. Again, we have to see the data. But I mean, people have thought about this and hoped that there was something that would restore the acute phase response in this disease for a long, long time.

And there are even people who are on protein replacement, who in the past, especially would hoard it and then try to infuse more when they were sick because they felt like they -- when they got sick that they had a step down in their lung function. So I think this is important, and I don't think the long-acting replacement is going to nearly match at least if these results are borne out, the infusion is not going to be as good.

And our next question coming from the line of Luca Issi with RBC.

Congrats on the progress here. Maybe, John, kind of high level, any quick thoughts on the competitive landscape here? I'm wondering what was your reaction to GSK return the rights to Wave. But maybe on the other side, also your thoughts on YolTech which I believe in China showed more than 20 micromolar of total protein, I believe it just 45 milligrams. So any thoughts there, much appreciated.

And then maybe super quickly, Giuseppe, on the regulatory side. Again, I appreciate there's a path here for accelerated approval on AAT biomarkers. But what's the bar here that the FDA is looking for? Do you need to show all patients above 11 micromolar? Do you need to show a specific ratio between MN Z? Like any additional color on what the FDA is looking for here, much appreciated.

Yes. Thanks for the question. So I'll take the competitive one as you noted. So we think we're in a very strong position. This is going to be a huge indication. We have a very clear first-mover advantage. We're now up to almost 30 patients and moving directly into a pivotal trial now with alignment on the FDA for the path to market. So that puts us several years ahead of everyone else.

There obviously will be more players, as you noted. I think the RNA editing field, I think we await more data to see if those agents can produce the kind of profile we're seeing here.

I think we clearly believe that this will be a best-in-class relative to that, but look forward to seeing more. And then for future DNA editing agents, obviously, I mean, YolTech, a couple of patients reported in China. We have to wait for more there, only one of which was at the level you described. Other DNA agents moving into the clinic over the course of this year, we would probably get some data in a year or so. I think we have a very strong lead over them. I think the most important thing is the fact that as Dr. Teckman was commenting on the risk levels, we think we've done what we needed to do to get rid of the risk of disease. So it doesn't clearly, to me, leave any room for a lot of improvement that would be detectable in any kind of reasonable clinical experiment you can do.

I mean I think we've -- that's the whole point of getting the carrier here is unless someone is a smoker or something like that, you're not going to see any progression in the disease whether you're -- where we are now or anywhere else that people can try to get to.

So bottom line, I think it puts us in a very strong position. The other thing competitors talk a lot about, as you know, is bystander editing and variant. I think we are very confident, as we've shown before in our preclinical data that the variant acts completely normally relative to the normal protein. And I think we have a lot more data now in the clinic building up that we can share over time. So that, I think, will also not be a source of competitive advantage over time.

In terms of the pivotal cohort, maybe I'll pass that one to Pino to address.

Yes. Look, in terms of what is approvable, there is no real sort of hurdle specifically in terms of the levels or MZ ratio that the FDA requires, certainly not expressed to us.

I think the way we handle the conversation with the FDA, we shared the data that we shared with you in last year. And basically, we asked the question, if you saw this in the pivotal trial, will this be approvable? And the answer is yes.

So the data that you see today is very consistent with that, and we do believe that there is approval. Obviously, in the pivotal trial, we will need to see consistent sort of responses to this data. And if we do so, we do believe that, that is approval.

Our next question coming from the line of Alec Stranahan with Bank of America.

This is Matthew on for Alec. Congrats on the data.

First one from us, I guess, just curious the percentage of bystander or passenger edits. Is it similar to the previous update at 60 milligrams and sort of how do those pan out at 75 milligrams in the multi-dose cohort?

And then maybe a quick one, double-clicking. Curious whether you're seeing those with higher AAT at baseline have more pronounced increases in total AAT or the proportion. Just trying to dig in there a bit.

Yes, maybe I'll handle that. So I think, again, nothing different clinically than we've seen preclinically in terms of the editing profile and the outcomes. And that's true at 60, 75 and multi-dose 60. So again, those are all quite comparable.

And then just your -- I guess, your question about baseline and just sort of patients higher or lower baseline. We do think that, that's probably physiology, right, that a patient who lives at the high end of maybe their baseline is going to be a higher outcome after editing versus low and low. But it's very small end, so you'll obviously be learning more over time about those nuances.

Next question in queue coming from the line of Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. We'll add our congrats. Just curious, are there -- has there been any discussion with regulators in terms of wanting to see an acute phase response in the pivotal? Will there be any endpoints related to that?

And then I guess, at this point, are there any more conversations that need to be had with the FDA? Or did they have all the feedback in terms of getting the pivotal started?

Yes, I'll take that. The answer to your second question is, no, we don't need to have any further interactions. I think we have clarity on what it takes to do the pivotal trial and what would be acceptable. And there was no specific conversations around needing to see an acute response in pal. However, we'll keep on monitoring, and we do believe that on average, we're expecting to see that just by virtue of the fact that people are exposed to various infections and so on. So we think it will be part of that data set, but it's not a specific requirement.

Our next question coming from the line of Myles Minter with William Blair.

Congrats on the data. My question is actually for Dr. Teckman. I was just wondering whether you're aware of the SPARTA trial that's going to read out at the end of the year for a double dose of AAT augmentation therapy. I know it's measuring lung function and liver with a doctor. I understand that.

But if that did show functional superiority with higher dose, does that move the 11 micromolar sort of bar that we're looking for, for efficacy associated with serum AAT levels that's the target here. Just curious if your thoughts there.

Right. So you're referring to the double-dose trial, which has been going on for a while. So yes, this is the -- the dose of augmentation -- protein augmentation therapy was arrived at almost 40 years ago. And the reasoning behind that has sort of been reworked and the thought -- part of the thought behind why augmentation doesn't return people to wild-type is that the dose is too low.

And also, when you talk about the dose and the levels reached, people are -- obviously, you give it and it goes down over time until the next infusion, right? So it was natural to somebody finally do a higher dose. It's hard to get payers at this point to pay for higher dose or double dose.

I think there has been some preliminary evidence that released from those trials, which might probably better, but it doesn't return the acute phase reactant thing. So I think there's more to do there. There's still the infusion burden. Infusion would be longer, it would be more expensive.

And the other thing we really didn't touch on so much is that there is this data and idea that the Z protein polymers are actually damaging to the lung. So in the liver, it's definitely a storage disease. There is evidence that there's polymer deposition in the periphery in blood vessels and in the lung. And there's evidence that these little polymers are chemotactic for neutrophils and alpha-1 emphysema is known to be more neutrophilic than the usual emphysema. So there's some evidence that this actually is a thing.

So getting rid of the circulating Z, 95% as was shown, that might also help the lung as well. And of course, protein replacement doesn't do that. So I think the protein placement has helped some people over the last 40 years, but I think it's ready to be replaced by better things. I don't think it's going to continue on with some of these new treatments, which are going to be so much better.

Our last question will come from the line of Patrick Trucchio with H.C. Wainwright.

This is Annabel on for Patrick. Congrats on the data. I guess I was wondering if you could comment on what drove the numerically lower AAT, the 14.4 versus 16.1 micromolar at the 75 versus 60-milligram cohort? And what drove the lower number instead of just a plateau? And then on the side of near saturation editing at 60 milligrams, do you have any direct measurement of editing efficiency in the liver? Or is this inferred from circulating protein biomarkers?

So I'll close with that here. So I think the -- on the latter, it's all inferred. We don't have editing rates yet. We'll pick that up over time with biopsies. But I wouldn't read too much into the 14.4 versus 16.1.

I think that if you look at the aggregate AAT levels across 60, 75 and the multi-dose 60, you look at the percent M we're all in that sort of low 90s, 90, 95. You look at the Z reduction, we think that those are more comparable than not, and they certainly overlap statistic significantly. So I don't think we're picking up any real signal there. Most likely, obviously, with more follow-up, we'll learn more over time.

And I will now turn the call back over to Mr. John Evans for closing comments.

Thank you very much. So yes, I want to thank you all for your time. It's an exciting day. We're so pleased to see this continue to mature and really looking forward to partnering with the community to getting this to patients as quickly as we can. I want to thank Dr. Teckman for joining us and for the great and insightful commentary and help along the way, and we look forward to sharing more of this with you as this moves forward. Thank you very much.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Beam's Conference Call to review updates announced this morning in conjunction with our fourth quarter and year-end 2025 financial results. You can access slides for today's call by going to the Investors section of our website, beamtx.com.

With me on the call today, with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Gopi Shanker, our Chief Scientific Officer; Sravan Emany, our Chief Financial Officer; and Dr. Kiran Musunuru from the University of Pennsylvania. Our President, Dr. Guiseppe Pino Ciaramella, will join for Q&A.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change. With that, I'll turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is straightforward, but ambitious: to provide lifelong cures for patients suffering from serious diseases. We believe base editing has the potential to deliver on that vision through onetime durable genetic medicines with predictable and reproducible outcomes. Today, we're excited to share several important updates that bring us closer to accomplishing this mission. First, leveraging our platform to bring forward a new and innovative development program to address a serious genetic disease, phenylketonuria, or PKU, and second, further solidifying our balance sheet to support the anticipated commercialization of a potentially transformative onetime base editing therapy for sickle cell disease.

Beam was founded on a simple concept: aimed at rewriting broken genes back to normal. Base editing is a next-generation form of CRISPR that allows us to make precise single base changes, resulting in predictable edits without the need to make double-stranded breaks in DNA. With consistent gene sequence outcomes conferring potentially lifelong benefit, base editing enables predictable, reproducible outcomes for patients. This scientific foundation underpins everything we do.

Predictability is a theme you'll hear throughout today's discussion. We believe it is a powerful driver of progress, not just for patients, but across the broader health care ecosystem. Predictable outcomes can streamline R&D, reduce development risk, accelerate regulatory pathways and ultimately improve confidence and deliver value for physicians, patients and payers alike.

Base editing is a highly modular and scalable technology. This means that the core elements of our therapies can be reused again and again. And once they are proven to work the first time, we expect to have a higher probability of technical success as we expand to other genes and other diseases over time. So the power of predictability is built into our business from the start. This is not a one-asset story. It is a repeatable, reproducible model. And as you'll see today, we are now applying that model across a growing pipeline. One of the clearest examples of this platform in action is our liver-targeted portfolio. We have built leading lipid nanoparticle or LNP capabilities to enable efficient in vivo delivery to the liver that can be leveraged for multiple programs, allowing us to move faster with each successive candidate. We're excited to share today that we're expanding this franchise with an innovative new development program for PKU called BEAM-304. BEAM-304 exemplifies how we can leverage base editing to directly correct not just one but multiple disease-causing mutations over time. PKU represents an important strategic expansion of our portfolio and an ideal application of our platform. To start, we have the technology and expertise that positions us well to address this condition. PKU is often caused by a single-point mutation in the phenylalanine hydroxylase, or PAH gene, exactly the type of error base editing is designed to correct. PAH is primarily expressed in hepatocytes, making it highly addressable through LNP delivery, which is an area where we have an industry-leading expertise. There also remains significant unmet need despite available therapies in a large population of approximately 20,000 individuals in the U.S. and many more around the world. As Gopi will describe in a moment, our initial focus will be on targeting the 2 most common mutations found in almost half of patients with PKU. In addition, taking advantage of novel and emerging regulatory pathways, we believe our innovative development approach gives us the potential to address mutations found in a majority of PKU patients over time. Blood phenylalanine or Phe reduction has been accepted as an endpoint for full approval in both the U.S. and Europe, providing an attractive opportunity for both early clinical proof-of-concept and an expedited path to market. Taken together, PKU is a compelling opportunity to demonstrate the scalability of our platform and to deliver potentially transformative therapeutic options to patients.

With that overview, I'll now turn the call over to Amy to provide additional context on the clinical manifestations of PKU and current standard of care.

Thank you, John. PKU is an inherited autosomal recessive metabolic disorder caused by mutations in the PAH gene, which results in the loss of PAH activity, failure to metabolize or break down phenylalanine, referred to as Phe, leading to elevated Phe levels in the blood, which can cause neurotoxicity. In the United States, PKU is typically identified at birth through the federally mandated newborn screening program, and genotyping of these patients is increasingly common as it can guide therapy. As shown in the large arrow, the severity of PKU depends on the amount of residual PAH enzyme function an individual has, which determines their pretreatment Phe levels that can range from 360 to 1,200 micromolar, with classifications ranging from hyperphenylalaninemia to mild, moderate or classic or severe PKU. Guidelines in the United States recommend patients maintain Phe levels below 360 micromolar across their lifetime. But as I'll show on the next slide, many patients struggle with uncontrolled disease, particularly as they age.

People living with PKU can face a significant impact on their health and quality of life as very elevated Phe can have serious neurologic and cognitive consequences. In children, very elevated Phe can result in impaired brain development, intellectual disability and seizures, with some of these manifestations being irreversible. In adolescents and adulthood, where adherence decreases dramatically and many patients are lost to follow-up, increased Phe can also have detrimental health consequences, such as cognitive impairment, headaches, anxiety and depression.

As you can see in the chart on the right, the majority of pediatric patients are within the recommended blood Phe levels of less than 360 micromolar up until about the age of 12. But this percentage steadily decreases with age and as adult, only about 25% of patients remain under control.

For pregnant women, strict control prior to conception and during pregnancy is required to prevent maternal PKU syndrome, which can result in severe irreversible fetal harm such as microcephaly and congenital heart defects. There remains a significant unmet need for new treatment options to address PKU that offer better control of Phe levels and that are less burdensome to patients and their families. Phe exists in most foods, including meat, dairy, grains, vegetables and fruits. Thus, people living with PKU must follow a severely restricted diet limiting protein intake from foods to only 5 to 10 grams per day, which, as you can see from the chart on the right, would mean 1 egg and a slice of bread. Instead, they require medical food without Phe, shown in the lower right-hand panel, to get their needed protein. Medical food is often poorly tolerated and very expensive. Patients with more mild disease and some residual PAH enzyme activity are able to take BH4, a cofactor used to stimulate the PAH enzyme to reduce their elevated Phe levels. However, people living with more moderate to severe disease would require enzyme replacement therapy to decrease their Phe to reach target. This type of therapy must be administered as a daily subcutaneous injection, and it often takes at least 1 to 2 years for patients to achieve target levels. Overall, this occurs in only about 60% of the patients. In addition, it requires frequent labs to adjust treatment based on diet and Phe levels and the discontinuation rate is high due to immune reactions and hypersensitivity. While these treatments help manage the disease, they are not curative and impose significant burden on the patients, leading to diminished quality of life and compliance. To guide our development strategy in PKU, we have anchored our target product profile to establish regulatory precedents, the literature, including the updated ACMG clinical guidelines for PKU diagnosis and management and direct feedback from clinicians treating this disease.

Importantly, the regulatory precedent in PKU is well established. Blood Phe reduction has been accepted as a surrogate endpoint for full approval in both the U.S. and EU. Within this context, a successful gene therapy would be expected to achieve significant and sustained Phe reduction below 360 micromolar, be well tolerated, enable normalization of diet, enabling people to get off of medical foods, which really has the potential to meaningfully improve quality of life. Ideally, this therapy would be delivered as a onetime treatment. These elements define the target product profile we are pursuing with BEAM-304.

I will now hand the call over to Gopi to discuss our base editing approach and early preclinical data demonstrating what's possible with BEAM-304.

Thank you, Amy. As John said earlier, PKU is an ideal expansion of Beam's genetic medicines pipeline and application of our platform technology. I'm excited to share the incredible rapid progress that has led us to the cusp of clinical development today.

In the United States, there are approximately 20,000 people living with PKU. To date, we have already identified 2 development candidates within our BEAM-304 program, targeting the 2 most prevalent PKU mutations, including R408W, which is the most prevalent. Together, these candidates have the potential to treat nearly half of PKU patients, and we have active research efforts to address additional pathogenic PKU mutations over time, covering a majority of all PKU patients. We plan to utilize an innovative development approach in which multiple mutation-specific base editors are developed within a single clinical program. With this approach, we believe that Beam has the potential to create a scalable path to get transformative therapies to the majority of patients with PKU as efficiently as possible.

BEAM-304 leverages our proprietary and clinically validated base editing technology together with our internally discovered and optimized LNP delivery system to precisely target hepatocytes in the liver and directly correct the disease-causing mutations. This technology is adaptable, utilizing a unique guide RNA for each mutation, while the rest of the components of the therapy can stay largely consistent. The advantages of LNPs as a delivery mechanism for liver genetic diseases are multiple. They can be dosed in an outpatient setting by an intravenous infusion. They are titratable and redoseable if necessary, and benefit from a synthetic and highly scalable manufacturing process. Once optimized, LNPs provide a predictable and reproducible platform for both tolerability and dose projection. LNPs also offer a more manageable cost of goods. At Beam, we have built significant expertise in LNP optimization of both internally developed and externally sourced lipids and have internal GMP capabilities to manufacture at scale in our North Carolina facility.

The BEAM-304 program builds on foundational work conducted in collaboration with Dr. Kiran Musunuru's lab at the University of Pennsylvania, which first established preclinical proof-of-concept for base editing in PKU. After adding our in-house capabilities in base editing and delivery, we have now advanced BEAM-304 to IND-enabling activities in less than just 2 years. We are pleased to have Dr. Musunuru here with us today to discuss this work as well as his pioneering work on the development of customized genetic medicines for rare diseases.

This slide highlights the preclinical data supporting BEAM-304, which demonstrate the potential of base editing to correct underlying PKU mutations and rapidly normalize plasma Phe levels. On the left, you see results from a mouse model carrying the R408W mutation. And on the right, data from a second prevalent mutation, which we refer to here as mutation B. Following a single dose of BEAM-304 at 0.3 milligrams per kilogram, we observed a rapid reduction in plasma Phe levels by day 7. In both models, plasma Phe levels were reduced below the therapeutic threshold, effectively normalizing levels in animals consuming an unrestricted standard protein-containing diet. These reductions were accompanied by robust on-target editing in the liver, consistent with correction of the underlying PAH mutation.

Here, we show the dose response relationship between on-target editing and plasma Phe reduction. As dose increases, editing in the liver rose in a predictable manner with even relatively low levels of editing sufficient to drive Phe below the therapeutic threshold. We are eager to advance BEAM-304 into the clinic and have already completed productive pre-IND interactions with the FDA.

Structured similarly to our BEAM-302 and BEAM-301 clinical programs, the planned Phase I/II study will be an open-label, single ascending dose trial initially in PKU patients with the R408W mutation. The study is designed to achieve early clinical proof-of-concept of plasma Phe reduction, establishing a potential path to market and laying the foundation for expansion of the program to additional mutations. Key endpoints will include safety, tolerability and reduction of blood Phe concentration. We expect to file the IND for BEAM-304 in 2026 following completion of pre-IND activities.

As we've laid out here today, our goal is to develop a onetime treatment for as many PKU patients as possible. Our underlying technology, manufacturing process, clinical learnings, regulatory path and commercial infrastructure for R408W will directly inform and support an efficient path forward for additional mutation-specific editors. In addition, our work in PKU builds upon our growing expertise in metabolic disease, along with our experience in GSDIa and has the potential to enable continued expansion into other metabolic disorders.

With that, I'd like to formally introduce Dr. Kiran Musunuru. Dr. Musunuru is a Professor of Cardiovascular Medicine, Genetics and Pediatrics at the Perelman School of Medicine and the University of Pennsylvania, and was recently appointed as the Co-Director of the Penn Orphan Disease Center. A practicing cardiologist and geneticist, his research focuses on genetics and genomics of cardiovascular and metabolic diseases with a particular emphasis on developing gene editing therapies. Dr. Musunuru is widely recognized as a leader in applying CRISPR and other genome editing technologies to prevent and treat heart disease. He also played a central role in the development of world's first personalized base editing therapy to treat an infant known as baby KJ, marking a landmark advance in precision medicine for ultra-rare genetic diseases.

Over to you, Kiran.

It's a real pleasure to have the chance to speak to you today. I've been working with my friend and colleague, Dr. Rebecca Ahrens-Nicklas at the Children's Hospital of Philadelphia, or CHOP, for several years now to develop personalized gene editing treatments for a variety of inborn errors of metabolism, including PKU. I should start by emphasizing the poor metabolic control achieved in patients with PKU under the current standard of care, even at an academic medical center where patients are receiving specialized care from a team of metabolic physicians. We looked at data from patients with PKU treated at CHOP, specifically all individuals with at least one copy of the PAH R408W variant, which is the most frequent variant causing classic PKU, that is severe PKU. We found that the majority of patients had at least a single Phe measurement above the recommended safety zone indicated here by the dotted line, 360 micromoles per liter. About 30% of patients had lifetime average Phe levels above the recommended maximum Phe level. There's clearly enormous unmet medical need here. There are more than 1,000 PAH variants cataloged in patients with PKU worldwide, and many are potentially amenable to adenine-based editing, meaning that like the R408W variant, they could in principle be corrected by A to G edits, either on the sense strand or the antisense strand. Rather than focus on the top few most frequent PKU variants, Dr. Ahrens-Nicklas and I chose to initially focus on a lower frequency variant, the PAH P281L variant. Early on in our work using a humanized mouse model with PKU caused by the P281L variant, we found that treatment with an LNP test article with an mRNA encoding an adenine base editor and a guide RNA specific to the variant caused the elevated Phe levels in these mice to be entirely normalized by 48 hours after treatment. This got us excited about the prospect of addressing not only the P281L variants, but a broad range of disease-causing variants in the PKU population.

Since then, Dr. Ahrens-Nicklas and I have found promising adenine-based editing solutions for other variants, which together comprise a majority of PKU patients. It's not hard to envision using the same LNP formulation, slightly different versions of mRNAs to cover a family of closely related adenine-based editors and individualized guide RNAs, effectively, variations on the same drug product to treat all these patients. That said, Dr. Ahrens-Nicklas and I are very committed to the idea that no patient should be left behind. Our goal is to be able to rapidly develop and validate a corrective editing therapeutic for any PAH variant in any patient with PKU. Solving a small number of variants isn't enough. What about the 1,000-plus other variants that have been cataloged? And that actually understates the problem. Here's a figure from the most comprehensive study of PKU variants worldwide published in 2020, plenty of data from some parts of the world like Europe, and then whole stretches of the globe from which there are little data, for example, the entire African continent and large parts of Asia. This highlights that you can't make gene editing therapies for patients if you have no idea what genes and variants are causing their diseases. As gene sequencing becomes more broadly accessible, we can be sure that many more PAH variants will be identified. It won't be feasible to design gene editing therapies for these patients beforehand for many of these patients will need to be able to make these therapies in real time. The problem is even more acute in another set of diseases on which Dr. Ahrens-Nicklas and I have been working, the urea cycle disorders. Variants in the genes encoding any of the 6 liver enzymes and the transporter shown here, which together comprise the biochemical pathway that converts the toxic ammonia that results from the breakdown of dietary protein into nontoxic urea, can cause very high blood ammonia levels shortly after birth, which in turn cause irreversible injury to the brain, coma and death. In principle, all 7 of these urea cycle disorders could be addressed by doing corrective editing in the liver, just like PKU. But these are ultra-rare diseases, and most of the patient's variants are N-of-1 and N-of-few. And so the treatments would need to be highly personalized, and in most cases, made rapidly in real time once a patient has been diagnosed. It goes without saying that the current regulatory framework was never intended to handle this type of personalized therapy and that regulatory innovation is needed. Dr. Ahrens-Nicklas and I have been extensively engaging with the FDA over the past couple of years, having interact in pre-IND meetings about gene editing therapies for patients with PKU or any of the 7 urea cycle disorders as well as a single patient expanded access IND for an infant with a urea cycle disorder, through which we were able to make a personalized adenine-based editing therapy for the patients in just 6 months. I'm not going to get into the details shown here, but instead give you the highlights over the next few slides. I should note that we've published some of our FDA interactions, the briefing books and written feedback, in the paper cited here in the American Journal of Human Genetics a few months ago so that everyone has access to them. We first asked the FDA whether we could include multiple PAH variants in the same IND application, a single application using the same LNP formulation, slightly different adenine-base editors and individualized guide RNAs. They were agreeable to this, opening the door to a so-called umbrella clinical trial. We then asked the FDA whether we could add new PAH variants to the umbrella clinical trial in real time, submitting rapid IND amendments that include only in vitro cellular on-target and off-target data with no animal data at all. And they were agreeable to this concept, and it lays the foundation for an eventual approval of a full therapeutic editing platform for PKU.

Finally, we asked the FDA if we could bundle all 7 urea cycle disorders into a single clinical trial under a master protocol. There's a primary IND with the master protocol and then gene-specific secondary INDs that heavily cross-reference the primary IND and to which new variants in any of the 7 genes can be added in real time. We think of this as an umbrella-of-umbrellas clinical trial. And our hope is that the FDA will be open to an accelerated approval with a relatively small number of subjects, either through the newly announced plausible mechanism pathway or another pathway. In all, we think this is a very positive development for the ultra-rare disease space and are excited to move forward with this kind of clinical trial for the urea cycle disorders with funding support from the NIH's Somatic Cell Genome Editing program.

Thank you, Dr. Musunuru. It's a pleasure having you here with us today. I'll now turn the call over to Sravan to discuss today's financial updates.

Thanks, John. In addition to PKU, today, we shared another important update that further strengthens our balance sheet and reaffirms our belief in the commercial potential of risto-cel, our investigational autologous cell therapy with potential for best-in-class profile for the treatment of sickle cell disease. This morning, we announced a strategic financing agreement with Sixth Street that provides up to $500 million in long-term non-dilutive capital to support the anticipated launch of risto-cel. The facility includes $100 million funded at close, up to $300 million available upon the achievement of certain regulatory, clinical and commercial milestones for risto-cel and an additional $100 million subject to mutual agreement during the 7-year term. Repayment of the principal is due in early 2033. This structure strengthens our balance sheet while preserving flexibility and enhancing our ability to both commercialize risto-cel as well as fund future growth and innovation across our pipeline. With this latest announcement, we have established a foundation of financial strength for sustainable growth. We ended 2025 with $1.25 billion in cash, cash equivalents and marketable securities. With the anticipated minimum draw of $200 million from the Sixth Street facility, we now expect our runway to extend into mid-2029. This supports Beam's pipeline execution through key anticipated milestones, including the launch of risto-cel, the BEAM-302 pivotal plan and clinical proof of concept for BEAM-304. We remain focused on being efficient with our investments, including building focused commercial capabilities ahead of the anticipated risto-cel launch and positioning BEAM-302 for a potentially accelerated path to market.

Finally, our pipeline is wholly-owned and addresses significant markets. Combined with our platform-enabled approach, we believe this provides a clear path to long-term value creation and sustainable growth. I'll turn the call back to John for closing remarks.

Thank you, Sravan. We believe our PKU program clearly illustrates the power of Beam's genetic medicines platform. By correcting the genetic cause of the disease, base editing is a potentially ideal onetime solution for patients with this severe disease. Further, we believe we'll be able to take advantage of the modularity of our platform to ultimately address additional mutations supported by emerging regulatory precedents. Like our other programs, BEAM-304 is a precision medicine with potential for early proof-of-concept in the clinic and a predictable pathway to a large initial market poised for significant growth.

As we look ahead to 2026, we believe BEAM is well positioned to realize the power of predictability across our growing portfolio. For our lead programs, we are accelerating the path to approval and look forward to providing updated Phase I/II data and next steps for BEAM-302 pivotal development in alpha-1 antitrypsin deficiency this quarter, followed by the anticipated submission of the risto-cel BLA as early as year-end.

In addition, we continue to advance and expand the pipeline. We expect to file the IND for BEAM-304 for PKU, report initial BEAM-301 data in GSDIa, complete the BEAM-103 healthy volunteer study and continue advancing our in vivo HSC editing efforts this year. As Sravan outlined, we are doing this from a position of increasing financial strength with a strong cash balance and new long-term non-dilutive capital from Sixth Street to support risto-cel. At Beam, everything we do is driven by our commitment to patients. The promise of base editing is not just scientific innovation, it is the potential to deliver onetime life-changing therapies to patients in need. We are grateful to all of our partners, employees, investors, physicians and above all, the patients who are participating in our clinical trials for making this work possible. Together, we are building a future where serious genetic diseases can be treated precisely at their source in a personalized and predictable manner to bring new options and new hope to patients with serious genetic diseases.

Operator, please open the line for Q&A.

[Operator Instructions] Our first question comes from Samantha Semenkow with Citi.

Congratulations on all the progress. I just wanted to talk a little bit about the regulatory path forward and addressing multiple mutations. From a Beam-specific perspective, how should we think about the opportunity and the time line to moving beyond the R408W mutation into other mutations?

And then just with the strategic financing for risto-cel, does this allow you to reallocate more of your existing capital to additional liver-targeted indications? And how should we think about the rollout of those additional programs?

Yes. Thanks, Samantha, and great questions. So maybe to start, I'll ask Gopi and then Amy to talk a little bit about how we see additional mutations rolling over time, first in research and then in the clinic. And then we'll come back and have Sravan talk a little bit about what this allows us to do financially. Gopi?

Thanks, John. Thanks, Samantha, for the question. On the additional mutations, our research efforts are already underway for other mutations beyond the first 2 mutations that I described. And we expect the time lines could be fast given that we are primarily changing the guide RNA. We believe this platform approach can act as a flywheel where we get faster and more efficient for each subsequent mutation. And based on our initial interactions with the FDA, we expect to be able to bring multiple mutations forward within one program.

Also just to add to what Gopi has said, I think as a first step, it's been very gratifying to work with the FDA, very collaborative in order to kind of get their feedback on this whole process. And I think our intention is to get proof-of-concept in PKU with the R408W mutation. And then we'll continue to work on adaptive trial design to accelerate development in some of the other mutations that also impact patients with PKU.

This is Sravan. I'll tackle the finance question. So I think we're really confident this financing gives us a lot of flexibility with the long-term non-dilutive capital to support the commercial launch and subsequent revenue generation for risto-cel. And I think you kind of hit the point, which is, it also enhances our ability to redirect our capital to the growth of our pipeline. For a novel platform and technology like ours, it takes a lot of fixed investment to get to at this point. But we really feel like the subsequent programs that are on top of our platform are exciting, and we look forward at some point in the future when they're ready to be shared to show.

Our next question comes from the line of Maury Raycroft with Jefferies.

I'm going to move to the next question. It comes from the line of Eric Schmidt with Cantor.

A couple of questions on 304 as well. First, it sounded like Dr. Musunuru's lab may have been first at kind of reducing the practice of base editing for some of these mutations. Is there some IP associated with either R408W or others that the company has access to?

And then second, in terms of the predictability of the platform, that seems to be the theme today. Does 304 use the same ionizable lipid or even same or similar lipid nanoparticle? What can you say about the delivery there relative to, say, 302 or 301?

Yes, great questions. I can handle those 2. So yes, so I think we will have access to all of the IP that we need here. Certainly, there is a lot of pioneering work from Kiran's lab to point the way in this indication. Obviously, a lot of work has happened at Beam in the last few years, as Gopi said, to then make these industrial and leverage all of the platform capabilities that we have as well.

In terms of the LNP, so yes, so it's broadly the same kinds of LNP approaches that we use with 302, 301. We do have our own a ionizable lipids at this point as a company, which we expect to use. But the way we make them, the formulation, the approach as well as the internal manufacturing, we'll all be leveraging the work that we've done for 302 and 301 as well.

One moment for our next question, it comes from Yohan Zhu with Wells Fargo.

A couple of questions. I wanted to take advantage of the presence of not only the company, but also Dr. Musunuru On the line. Yesterday, FDA provided a draft guidance for individualized therapy. One thing that's not quite clear is how rare [ does ] the disease has to be to qualify for this new framework? I am wondering within the PKU range of mutations, are there any that are some or a lot of the mutations would have fall under this new framework? And if I may, 2 quick technical questions. For the 304 product name, are there going to be 2 different guide RNAs targeting the 2 different mutations or the same guide RNA? And if you can also talk about in your preclinical work, the presence of bystander editing, that would be great.

Great. Thank you, Yanan. Yes. So I think you're touching on some of the more innovative aspects of what we're doing here, which is quite exciting. So maybe I'll ask Dr. Musunuru First to say a bit about yesterday and the plausible mechanism pathway. And then Gopi, maybe you can cover the multiple guides in the bystander [indiscernible].

Yes. Thanks, John. So my perspective on the plausible mechanism that was announced yesterday is that it's primarily talking about potential approvals of platforms. And so you have to make a distinction there that it's about ultra-rare diseases, at least that's what is explicitly stated in the guidance, for which it is not feasible to do standard randomized clinical trials. And there are a bunch of conditions that are set there as to what particular types of diseases might qualify under the plausible mechanism framework. But it's ultimately geared towards either accelerated or potentially full approvals, in this case, because we're talking about gene editing therapies, we're talking about biological license applications. It's not necessarily prescriptive about clinical trial designs per se. And so what I should say with respect to PKU is that there's some ambiguity there. So if you're talking about urea cycle disorders, which I mentioned during the presentation, those are very clearly ultra-rare diseases. You're talking about perhaps a few dozen patients at most who are born in any given year who might be amenable to this type of gene editing approach. What's less clear is with a disease like PKU, where there's a wide spectrum of mutations, there are relatively frequent mutations where potentially you could contemplate doing a standard randomized controlled trial. But then if you go to the other end of the spectrum, there are N-of-1, N-of-few type scenarios that would be individually considered ultra-rare. And so I don't think it's clear. I'm not sure the FDA necessarily has thought about this so much. Dr. Hoeg, the acting CDER Director yesterday during the press conference when asked about this very issue, demurred to some extent and said that the agency doesn't want to be prescriptive, at least at this point as to what distinguishes ultra-rare from rare. She expressed openness to the idea that it doesn't necessarily need to be an ultra-rare context in order for the plausible mechanism framework to apply, but he didn't give much specificity. And I would point out again that this is a draft guidance, not the actual final guidance. And so there will be 60 days in which members of the biomedical community can give feedback. And I expect this will be one of the issues where they will receive a lot of feedback. And so we'll have to see what the final guidance says.

The other last point I would make is that, as I mentioned during my presentation, my academic group has been having interactions with the FDA about clinical trial designs. I outlined some of them. Those predate the announcement of the plausible mechanism framework, both what happened yesterday as well as the original New England Journal of Medicine article published by Dr. Makary and Prasad back in November. And so those clinical trial designs where one can include multiple variants in the same IND under a single umbrella clinical trial, those are relevant regardless of whether the disease itself would qualify for the plausible mechanism framework or not. The clinical trial designs will stand on their own. It's very clear that the FDA is open to those types of designs, whether there are going to be accelerated approvals under the framework that was announced yesterday, less clear. I think that would entail discussions with the agency on a case-by-case basis.

Our next question is from...

I just wanted to add one...

One moment. I think we have -- we wanted Gopi to answer the second half of Yanan's question. Gopi, over to you.

Yes. Thanks for the question. So the 2 mutations that I described today, the guide RNAs are unique. And in general, for this program, we expect to be developing mutation-specific guide RNAs and editors. So the guide RNA will be unique for each mutation, but they'll all be part of a single clinical program. That's how we intend to carry this forward. And on the bystander profile, even though we didn't disclose details today, we feel confident about the on-target editing and the benefit risk profile.

And Amy, did you want to add something to Kiran's discussion?

I would just indicate that we've had also very good meetings with the FDA, and they're supportive of this platform approach where multiple variants could be treated under one single program or one type of IND. So I think that it is something that, although it's not necessarily the same as a plausible mechanism, they're clearly showing interest in adaptive designs to enable basically acceleration to patients.

Our next question comes from Cory Kasimov with Evercore ISI.

This is Adhi on for Cory. I wanted to ask a question on sickle cell given the new financing. The recent increase in uptake of approved ex vivo therapies, can you help frame your current view of peak penetration or sales for ex vivo modality? And specifically, what market share assumptions do you currently expect for risto-cel, assuming its differentiated profile continues to hold?

Yes. Thank you. So maybe I'll have Pino talk a little bit here about our view for risto-cel. Of course, we wouldn't be giving market share or other specifics like that at this stage. But I think we do have -- we have been watching, obviously, the market evolve and have a lot of perspective on that. So maybe, Pino, you want to talk a little bit about how the market is coming along and what we think [ about ] risto-cel?

Yes. Thank you, John. Yes, I guess what we have seen about the market is consistent with some of our sort of intelligence gathering that we've been doing over the last year or so. And that is that clearly, there is a significant demand for a program such as the risto-cel that we're developing. And that's -- as you can see, there are basically patients waiting in order to do that. Also, other aspects of the market are very positive, like, for instance, to our knowledge, nobody has been refused the payment despite the fact that these treatments are north of $2 million. What has been a situation so far has been the somewhat limited ability to support the demand that exists on the basis of the manufacturing process that the current programs seem to have. And in particular, what we have seen is that many patients have had to go through several rounds of mobilization before they're actually being dosed. And so that causes also limitation on the overall capacity of the system as well as not making the money essentially on behalf of this company. We have really from the get-go, optimized our manufacturing process very strongly so that you can see our median mobilization cycle is only one. And that's also likely helped by the fact that we don't make double stranded break. So we do believe that we have a very competitive product and that it will hopefully help to satisfy the significant demand that exists for these products.

One moment for our next question, it comes from the line of Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. Maybe jumping over to the AATD. Can you just help us set expectations into the upcoming readout? How should we all be thinking about what is good in terms of AAT levels from the 75 and the 60 milligrams double dose?

And then for the pivotal, I guess, how confident are you that we'll have what we need with the next data update to pick a dose and move forward into the pivotal?

Yes. Great. So I'll handle that one. So we're obviously on track to give that update. I think we've shared prior, there will be a pretty comprehensive set of data there. So as a reminder, for that trial in alpha-1, so with 302, we're dosing additional 60-milligram patients, just given the strength of the data we showed last year and then continue to explore dosing schedule, looking at a 75-milligram dose and a 2x 60. So we'll put all of that together. And as a reminder, what we're looking to see there is, is there any evidence of increases in alpha-1 sort of versus how close are we to saturation in the liver already. So that will be sort of part 1. We'll also be looking at patients with -- this is all sort of Part A with lung. We're looking at patients in Part B who have the sicker livers. We're trying to see if there is similar efficacy and safety as in Part A. And then depending on what we see there, there's certain things we can think about. We'll also be, of course, showing durability. So we'll have a significant amount of time now with patients who are in the update from last year out 12-plus months and then a range of follow-ups from there.

So I think in terms of your second question, I think we said before, we do expect to have sufficient insight over the course of the beginning part of this year to finalize dosing schedule and anything else that need to go into the protocol. I expect that the data set will be hopefully helpful there, and we have it or we'll be able to have it soon. But it's [ not we're ] limiting at this point. We're already operationalizing the accelerated approval cohort and that can just take in the input from the rest of the part of the Phase I/II. So that is very much on track for getting started.

Our next question comes from the line of Brian Cheng with JPMorgan.

First, just on responses in PKU. Do you have a sense of how well these R408W carriers behave and respond to current options like Kuvan, Sephience or Palynziq in the real world? And any thoughts on their uniformity in terms of response to a base editing approach?

And then second, just on the Phase I/II design, can you talk about the age range you're thinking of recruiting here? And how quickly can you get to the newborn at the time of their diagnosis?

Yes, great question. So as a reminder, the mutations we're going after are really in the classic kind of severe PKU part of the market. So maybe, Amy, if you could speak a little bit to for those patients, responsiveness to current therapies, and then a little bit of how we think about getting to different age ranges over the course of the clinical trial.

Sure. Thanks, John. So it turns out that the first mutation, the R408W is called classic or more severe because the amount of PAH enzyme activity is really almost 0. And so from that perspective, these patients would not respond to things like BH4 or co-factors that you mentioned because that requires some residual enzyme activity in order to have any types of utility. And so typically, that would be for more mild or moderate cases and not necessarily for this R408W. There is, as we mentioned, the enzyme replacement therapies, but these are quite cumbersome. And even then only about 60% of patients after a couple of years of therapy can even get to the target below 360 micromolar. So even in those patients with this cumbersome therapy, we're still not addressing and getting people to have full diet liberalization with the therapies that are available.

As far as the pediatric population and getting into those patient populations, I think the FDA has shown signs of being very collaborative. And typically, when we do go into these patient populations, we will stage [ gauged ] a little bit and typically start either at 18 and above or, for example, sometimes you can get an indication directly to go to 12 and above. And then once you get some data, then working with the regulators to then be able to open up cohorts that are younger and younger. And some of this also can be done with some, obviously, PK/PD modeling and other kind of things to kind of figure out dosing, et cetera. But we are very confident that we will be able to get to the patient population that, frankly, would benefit tremendously from this because those are the patients who are having brain growth in development, and it's critically important that they have their target levels less than 360, even though we have increasing evidence that adults and others should be treated for a lifetime with the goal of being under 360 given impact on cognitive and executive function.

Our next question comes from Luca Issi with RBC Capital Markets.

Congrats on the progress. This is Cassie on for Luca. A quick one on A1AT. I appreciate that you are DNA editing and some of your competitors is RNA. But what is your read on GSK returning the rights on A1AT? And also maybe a longer question for A1AT's pivotal, has the FDA discussed with you their minimum requirements for representative U.S. enrollment? If -- correct me if this is not right, please, we see on fda.gov that the Phase I/II are ex U.S. Would this mean that your pivotal of [ NL50 ] will have to be mostly from the U.S. if the agency does require a majority of patients in the approval package to be U.S. patients? Any color there is much appreciated.

Yes. Thanks. I can handle some of those. So the first question on RNA editing, I mean, I wouldn't want to comment on another company's situation. I think you just have to ask them. I think our belief remains that, all things equal, that having a one and done for alpha-1 is going to be a preferable target product profile if you can achieve it, which we believe we can. And then obviously, just doing head-to-head on the different data sets that have currently been disclosed, we continue to believe that BEAM-302 has shown the best-in-class data in terms of alpha-1 levels as well as the composition of that -- of those levels as well between MD production.

So in terms of U.S. ratio, I think it's probably premature to talk about that. I think we are -- we obviously have an open IND. We will be active in the U.S. That will be a big part of the entire trial going forward, along with the ex U.S. regions that we're in. So we'll certainly be keeping an eye on that and make sure that anything we need for U.S. approval will be satisfied, which I'm sure.

Our next question comes from the line of Sami Corwin with William Blair.

Congrats on the progress. I was curious for the clinical development in PKU, if it will be required that patients have 2 copies of the same mutation. And if not, how that could impact the range of benefit observed?

Yes. Great question. Maybe, Gopi, do you want to talk a little bit about the preclinical work we've done on that subject? And then Amy, if you want to expand on that [indiscernible]?

Yes. Thanks for that question. As you saw in the dose response data I showed, the level of correction that is required in order to reduce Phe levels below the therapeutic threshold is relatively modest, and that is one copy of PAH gene corrected is sufficient. A large number of patients do -- are compound heterozygous, so they will have 2 different mutations on each of their alleles, and it's sufficient to correct one of them. And to model such patients, who've actually used compound heterozygous mice, meaning mice that have 2 different mutations, but we were only correcting one of the mutations and then demonstrated that, that was sufficient in order to reduce the Phe levels to below the therapeutic threshold.

One moment for the next question, we have Maury Raycroft from Jefferies.

Congrats on this update. Maybe just a quick one. For the in vitro data that you have for the different variants, can you just provide more specifics on how much of that you already have? And I don't know if there's any more practicalities you can comment on for how new variants are going to be added into this Phase I/II study and how the Phase I/II is going to work from like a dosing standpoint to adding these new variants?

Yes. I think -- I mean, maybe I'll just give the high-level answer, which is, we are quite far at this point through all the preclinical preparations. We've already had interactions with the FDA, which have been supportive of this approach, which has been very encouraging. And I think as you've seen, we've guided to IND filing this year. So clearly, we're in the final steps here. And then I think the other piece about bringing more mutations in over time, I think we obviously are going to start with 2, but there is an understanding that we can then append additional mutations into the same IND over time. That's basically the framework that has been put forward here. And so as the research team brings them along, we can then adaptively put that forward. Some of the nuances of exactly how we manage the trial over time and mix these different populations together on our approval pathway is obviously some of the work that Amy and her team will do in consultation with the FDA, and that's where we're going to continue to sort of pioneer this. But we feel quite confident, especially with the well-precedented endpoints in this disease that we will be able to do that.

Got it. And for dosing, is there anything from the AATD study that just kind of informs where you can start out with dosing here?

Yes. Either Gopi or Amy, you want to talk about sort of initial dose selection and escalation?

Yes. I mean I think, again, it depends a lot on what we see in our nonclinical, and we do PK/PD modeling. And obviously, it's unique for each kind of LNP and drug product that you make. And so I think we're just going to base it on kind of those analyses like we have in the past for 302 and 301.

I think you can expect it to be standard would be what I would say.

And maybe I can just add that as you saw in the preclinical work, we were able to bring Phe levels down to below the therapeutic threshold at relatively low doses of LNP. So we expect to be able to do the dose finding relatively efficiently.

Our next question comes from William Pickering with Bernstein.

First is, could you explain why a lower editing rate seems to be needed here compared to, say, sickle or AATD and any risk that translating to humans? And then on OpEx, could you just ballpark how much incremental OpEx you'll be taking on over the next couple of years to advance the PKU program? And how does that scale with the number of unique mutations you take into the clinic?

Yes, good question. Maybe Gopi, why don't you start with the first question just about the low threshold for [indiscernible] here? And then, Sravan, do you want to talk about how PKU appears in our cash planning and runway guidance?

Sure. So PKU is caused by what's called recessive loss of function mutations, which means both copies of PAH need to be nonfunctional in order to have PKU. And it's often not required in diseases such as this caused by recessive loss of function mutations to have full restoration of the enzyme activity in order to reduce the phenylalanine levels. And as you saw from the mouse data, it's sufficient to only get modest levels of the enzyme activity restored in the liver for the enzyme to then reduce the phenylalanine levels and to be active. And you see this in other diseases in addition to PKU as well.

And then on the question about runway in operating expenses, I would say that first, and I guess the most important thing, PKU is already baked into the operating runway guidance we provided at the start of the year and updated today. And that we're just at this point in time, probably not going to disclose the level of detail around cost by program as it's kind of balanced across the entire portfolio. And I think I mentioned already as a platform company, we've got a lot of fixed investment. But as we evolve as an organization, start to see some of the benefit of taking advantage of that platform as subsequent programs come online.

Yes. And if I could even just underline that last point. I think it's generically as the platform gets built that an entirely new program is easier and faster and more efficient and more likely to succeed when we do it at the second time or the third time or the first time. And I think we're already experiencing that to a degree with PKU BEAM-304 coming after 302 and 301. The adding additional mutations within the same program is even more efficient, right? I mean the flywheel now is simply an additional guide RNA, some minimal testing and then you're off the races. So we do think these are continuing to drive down the kind of incremental cost of the additional editor as we continue to mature the platform.

One moment for our next question, that comes from the line of Alec Stranahan with Bank of America.

Just a couple from me. Maybe just a follow-up on the plausible mechanism pathway. I know ultra-rare was mentioned. Curious if you have any thoughts on the FDA comments on plausible mechanisms, specifically related to AATD. This seems consistent with the biomarker-driven [ patient ] path you're pursuing, but any additional thoughts relating to the applicability to AATD would be great?

And then just given the increased attention on vector safety in the liver, could you maybe talk a bit more about your LNP for the PKU program? Any structural modifications you're making here, specifically thinking for optimizing safety and specificity?

Sure. So maybe on the first point, so I think, as Kiran already mentioned, I think the plausible mechanism pathway is sort of one way that the FDA anticipates getting these sorts of programs to approval, but it's not, of course, the only way once you're in this sort of platform world. I think with alpha-1, we can say that we think we're taking a, frankly, more traditional path, which is an accelerated approval pathway [indiscernible] root cause of disease, followed presumably by some kind of confirmatory experiment. So we don't need an innovative new pathway for that. That's pretty traditional. That said, obviously, it shows that what we're doing in alpha-1 is broadly aligned, I think, with the kinds of programs working on the kind of root cause of disease that the FDA is clearly leaning in on. And then lipid nanoparticle, I mean I think broadly, I think we think that LNPs are the best available option for the liver in terms of getting there. We think we've got a lot of expertise in that area. And I think as I mentioned before, we're building on that clearly with the 304 IND and look forward to updating you over time.

Our next question comes from the line of Michael Yee with UBS.

This is Matt on for Mike Yee. Maybe one on the next-gen sickle cell program. It seems like in vivo has maybe leapfrogged ESCAPE in terms of priority. Could you just speak to what goes into choosing the right next-gen program for sickle cell? And what gives you confidence in the in vivo program and the HSC targeting that you might use there? Just any you can say there would be great.

Sure. Pino, do you want to maybe just talk a bit about our prioritization of in vivo and prospects there?

Yes. Definitely, the consideration here is the fact that with LNP, of course, we can deliver a product much more easily than an ex vivo approach, and therefore, it would provide support for a larger number of patients if the efficacy, obviously, were proven to be equal or certainly manageable from a disease point of view. I think the important aspects of -- and because we're making progress, frankly, and preclinical studies would suggest that, that can also move relatively quickly in clinical studies. And therefore, that's what is guiding us to making that choice. We also have opportunities, obviously, to further enhance the engraftment rate, if you will, of an LNP with the use of our ESCAPE-like technology as well. So I think that gives us the confidence at this stage to move that program as quickly as possible. And obviously, we're doing everything we can to move it at speed.

One moment for our next question, it's from the line of Patrick Trucchio with H.C. Wainwright.

Luis here. A question on -- for the go and no-go decision for 103 in healthy volunteers, how are you thinking about that? And comparing to the in vivo editing in HSCs, how are the efficiency -- the editing efficiencies compared?

Sure. Pino, do you want to talk a little bit -- I think you just sort of talking about this about the role of ESCAPE, obviously, broadly, but also in the in vivo context.

Yes. Also, the initial question was not clear, but I heard the healthy volunteers. So...

Yes, 103, yes.

Yes, 103. So what we're doing with the healthy volunteers is basically, we are dosing just the antibody component of the ESCAPE technology. This is the anti-CD117 antibody. And what we are doing there is in addition to obviously confirm the safety of that antibody, we're also developing a PK/PD model that would guide us the dosing in the context of the sickle cell patients that we plan to test in subsequent studies. We do not have any editing in that particular healthy volunteer study. And the other thing to confirm is that by having the additional edit that essentially protects the edited cells from the binding of their antibody, it gives us the opportunity for edited cells to basically survive over the unedited cells even in the context of an in vivo delivered technology.

And the efficiencies compared to the in vivo program?

The efficiency, do you mean, of editing in combination...

Editing the 2.

Yes, it's very high. So it's comparable.

Thank you, ladies and gentlemen. This will conclude our Q&A session for today. I will pass it back to John Evans for final comments.

Thank you all. It's obviously a lot of exciting updates. We continue to be really pleased with our momentum here across the board and very excited about what's ahead. I also want to thank Dr. Musunuru for joining us and for all of his pioneering work along with his colleagues and Dr. Ahrens-Nicklas for really opening the door to some of these new approaches. I look forward to continuing the partnership. So thank you all for your time.

This concludes our conference. Thank you for participating, and you may now disconnect.

Good afternoon. Thank you for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. On stage, we have the CEO of Beam Therapeutics. I'll now pass the mic to their CEO, John Evans, for a short presentation, followed by a live audience Q&A. John, the stage is yours.

Thank you very much. So yes, my name is John Evans, here to tell you about Beam Therapeutics and some of our medicines. And I'm going to talk about the power of predictability in the technology that we're using. So as a reminder, I will be making forward-looking statements today.

So at Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. This is gene editing for rare and common disorders. This means the potential for onetime curative therapies with lifelong effects. And this is a platform that can potentially create a large number of medicines over time. So it's been a remarkable 12 months for base editing, and I just want to walk you through some key events.

So at the very end of 2024, we revealed data of base editing for severe sickle cell disease, showing dramatic results. Shown here is Brandon, patient #1 on that trial, who was treated at Boston Children's Hospital. Just a couple of months later in March, we published the first data for base editing and alpha-1 antitrypsin deficiency using BEAM-302. This is in vivo editing this time. And now for the first time, we're literally rewriting a broken gene back to normal, which has never been done before.

Two months after that, a team at the Children's Hospital of Philadelphia published dramatic results where they created a customized base editor for a baby named KJ, who -- the editor was only developed over the course of about 6 months while the baby was being born, and it worked.

So you have three very different settings, very different context and yet base editing went 3 for 3, okay, with dramatic results. And that's not an accident, okay? And I think it's a sign of the predictability and the power that this technology can bring.

So at Beam, we're not surprised. So Beam was founded around this technology. It's a simple concept, but it has many profound implications. So with base editing, we're using CRISPR to target within the genome precisely. But once we get there, we're not going to make a double-stranded break or a cut. We're instead going to make a single-letter change in the gene, and we are going to have total control of those strains.

This has a couple of outcomes. So first, we're going to have consistent gene sequence outcomes. So we're going to know the gene sequence that is going to result from our edit in every case. Second, this will be, of course, durable. We're going to have lifelong correction, onetime curative potential.

And finally, because we're not making the double-stranded break, we're going to have less genotoxicity. The cells are going to be healthier, potentially happier than in traditional gene editing.

So you put all that together and what we believe we're going to have is more predictable and reproducible outcomes for patients. So if that's possible, what could that mean? So we think that the products that we're going to create here that have that predictability are going to have profound ripple effects across the health care and biotech ecosystems.

So first, the predictability that we're predicting here is going to mean streamlined R&D cycles. That means reduced development risk. We're going to be able to predict that this drug ought to work every time. That's going to shorten timelines and make our investment more effective.

Second, regulatory acceleration. The FDA is more than willing to work with you to move programs to patients faster so long as the science is really clear. And here, it is, and we're already seeing this FDA open up the door to more flexibility for these kinds of medicines.

Third, physician confidence. These are not drugs where you might get a 10% or 20% response rate. These are drugs where everybody responds and everyone has a profound impact from this editing. That's going to mean predictable safety, durability and efficacy that can give physicians confidence.

Of course, patients are also very interested in that same kind of predictability. And they're eager to be done with their disease. They want to get that benefit and hold on to it. And the unique part about lifelong cures is the patient doesn't have to worry now about maybe their insurance is going to change or they're going to lose access to their chronic medication. They're going to get that benefit, and they're going to be able to rely on that benefit for the rest of their lives.

Finally, payers. We all know we need to be more efficient in our health care spend, and we're so confident that the profound changes and the lifelong changes that we're going to provide here are going to reduce lifetime health care utilization costs across the health care system with outcomes to back it over the long term. Payers are going to be very supportive of that, and we think that will be another tailwind in favor of this kind of therapy.

So beyond that, there are also advantages to Beam as we build a company around this technology. So this is a true platform. So what does that mean? That means that base editing is easily adaptable. Once we've made it work in one target, one cell type, it's very quick to then put it on to the next target and you have an entirely new program.

Delivery technology, things like the LNP we use to deliver to the liver, that's reusable. If it works once, it's going to work again and again. That's going to mean consistent preclinical and clinical outcomes.

Manufacturing is highly scalable. And the more we do it, especially at Beam, where we're doing it internally in our own team, our own facility in North Carolina, the better we are at it.

And finally, as I said, the flexible regulatory frameworks that are emerging. So this flywheel is now spinning faster and faster and the confidence that we're generating is only going to go up from here.

So I think the evidence for this vision is already clear. At Beam, we have multiple growing high-value franchises in view. Because of the success of these early programs, we are eager to now double down and expand the pipeline, bringing more programs in that can take advantage of the derisking and validation we've already established. And this platform is going to generate excess value beyond even what we can capitalize on ourselves, and that's going to be a substrate for some really exciting and creative platform partnerships.

So of course, none of that can be done without a foundation of financial strength, and we have that at Beam. So Beam has $1.25 billion in cash at the end of the year. That gives us runway now into 2029, which will carry us through the launch of Ristacel, our sickle cell disease product as well as full execution of the pivotal development plan for BEAM-302.

We remain focused on our spend strategy, managing expenses over the long term. The commercialization of Ristacel and sickle cell is actually quite efficient. And as I said, I'm going to go into this in more detail, the development pathway for 302 is also efficient as well.

All of this gives us a very clear path to value creation with a wholly owned pipeline addressing significant markets and behind that, a sustainable growth engine based on this platform.

So 2025, I think, was the year that all of this became visible. This has been our vision and dream for the 8 years since we founded the company, but I think 2025 was really the proof.

So as I said, first human proof of concept ever for an in vivo correction of a gene in alpha-1 with 302, continued differentiation of Ristacel and sickle cell disease, now FDA regulatory alignment on the path to market for both of those programs, as I will describe; exceeding our clinical enrollment, advancing our next wave programs, a very significant financing early in the year and as I said, now runway into 2029. So we're very excited leaving the year and couldn't be more eager to see what comes next.

So let me dive in now to some specifics, and I'll talk a little bit first about our liver programs and then turn to hematology.

So in liver, the lead program here, as I think everyone knows, is our alpha-1 program, BEAM-302. This is a potential best-in-class and first-in-class program disease-modifying for alpha-1 antitrypsin deficiency. Because of its success, we're very excited now to expand the pipeline and bring more assets forward. We will be announcing another liver program soon.

All this is built on our industry-leading LNP capabilities, enabling delivery to the liver. And so far, LNPs have been well tolerated clinically. Finally, this entire area has platform synergies that make it perfect for the kinds of novel regulatory pathways that the FDA is flashing the green light on, so we can go faster and faster and reach more and more patients.

So now let me dive into alpha-1. So alpha-1 antitrypsin deficiency is a severe genetic disease, characterized in almost all patients by a single letter misspelling in the SERPINA1 gene, which makes the protein alpha-1 antitrypsin. So that [ GA ] point mutation, we call it the Z mutation. And patients who have 2 copies of that mutation called the ZZ genotype, have the disease.

So when you have this disease, you get two problems. First, you have a progressive lung disease. That's caused by low levels in your body of the alpha-1 protein, which is designed to protect your lungs when you're infected. And in addition, what little alpha-1 protein you have is the Z form of the protein. It's a mutant form, and it is not as effective. It actually causes problems, it can cause inflammation and aggregation.

In addition, there's a progressive liver disease, and that is caused by the fact that, that Z protein is actually building up in the liver in a toxic way. It's causing aggregation and accumulation. And that causes a progressive liver disease and gradual liver failure. There are very few therapeutic options for patients. They are generally unsatisfactory. We clearly need to do better and nothing addresses the full spectrum of the disease.

So that's what BEAM-302 is designed to do. So with BEAM-302, we're going to use base editing to correct the single letter misspelling in this gene and turn it back to normal. That will address the root cause of the disease and restore physiologic control of alpha-1.

So what would success look like? We would see the liver producing the normal form of this protein for the first time. We call that the M form. If we're doing that, we would, of course, significantly reduce the amount of Z in the body, which is the bad actor. We would see total alpha-1 levels rise above the 11 micromolar protective threshold. It would rise because the M form is so much better secreted from the liver than the Z form.

And we know 11 micromolar is protective because clinical genetics tells us that patients with this disease where you have 2 copies of Z have alpha-1 levels in the 4 to 6 range. No one has 11 or above. If you're in the teens, 10 to 20, you're generally a carrier. You might have only one copy of Z and you have no progressive disease, you're safe.

We would also, of course, want to know that the AAT we produce is functional. And finally, this is an inducible gene. So when you get sick, you create a lot more, and we'd want to see that the AAT increases with inflammation. All of this would be in a durable single-course treatment, one time for life, addressing both lung and liver.

So it sounds very exciting, and it turns out that's exactly what we've shown with BEAM-302 so far. So here, this is the data that we showed in March. This is the 60-milligram cohort. And you see on the left-hand side, total AAT levels indeed rising above 11, here reaching 12.4 micromolar, and that's at day 28 after a single dose on day 0.

We also then show significant reduction of the Z protein because we're literally converting Z genes into M genes. Here showing almost 80% reduction again at day 28. Finally, the composition of the AAT in the body has shifted. You see here going from 0% at baseline to 91% in circulation again at day 28.

So all of this is truly indicative that we've achieved those therapeutic goals that we've converted these patients from disease to carrier where they shouldn't have any progression anymore. We really believe this could be a functional cure.

So what have we been doing since then? The trial is very active. So we're hard at work dose exploring. We're treating more patients at 60. We've gone up to 75 milligrams. We're going to try 2 60-milligram doses, all just to explore different variations of dosing schedule.

We're also running a Part B in patients who have very sick livers. This is a minority of the population. But given that our program is liver directed, we want to make sure there's no change in safety and efficacy in that population.

And all of this is to identify the optimal dosing schedule for a pivotal study. So we look forward to giving updated clinical data across all of these cohorts, and that is expected by the end of the first quarter of this year.

So clearly, we believe this is the most advanced genetic and disease-modifying program for alpha-1 in the clinic. We've actually treated over 25 patients at this point and still going, and there is quite significant patient and physician enthusiasm.

Excitingly, I can now add FDA alignment to the list for BEAM-302. So the timeline goes like this. So in March, we showed the clinical proof of concept, that 60-milligram data, got the IND open in the U.S. shortly thereafter. And that data was submitted to the FDA for RMAT designation.

So RMAT may be less familiar, but it's basically the breakthrough designation for gene and cell therapies. And to get that, the FDA will review your data and has to decide that, yes, this is worthy of trying to work with you to accelerate the program to get to patients faster because RMAT allows you to have multiple meetings with the FDA in a sort of continuous manner. And so they said yes, they invited us in.

So we've been working with them ever since. And I'm happy to say that in Q4, we did indeed reach alignment with the FDA on a potential accelerated approval pathway for this drug in alpha-1.

What does that look like? The primary endpoint is expected to be based on AAT biomarker, so levels of alpha-1, functional alpha-1, M level, Z levels, all the things that we've already shown, measured over 12 months. So clearly, we want to be able to show we've changed AAT physiology and that it's durable.

We anticipate enrolling approximately 50 additional patients in an expansion of the existing Phase I/II trial. So that's going to be a very efficient approach. We're already open in many countries and sites around the world, and we think this will be easy to implement.

We are also accepted into the FDA's CDRP program, which is basically designed to give CMC consulting advice to companies and programs that are on expedited pathways with the FDA. So great progress. We're so excited to bring BEAM-302 to patients with alpha-1 who really desperately need new options as quickly as we can.

So one quick update on our next program in the liver. This is BEAM-301 for glycogen storage disease 1a, patients with the R83C mutation. So this is a very orphan disease. Patients have to continuously take in cornstarch every few hours, including overnight, or they can potentially die of hypoglycemia. So this is much slower to enroll because it's much more rare, but we're actually making good progress here. And now we do plan to report our initial clinical data from this program by year-end.

Third, in the liver, as I said before, we look forward to sharing an additional liver program that will be added into this portfolio, and that will come out in the first half of this year. So we look forward to that as well.

But now let me turn our attention over to the hematology franchise. So here, as you may know, our major focus is sickle cell disease. And we now see an opportunity for really a pair of complementary approaches, one, near-term ex vivo approach that is a near-term commercial opportunity; and then longer term, an in vivo delivery approach to achieve maximum scalability and reach all patients.

So for ex vivo, we're focused on the severe sickle cell market. This is about 10,000 patients in the U.S. We believe it's really poised for growth at this point going forward. And we see very clear clinical differentiation for Ristacel based both on the mechanism of base editing and on our very advanced manufacturing process.

For next-gen technology, we do still have the ESCAPE program that is very exciting and can be used in a wide variety of places. But at this point, in vivo delivery to hematopoietic stem cells has made enough progress that we're moving that into our preferred position as the platform for our next sickle cell program after Ristacel.

So on Ristacel itself, as I said, we see three major areas of differentiation. So first, we're achieving deeper resolution of this disease. So we're trying to raise field hemoglobin to higher levels to protect these cells. We're achieving over 60% F that's higher than anyone else is achieving in the field. And at the same time, we're driving sickle protein down below 40%.

So those numbers are comparable to sickle trait, a carrier, okay? And that tells us that we're finally achieving a normalization of the biology for these patients. We're also fully resolving anemia and markers of hemolysis and oxygen delivery are normalized or improved.

Second, patients are spending less time in the hospital after the transplant. We think because the base editing doesn't make that double-stranded break, the cells may be a little more viable, a little more ready to turn on more quickly.

And we're seeing rapid neutrophil and platelet engraftment, okay? When you get the transplant, you have to wait until those cells appear again from your new graft before you can go home. And so this could mean an overall safer transplant journey and, of course, a faster time to return to life.

Finally, predictability is about not just editing or delivery. It's also about things like manufacturing. and we're seeing that. So we have a very advanced process. At this point, patients are seeing a median of one collection cycle for mobilizing those cells that we can make a dose out of. We're seeing consistently high yields and viability.

And we really think that's a function of both the base editing mechanism as well as the fact that we have our own facility in North Carolina, allowing us to have our internal team do all of the manufacturing and release in a seamless way.

So we get a lot of questions about the market for this drug and sort of where is it? And haven't -- have the launches gone as expected from some of the other players in the field? So our perspective is there's actually a lot to like about what we've seen so far.

So first, there's patient interest. There are waiting lists in most of the major centers. Patients are eager to participate. Treatment centers. There are 70-plus centers where whole teams of people have trained themselves to get ready to do this work. So they are motivated.

On the other end of the spectrum, patient outcomes have been positive. And payer, we believe that there have been no payment rejections to date as far as we have heard. It's still very bespoke, but that's going to get more systematized over time.

The major issue, we believe, has been in that cell collection and manufacturing process. These are challenging processes. So we hear reports of inefficient or unpredictable processes, patients facing multiple cell collection cycles with a lot of uncertainty and then manufacturing slot limitations as they try to work through that.

So we expect some of these things can be improved, but they're clearly holding back the market as of today. So that creates an opportunity for Ristacel. And in fact, the data we're already seeing in BEACON shows that we actually address these problems quite directly.

So if you focus in on the collection and manufacturing steps of this process, as I said, 1 cycle per patient median, we're actually running -- if you start from the beginning of mobilization to when we release the drug, it's about 3 months.

From the beginning of mobilization to when the patient receives the drug, that sort of vein-to-vein time, that's 4.5 months, okay, with high predictability, and that's for the majority of patients. At that point, you benefit now from the faster time to engraftment, okay, under 20 days for neutrophil and platelets to turn on and get you home. So in total, we're looking at 4 to 6 months for the entire journey to potentially cure yourself of sickle cell disease.

So clearly, we believe this would be very attractive and bode well for Ristacel's uptake within the market. But in fact, we think we can actually grow the market because you can use an existing amount of clinical infrastructure and potentially with numbers like these, treat more patients. So we're very excited about the potential of the program and its differentiation.

So what have we been doing with this? So we've actually been engaging with regulators continuously also on this program through 2025. We do have clarity on that BLA package now, and it's very consistent with what we had been expecting. We've actually completed manufacturing of all doses on the trial. Dosing of the final patients will sort of occur through the beginning of this year. And so at this point, we are able to guide that we plan to submit the Ristacel BLA package as early as the end of this year.

In parallel, we'll be initiating our commercial build. And as I said before, it will be a very efficient build. Again, there are 70-plus centers we need to focus on. We're already doing the manufacturing out of North Carolina. That facility can go commercial, it was always designed to. So this is not a big lift. This is an upgrade and a scale-up of the things that we're already doing quite well.

So I couldn't be more excited about the potential of Ristacel for sickle cell disease, and that's for that 10,000 sickest patients for whom a transplant makes sense. Let me turn our attention now to what are we going to do for the rest of this population.

We're not satisfied only treating 10%. And so here, we're looking at this next wave, and we are prioritizing in vivo delivery using lipid nanoparticles. So this is really building on breakthroughs that have been made recently on how to make these sort of particles reach these cells in the marrow. We do still have the ESCAPE technology, which we've talked a lot about. It's a powerful approach. BEAM-103, the antibody is in the clinic and advancing.

We can always do it ex vivo and pursue a sort of nongenotoxic transplant. But at this point, we think the in vivo approach is going to go faster and is ready to accelerate. And we have the optionality, of course, to use ESCAPE with it if we choose.

So why now? At this point, we believe Beam actually now has all of the capabilities needed to do this. That includes the LNP, of course, as you saw from our liver portfolio, we have many potent lipids in hand and proprietary LNP processes. But importantly, now we can do extrahepatic delivery. That takes two things. So one is you make modifications to the LNP to de-target the liver, which is where LNPs usually want to go. And then you add targeting binders that can enable cell-specific delivery in vivo.

So in addition to that, of course, we have the efficiency and potency of the base editing payload, and as I said, the option to use ESCAPE as well.

So the proof points for why we think this is ready now, we've actually worked on this for several years. A company that we helped start called Orbital has been using beam reagents to do this exact approach to deliver LNPs to T cells in the body for autoimmune disease. They showed really beautiful NHP proof of concept last year. That program is now progressing to clinical studies and was actually acquired by BMS for $1.5 [ billion ].

In parallel to that work, we have been working on the HSC delivery side. HSCs are going to be a little harder than T cells, but not a very different concept. And at this point, we have multiple HSC targeting LNPs in hand and identified. The development scale-up for that program already largely in place, and we are in lead optimization. So stay tuned. We look forward to updating you on this exciting program as it advances as well.

So let me spend one moment now on our partnerships. So this has been a strategy we've taken to really drive both value creation for the company as well as therapeutic impact. So at this point, our partnerships have resulted in over $900 million in nondilutive funding for Beam over the course of our 8 years in existence and by the way, gained rights to both innovative and complementary technologies for us to use.

In addition, it's allowed us to move some of our science, be it delivery technology, editing technology or otherwise; towards patients in areas that we were not going to be able to get to ourselves. So it's been a big success. We couldn't be more happy with this. And I think you should expect this to be a big part of our business model going forward, and we expect to continue with this track record.

So I'll now close just by talking a little bit about what we expect for 2026. So as we noted, the headline here is we're going to be pursuing a path to approval for both of our lead programs. For BEAM-302 in alpha-1 antitrypsin deficiency, we'll be reporting updated Phase I/II data and giving a little more clarity on the timing for our pivotal development program by the end of Q1 this year. And then for Ristacel and sickle cell disease, we plan to submit that BLA as early as year-end this year.

So building on the success of those programs, we're now also quite eager to take advantage of that, right? If this technology is as predictable and reproducible as I think it is, then we're very excited to do more for patients. So we'll be disclosing along those lines another liver-targeted genetic disease program in the first half of this year, and we'll be reporting the initial data for BEAM-301 in GSDIa by year-end.

On the hematology side, we'll be completing the BEAM-103 healthy volunteer study in the first half of this year and then advancing that in vivo editing program, all while maintaining financial strength with $1.25 billion in cash. And as I said, runway through into '29, including the anticipated launch of Ristacel and the execution of the 302 pivotal development plan.

So really, we're at the point where we have the funding we need to get to that commercial transition and begin generating sales as a company. So it's a remarkable place to have gotten to, and we couldn't be more excited about it.

So I'll close by saying thank you for your time, but also thanking the patients and families, who have partnered with us on this journey. They are on our minds all the time, they are waiting for better and curative potentially therapeutic options. And in addition to helping them, we want to get to more patients and more diseases. The impact we can have, I think, with these technologies is quite profound, and we look forward to working with you all to move this forward.

So with that, thank you, and we'll take some questions.

Great. Well, let's start with the Q&A. [Operator Instructions] I want to start off with on what happened. I think the news really caught us by surprise in a really good way, right? What a great surprise to kick off the week.

Can you walk me through the interactions that you have had with the agency? How do we get to the accelerated approval path now in place? I think I also get this question of, have they seen data from the higher dose? Have they seen the double dose cohort? Can you just kind of walk me through what they have, what kind of interactions you have had with the agency?

Yes. I think, in many ways, I think this is a classic accelerated approval program, right? FDA likes it when you have -- you're on mechanism, right? We know the problem here, it's the mutation. We have a mechanism that directly fixes what's wrong. And then they want to see that the science they're showing is consistent with that, right?

And all of the biomarkers I just described are going in the right direction, consistent with that functional cure. So I actually think that the FDA has been thinking about an accelerated approval pathway themselves for some time.

To answer your second question, they have seen -- the only things that they saw to make these decisions and put us on this pathway was the same things that we've shown today, okay? So it's the same data set that we shared back in March. They haven't seen some of those newer, more recent things, and those will come out at the end of Q1.

The timeline I described, I think, is really descriptive, right? That data came out in March. We had RMAT designation with the FDA by April, I think it was. And again, RMAT is explicitly about we want to work with you to find a way to go faster to get to patients. I think everything else was really just working with them on the details, okay?

I don't think it was a big picture disagreement. It was more, okay, what does this cohort look like? What's the follow-up? How do we manage variability, all the classic development questions that come up.

Great. And then maybe just turning to the primary endpoint of the trial. We noticed that the press release sets biomarkers, plural. How should we think about the selected biomarkers? Are these known biomarkers to those of us who have been trafficking in alpha-1? How should we think about just the selection of it?

On PMS and cycle?

Yes. Maybe I'll take it. First of all, my name is Pino Ciaramella. I'm President of Beam, and it's great to -- for your interest and participation today.

So a couple of things maybe just to complete the prior conversation. I think actually, it was really pleasant for us to see that we could come to this agreement with the FDA, but it wasn't completely a surprise. In fact, in the pre-IND conversation that we had, they did open the door to an accelerated approval on the basis of biomarkers.

And the biomarkers fundamentally are essentially exactly what you've seen. As John mentioned, the data package that you've seen has been disclosed is exactly the same that the FDA has seen. And essentially will be obviously total AAT, but will also be functional AAT. We'll obviously be interested in the levels of [ M ] relative to Z, and all of those will be the kind of biomarkers we'll do.

There's nothing new that we need to develop or novel assays that the FDA has requested on that. So it's really just a confirmation of what we've seen, but in an extended data set.

Great. Any questions from the audience?

Thank you for being here today and sharing your perspective. As you think about base editing technology scaling, what do you think the biggest bottleneck is going to be? Is it capital? Is it talent? Is it operational know-how, something else?

That's a great question. I think -- so the question was how are we going to scale base set in technology. Just from a pure manufacturing perspective, it is highly scalable. These are synthetic, easily manufactured intermediates. We're doing it ourselves in North Carolina.

I think that it really just takes the time to develop the science and the evidence base that we can do this safely, that we can do it with efficacy, that we understand how to deliver to a certain organ. And then once you've done that, doing it the next time is going to be much more predictable and more repeatable.

So I think we're just building that track record now. And you can hear from my presentation that we do feel like we're kind of at that inflection point where now we have enough of that evidence and the foundation built that we can start to shift it into higher gear and do more things in parallel.

Yes. I would say, certainly from a manufacturing point of view, we deliver the base editor as a messenger RNA and enveloped into an LNP. It's exactly the same technology to some extent as what has been developed with vaccines for mRNA. And you have seen there have been literally billions of doses have been able to manufacture a very managed cost. So I think the scalability from a manufacturing point of view is not an issue.

Really, then it depends on how many tissue you can successfully deliver. And I still believe that delivery is somewhat of a rate-limiting step in how many tissues you can actually afford that.

The good news is that the LNP technology actually is making progress in going to other tissues and other cell types, particularly with now the ability to target different cell types by coating the LNP with different [ moidays ].

So I think the field is moving along and the strength of the base editing is the predictability that we just said. We know that if we can deliver to the cell that we want, we know what the outcome is going to be.

Just turning to the first quarter update by the end of this first quarter, what is expectation? And what do you ultimately want to see, especially among the new cohorts, the 75 mg, the double dose cohort? And we're also going to see liver plus/minus lung disease patients. So ultimately, what do you want to see so that you have the best view going into the expansion part of the study?

Yes. Great question. So I think as we've tried to communicate, we're very confident we have a potential drug here at the 60-milligram data, and I think the FDA agrees, as far as we can tell. So really, what we want to do in addition to moving it forward is do a few last checks to make sure we have the right path going forward.

So one of those is to make sure we've optimized dosing schedule, right? So we've clearly edited a substantial portion of the liver here with the 90% M that you see, the 80% reduction in Z. At the same time, we haven't edited all of the liver because there's still some Z there. So we want to make sure we don't leave efficacy on the table, okay?

And so the 75-milligram cohort, the 2x 60, we're actually adding more 60s. All of this is just designed to test for, is there additional efficacy to be gained, higher levels that could be achieved without compromising safety, we wouldn't want to do that. And so that's sort of one set of data that we're going to get. And that will inform sort of a final recommended dosing schedule, is it 60 or is it one of these other flavors? But importantly, all of them we expect to be therapeutic and plausible.

And then in the liver cohort, the sort of Part B of the trial, we're asking a different question, which is, as we know, alpha-1 patients are on a spectrum from liver and lung involvement. So in Part A, we excluded patients with really sick livers because this is a liver-delivered therapy. So just to be conservative, we wanted to first target patients who didn't have sick livers. And then in Part B, we're testing in those patients.

And so we want to see there is does the safety and efficacy look similar in those patients as in the Part A. If it does, we will collapse the back together and just treat everybody as one group. If for some reason, it looked different, then we would have a different modified approach to treating those patients. So that's the second big question we want to ask. And I think we'll have plenty of data, I think, to have a conversation about both of those questions at the end of Q1.

Great. I want to touch on a relatively frequently asked question, which is, is 20 micromolar the new bar? We have been hearing 11 micromolar is the protective threshold for a long time. And if you look at some of the older agents, that's where it should be, right? What's your take on that? There seems to be a bit of a debate on where it should be to get a meaningful benefit in the clinic.

Yes. Maybe I'll start and then, I don't know if you want to expand. But remember, the disease is in that 4 to 6 range. A carrier is in the 10 to 20 range. and carriers don't have the disease. So I think the difference between 11 and 20 is -- would be undetectable from a clinical perspective.

So I think at the end of the day, the reason 11 is the number that people focus on is that's the breakpoint where you would stop seeing symptoms. I think that's what ultimately matters. Of course, if you can go higher, you would.

Yes. Yes. Of course, 20 is the sort of -- typically 20 and above is where normal MM sort of phenotype lives. But as John says, basically, as long as you are out of the disease and you are in the 10 and above, you essentially you do not show any progression of the disease.

So really, what our technology and the data that we have already shared already does is to set these individuals as essentially heterozygous. And as a consequence of that, they're not expected to have a progressive disease. And not only that, we've demonstrated with the -- all the biomarkers that we have disclosed is that the functionality of the gene has now been restored. So you essentially eliminated the cause of the progression of the disease from the body.

So we think that, that 11 micromolar is really the threshold to be worried about. And then, of course, you try and generate as much as possible, but the reality being able to demonstrate clinically the benefit of a difference will be very challenged.

Let me add one other point because people sometimes are comparing us with augmentation, which is a very different paradigm. The numbers we're sharing, so the 12.5 micromolar at 60 milligrams, that's a floor, not a ceiling, right? And so because this is an inducible gene, we would expect when you get sick, the gene will turn on and you actually go -- you go up from there, right?

Whereas augmentation, exogenous protein that you put in is basically washing out and it's not regulated. So you're not ever going to get more until you get another dose. So I think it's important also to keep track of the very different sort of profile of the AAT levels in the body based on these mechanisms.

Well, in the last 2 minutes we have, one quick one on GSDIa. I don't think we touched on that quite a lot. We're going to get some data, first class of data this year. Where should we focus?

I think GSDIa is really an important disease with very strong unmet medical need. And the R83C mutation in particular, we're targeting is the most severe form of that disease.

What we're hoping to demonstrate is that a proof of concept that we've essentially restored the glucostasis in these individuals and also rectified many of the negative biomarkers that are associated with the disease like, for instance, enlargement of the liver, high levels of triglyceride, cholesterol and so on.

And this is obviously an ultra-rare disease, and therefore, there are fewer patients, but it will -- we expect demand the opportunity for, obviously, high prices, but also the ability with very small number of patient data set to hopefully achieve a licensure very relatively quickly as part of that.

So we think it is a program that has benefit both from -- certainly from an unmet medical need, but also potentially from a small commercial opportunity that will be a meaningful one. So that's what we're hoping to be able to show you that progress.

Looking forward to it. Thank you so much for your time, and that's all we have for today.

Thank you.

Thank you.

Great. Good morning, everyone, and thank you for joining H. C. Wainwright's 27th Annual Global Investment Conference, September 8 to September 10, 2025. My name is Patrick Trucchio. I'm the senior healthcare at H. C. Wainwright. It's my pleasure to introduce our next company, and next speaker. It's my pleasure to welcome Beam Therapeutics, a biotechnology company, leveraging its fully integrated precision genetic medicine platform to bring lifelong cures to patients suffering from serious diseases.

Beam's suite of gene editing technology is anchored by base editing, a proprietary technology, that is designed to enable precise predictable and efficient single-based changes at targeted genomic sequences without making double-stranded breaks in the DNA. And with that, it's my pleasure to introduce the CEO, John Evans. Welcome to the fireside chat today.

Great to be here. Thank you.

So first, maybe you can briefly introduce Beam's base editing platform, how it differs from first-generation gene editing and what it enables clinically?

Great. So Beam is working on a next-generation version of CRISPR gene editing. It's called base editing. And with gene editing in general and CRISPR specifically, we have the amazing ability to target the genome very precisely. We can choose one spot across 3 billion different letters of your genes, where there's an error and go in and try to fix it. What is different about what we do is that once we get to that target site, we have the ability to make precise single letter changes to rewrite the DNA at a single base pair level rather than just the cutting, which has been the characteristic of previous generations of technology where you can't control the sequence, you're going to get out of the other side of the edit.

So that precise editing is really important because it opens up a lot of new therapeutic territory for us that hasn't been available before. So one is to make more precise and efficient changes, things like upregulating fetal hemoglobin into more uniform and potent way, which we are doing with BEAM-101 in sickle cell disease, but also to rewrite the genome to correct mutations. So a single letter misspelling can cause a lot of genetic diseases. We can now take that single letter, turn it back to normal and leave you with a functional gene. That has not been possible in the past. We deploy that in, for instance, our BEAM-302 program for alpha-1 antitrypsin deficiency, where we correct the single point mutation that drives that disease in the vast majority of patients.

You've demonstrated clinical proof of concept in both ex-vivo and in-vivo base editing. How does this validate the broader platform vision?

Yes. So the beautiful thing about these platforms, these genetic medicines are very complicated to make work. But once you get them to work, they start to work again and again because they're fundamentally programmable. So once we tested in a cell that we can deliver the editing machinery along with the targeting element that takes it to the right place in the genome, and we can detect that we've made the right kind of single letter change, then if we change the targeting element to alter a different part of the genome, it should work and indeed it does.

So the repeatability and the predictability of these tools is quite significant. The same is true of delivery. So in the human body, once we know we can take the blood cell out of the body, put our editing machinery in and correct those cells and put them back in and it works, then we should be able to do that again and again with other blood disorders, same thing in liver. So once in the liver, we do in-vivo deliveries. So now if we take a lipid particle, to package our editing machinery. We can deliver that successfully in an infusion to the liver and treat a patient, then we should be able to do that again and again.

And so what it does is it really sets up a platform, allowing us to make a large number of medicines over time where the investment and maybe the risk we're taking on the first such programs in each of those areas is maybe high but then it gets dramatically lower for programs 2, 3, 4, 5 and 6. So this is really important because what it can do is it can fundamentally change the math of building a drug company and creating a pipeline of medicines, right?

Because now we don't have to guess for programs 2 and 3, are they going to work? Will they get to the target? We know they will, and we can build on the derisking that's already been established in these other areas.

So just moving on to BEAM-101. This is ex-vivo base editing in sickle cell disease. Can you walk us through the therapeutic hypothesis, the edit and how it's intended to work in sickle cell disease?

Yes. So in sickle cell disease, we are creating an upregulation of fetal hemoglobin. This is the protective form of fetal hemoglobin. And we do that by making precise single letter changes in the promoter region of these genes that are known to turn on the fetal hemoglobin. We do it so potently and so broadly across all these cells, they were also really turning down the amount of sickle protein that is being produced. That's the protein that causes the sick cell disease.

And fundamentally, base editing has enabled a deeper resolution of the genotype so that we are getting the blood of these patients farther into the normal range than has been seen before.

So EHA 2025 reported that all 17 evaluable patients that trait like HbF/HbS ratio. Can you expand on the significance of that finding?

Yes. So trait is what we call a carrier in sickle cells. So this is somebody who has 1 copy of the mutation and then 1 copy normal. And they don't have the disease, that's very important. So in genetic disease, we usually look at the carriers as the threshold for where we want to get a patient to because then they would no longer be the disease-carrying patients. And so in sickle cell, a trait person, somebody who has that characteristic, generally has about 60% normal globin in their blood and about 40% sickle globin in their blood.

And that's the bar we got to. We have -- we are actually over 60% fetal hemoglobin, which is protective under 40% sickle globin. And when we looked at a whole wide variety of other exploratory assays, testing the blood under low oxygen conditions, things like that, in all cases, we saw that the blood of the corrected cells that we had edited was performing like a trait person's blood or better.

And then anemia resolution EPO normalization were also reported. How do those markers relate to long-term functional benefit?

Yes. So I mean, anemia, sickle cell anemia is of course the original name of the disease. So we clearly want to resolve anemia, and we do. And I think some of the other programs in the field, maybe aren't quite getting full resolution in all patients of getting up into the normal range of hemoglobin. So that's important. EPO is a sign of adequate oxygen delivery to the body. And so you want to see that come down. That's a sign that, again, the blood is functioning better. It's delivering the oxygen where it needs to go, and the body is reaching homeostasis.

So just all different signs that we can look at that suggest that the drug is working. Of course, along with reduction of vaso-occlusive crises. These are the pain crises sickle cell patients go through and these gene therapies have been really transformative there. We, of course, have not seen any VOCs either here with BEAM-101. So really, the constellation of medical outcomes looks like we are achieving so far, a very robust transformation of these patients.

Right. So no VOCs to date. So I'm wondering how will that translate into your registrational strategy?

Yes. So the registrational strategy here is quite simple. There are a couple of drugs already approved, which we think are really strong with LYFGENIA and CASGEVY. In the case of CASGEVY, that was approved on a single trial with a patient cohort of about 30 patients followed for about 15 months to just test how many of them would have these VOC events. And we believe that same registration path will be open to us. And so something very similar is planned. So we're doing a single trial called the BEACON trial, where we will ultimately treat about 50-plus patients, but the 30 patients, the first 30 will really form that same core data set that was available for the CASGEVY approval, and we've already dosed the 30th patient, that happened over the summer.

So at this point, the clock has started now. We're going to be following those 30 patients that will most likely, we believe, set the timeline to having the data we would need to file.

So can you discuss the timeline more specifically and whether the BEACON trial could support a BLA filing?

So we believe it could. Of course, lots of confirmation still needed over time. But we are certainly planning in that direction, and I think all of our regulatory interactions to date have been supportive of that idea. And so that would mean that once this sort of 30-patient cohort had gotten out to 15 months, we're in the latter part of 2026 now. You would then have all the final data you would need to start writing the BLA and think about getting it on file.

How do you see BEAM-101 ultimately competing with the approved sickle cell disease treatments?

It's a great question. And again, the approved treatments are -- have been transformative for the field and are true breakthroughs for patients. We think BEAM-101 can provide meaningful additional options for patients and a best-in-class profile. So what we bring to the table are potential improvements in manufacturing. We've worked very hard on that. We have a low number of cycles of mobilization. That's the way in which the cells are collected. And so the fewer cycles you go through, the shorter the time between beginning the process to get into your dose.

We have, so far, rapid time to engraftment. That means that when you go into the transplant to get your edited cells, how long does it take you for the new blood to turn on and to start creating immune cells so that you're not vulnerable to infection, creating platelets, you're not vulnerable to bleeding. And so far, we've seen a very rapid onset of drugs. We hypothesize it may be linked to the gentleness of base editing and the lack of gene toxic stress because our edit is so gentle leaving the cells in a really viable state ready to engraft.

And finally, of course, the hematology side, we have the strong 60-40 ratio, the resolution of anemia, et cetera. So we think it's a great option for patients that were eager to see -- reach them. And that said, there's obviously going to be a strong role for the other programs in the field. This is one where I think the industry as a whole is going to need to build up supply and I don't think we will struggle to gain share with the profile that I've just mentioned, but still more to come.

Great. And then just now shifting to ESCAPE. Can you introduce the concept behind BEAM-103 and BEAM-104?

Yes. So with sickle, maybe I'll step back. So everything I just described with BEAM-101 and CASGEVY and LYFGENIA are treating what we consider to be the most severe patients. And in our minds, that's about 10% of the population, where there's -- disease is severe enough where they are going to seek a transplant with chemotherapy because it's the chemotherapy that allows you to get rid of the old blood cells and so that your new edited cells can engraft and take hold. And that's about 10,000 patients in the U.S.

So it's a big market that is ready now for treatment. Our ambition is to go beyond that. We would like to treat all 100,000 patients with sickle cell disease in the U.S., not to mention the millions globally who have this disorder. But to do that, we have to get rid of the chemotherapy. And so we have two basic ideas to do that. So one is to create another ex-vivo version, which is just like BEAM-101, but instead of using chemotherapy, we're going to use an antibody much more precisely to get rid of the old stem cells, replace them with the new ones.

But to do that, we have to make it so that our new edited cells don't get hurt by the antibody, right? And so we have a technology called ESCAPE, which does this. And so with ESCAPE, what we do is we add a second edit to the cell. So one edit is fixing the sickle cell disease. The second edit renders it invisible to that antibody. And all you're changing is a single letter back to base editing, single amino acid, which changes the epitope, the place where that antibody would bind on your edit itself. So now it can no longer bind there.

And so now can independently have the graft growing within the body and the antibody suppressing old cells. So BEAM-103 is the antibody, BEAM-104 is the cell product. So that is moving forward. So BEAM-103 is going to be starting a normal healthy volunteer study just to get the sort of PK/PD parameters on that antibody that will start this year. And that would put us in a position for a filing for a patient IND potentially next year.

In addition to that, we have what we call a Wave 3, which we'll be looking at putting all of that in-vivo. So we would like to just -- now we're using our lipid nanoparticle technology from the liver side of our company to see, can we do an infusion, get to the marrow and do the editing there. And we do see real traction on that and promise on that wave as well. So I think very exciting times to come. I'm quite hopeful. And the bottom line is we're not going to rest until we find a way to get this kind of curative technology to everyone who can potentially benefit from it, well beyond the initial severe population.

And so if ESCAPE is successful, do you envision it would eventually replace BEAM-101 or are these programs complementary?

It's a great question. We don't know. So I think at the very first level, it expands the market for curative therapy because the other 90% of patients will get no gene therapy, right? And so they're just waiting. And so I think it will certainly expand the market. The beauty of ESCAPE is in theory because you're selecting and you're driving away all the old cells, hopefully, as much as possible, you should be able to reach a very high level of efficacy.

And if we do, then I think ultimately, it would cannibalize BEAM-101. If we fall short of that, if we're sort of in the middle on efficacy, or if like an in-vivo set of programs as possible, but reaches only mixed chimerism, that would be therapeutically meaningful for the other 90% of patients. But the very severe patients might still really need that 90% plus cure. And so I think whether it would fully cannibalize or they would live alongside really depends on the efficacy level we achieve for these next-generation programs. With ESCAPE, our ambition is to get to full BEAM-101 like efficacy.

Right. So before we move on to BEAM-302, are there any questions in the audience in the sickle cell program?

Yes. Can you talk about the cost of these therapies and for example, it is the new technology, is it more expensive, less expensive? And then sort of related to that to approvals and that kind of thing.

Yes. So cost is important subject in gene editing, obviously. So the currently marketed therapies are in the $2 million to $3 million range which is high, but it is a really clear value story for the healthcare system. So these are patients who are constantly sick. They're constantly in the hospital. They have certainly lost productive years of their lives and they're on chronic therapies, which are often expensive. So you put all that together and the lifetime cost of a sickle cell patient, who is severe, is in the many millions of dollars, okay?

So ICER is the U.S. cost-effectiveness research body, and they already came out with a report saying that a price of $2.1 million was justified based on those lifetime costs. More recently, actually, Dr. Oz, the Head of CMS, was out making statements about this exact point and made the point again that, yes, these are high prices, but they're worth paying because we're getting patients to a healthy state, and they're no longer going to spend $5 million or $10 million over their lifetime on medical care, okay?

So that's important. So there is actually really broad alignment across the government, across payors to organize around these kinds of payment models, but it's because we're not going to do this for life. We're going to do this once and then you're going to be healthy. So like that's the trick. It has to be a good bargain for society and for the families as well. And we think clearly that this is. So I think there's a lot of tailwinds actually for this pricing model, at least for the severe genetic diseases.

What is the potential for reducing costs? I imagine it is not really [indiscernible] to comment on scale, but maybe you can talk to that.

Yes. No, the costs will go down over time. The cost of goods on an ex-vivo therapy are high, but not nearly $2 million, so there's a perfectly reasonable business case here. The percentage cost of goods is actually pretty normal for a biologic. And over time, we've seen this in the CAR-T therapies that can go down because as you get up to scale, you do this more and more regularly, you can continue to drive that down.

And then as we move into things like in-vivo therapies, those are even more scalable, of course. And I would also acknowledge, I think, the business I just described of a high-priced therapy, ex-vivo in hospital settings, that will primarily be a business in the U.S., in Europe, Middle East, it's for the developed world. I think the other kind of point is that as we get to more and more scalable technologies like in-vivo, that will be required to go global and reach everyone with these diseases.

In-vivo, just in general.

Yes, it's a lot less because you're making 1 batch and then you have vials, right? So it's not 0. It's still complicated technology. But at some level, our in-vivo therapies are the same technology as is in the mRNA vaccines, right? So it's actually pretty scalable to a very high degree. Of course, we give a higher dose, and so that does drive differences.

Do you expect the [indiscernible] where you see that going [indiscernible]?

Yes. So I think, again, I think the general biologics margins are achievable. So are you in the 20%, 25%, 30% range for a while. I think that's a reasonable place to be. Because again, I think it has to be a sustainable business, right? So we need to be able to treat these patients and move on and treat more patients. It has to have value for society, right, where we're going to be helping the system save money over time by helping cure these patients and the technology has to be scalable enough to reach the patients who need it. Those are the constraints that I've seen.

So I did want to get on to BEAM-302 with some of the time we have left. So maybe you can walk us through the mechanism, mutation you're targeting, what makes this a dual action therapy? And then maybe you can talk us through some of the initial data that's been generated and why it's so promising?

Absolutely. So BEAM-302, as I said, is correcting the single point mutation in alpha-1. It is a dual action therapy because what we're doing is we're treating the disease at its root cause, right? So we fixed the single letter that's wrong in the organ that makes this protein for the body. That's the liver. And so you have two toxicities of this disease. One is it creates a mutant form of the protein that builds up in the liver and causes liver failure. And because of that, it's not secreting, you have low level systemically and the protein is less functional, so you're not getting protected. Your lungs are actually vulnerable when you're infected to degradation and you get this emphysema, lung failure.

So simply by editing the gene and fixing that 1 letter misspelling, we simultaneously stop making mutant protein that will hurt your liver and start making normal protein that will secrete, raise your blood levels and will protect your lungs and stabilize your lungs. So it is a dual mode of action. It's also, of course, going to be normally regulated, which means it will turn on and off in the body the way that it normally would because we fixed it in its normal location in the genome.

So we've already shown at our third dose cohort of our trial, we showed this in March. At 60 milligrams, we got patients into the double digits for their total alpha-1 levels. They generally live in the maybe 4 to 6 range for alpha 1. It's all Z, the mutant protein. And we got patients up to 12.5. Anyone in the 10 to 20 range looks like a carrier, so similar to the sickle story, that's a person who should not progress and should be safe for the long term. And of that 12.5, 90% of it was the normal protein as opposed to the Z toxic protein.

So that's a really major transformation of the profile and the normalization of the AT physiology that we think looks like a curative therapy. We're now in, what I consider, late-stage dose escalation, sort of trying to optimize the dosing schedule and make sure we have all that correct, get the right balance of safety and efficacy before we think about moving forward to hopefully registration.

So program received RMAT designation. I'm wondering if you can talk us through the regulatory strategy and what your conversations with FDA will look like from here?

Yes. So RMAT is the breakthrough therapy designation for gene therapies. We've received one for sickle cell BEAM-101 and one for BEAM-302. And the FDA looks at the data before they give you that. So you can interpret from that, that they're at least enthusiastic enough about the data to talk to us more because that allows us to have more frequent interactions with them. And generally, I think the goal here is with them to identify what that path to market is. There's a variety of options ahead for us.

I think we have been pretty open that all things equal when you are a precision medicine like this, you know who you're treating, you're right on the fundamental disease mechanism and you have the kind of dramatic results we've already seen early in Phase I. Generally, as a drug developer, I think that sets itself up well for something that is more accelerated. And there's different flavors of how to do that. And that's certainly what we'd like to explore.

Of course, also over the longer term, generating the kinds of longer functional outcomes that, of course, are interesting to regulators as well. So that's the zone where we're working. I think we'll be working with the regulators frequently over the near future. We hope in early '26 to be able to give both a next data update, but also potentially give some insight into where we've gotten with the regulators on the path to market. But I'm pretty bullish about finding a path to patients for this pretty exciting drug.

Great. And then maybe just briefly on BEAM-301 for the audience, if you could introduce this program and just sort of what's the status of this program?

Yes. So BEAM-301 is another liver program. So back to where I started. Once we've done it once, it should be easier and easier to do it again and again. This is the same LNP, the same kind of editing, just a different targeting element to take us to a different part of the genome where these patients have another single letter misspelling that we can try to correct. And in this case, patients can't fast. They can't turn glycogen back into glucose from their livers, including when they sleep. And so they're constantly going hypoglycemic and that can literally be fatal. So it's a terrifying situation at kind of constantly eat cornstarch every few hours to survive and we would like to normalize that and cure them.

So this is a much more orphan disease than alpha-1. Alpha-1 has about 100,000 patients. Here, there's hundreds in the U.S. with a single mutation, but we're testing it, and we hope to see something dramatic there. This, again, would set up for then future liver programs. And we have a pipeline coming of other liver diseases that we think would be curable with the same approach, always using LNP delivered to the liver and base editing.

So again, once you get the variables out, you're starting to do the same thing again and again, we think we can move faster and faster and treat hopefully, a large number of people with some severe disease.

And just as a final question, what should investors be watching most closely for the remainder of 2025?

Yes, great question. I think for the remainder of '25, we have, obviously, our ASH update, so we'll get another look at BEAM-101 in sickle. I think the -- just operational progress across the board continue to move forward on 302, we're quite excited about. And then sort of where I landed at the end, I think maybe not this year, but hopefully, sometime in '26, we can give a little bit of insight into some of the other things we're working on and where this platform is going to take us because we do see a really dramatic potential to impact a lot of people.

Terrific. Well, thank you so much, John, for joining us. Thanks to Beam. Thanks for everyone. It's great to see you at the conference.

Thanks, everyone, for being here. My name is Yanan Zhu. I'm one of the biotech analysts here at Wells Fargo. It is my great pleasure to introduce our next fireside chat. We are privileged to have the Beam Therapeutics team with us. And here on stage are John Evans, CEO; and Pino Ciaramella, President of the company. Thank you, Pino, and thank you, John, for being here.

Thanks for having us.

Great. So I was wondering if you could start off by providing an overview of the company and any upcoming catalysts that investors should keep in mind?

Sure. So Beam Therapeutics is a next-generation gene editing company. We use an important form of CRISPR called base editing, in which we use the same precision targeting ability of CRISPR to edit any spot in the genome, but we've modified the system so that it doesn't make double-stranded breaks where you lose control of the sequence. Instead, we're making precise single base changes at the target site.

So much more precise and much more predictability in terms of the therapeutic outcome that you're going to have, all for a durable onetime therapy for very serious diseases. We're applying this very broadly, but probably our core franchises are in 2 areas. One is hematology. So this is where we take the blood cells, we edit them directly to try to cure disease, lead programs in sickle cell disease.

So BEAM-101 is our version of correction edit for sickle cell and an ex vivo transplant that is mid-clinic. We've shown dramatic proof of concept there. We believe that's a best-in-class product moving rapidly through the clinic. That is then followed by 2 more waves of technology, which will come to try to treat sickle, may have applications beyond that, which would try to bring that same functional cure to many more patients.

First, by getting rid of chemotherapy in the transplant process. We call that the ESCAPE technology moving to the clinic in the medium term, followed by in vivo delivery directly to the bone marrow. So a series of technologies that I think could be transformative for these patients. The second big franchise at BEAM is our liver franchise, where we're going to be using simple lipid nanoparticles to do in vivo infusions, just a couple of hours in the chair to then edit the liver directly to correct a variety of severe genetic diseases. The lead program there is for alpha-1 antitrypsin deficiency. So BEAM-302 is our program there.

BEAM-302 is a single base correction of the point mutation, the single-letter misspelling that causes alpha-1, a very severe condition. And again, as with sickle, we have shown dramatic proof of concept for BEAM-302 in patients in early Phase I data. That was back in March. We believe that is a best-in-class profile and now, again, starting to accelerate in the clinic for a very high unmet need, very large patient population. Behind that, we have BEAM-301 for glycogen storage disease and a variety of other liver programs beginning to line up behind that.

Great. Let's jump into the AATD program, which seems to be the primary focus for investors now. Can you give us a quick review of your Phase I/II study, including the data that you reported for the first 9 patients in the 15, 30 and 60 mg group? And you have since dosed more patients? And can you talk about initial observation from the additional 8 patients you dosed?

Sure. So I'll do a fly over here of the data we presented in March. So we're doing a dose escalation where we give increasing amounts of the drug over time. We did 15 milligrams, 30 milligrams and then 60 milligrams, 3 dose cohorts, 3 patients each. That was a 9-patient data set. And we saw a very clear dose responsive effect, and specifically, at the 60-milligram dose, that third dose cohort, we saw therapeutic effects. So beyond all the thresholds we would think would be needed to cure the disease.

And so specifically, what that showed was patients who were going from a baseline where these are patients who are only making the mutant form of the alpha-1 protein. We call that the Z protein. So these are patients who have a ZZ genotype. And they're may be in the mid-single digits for a level of alpha-1 protein in their body, and that's all Z. So Z is less functional. It is less effective. It also causes toxicity, both for the liver and systemically. So there may be 4 to 5 micromolar of Z. On therapy after the 60-milligram treatment, we turned that into 12.5 micromolar of total AAT. So obviously, a dramatic upregulation there.

And the mixture of that AAT is almost all what we call M, which is the normal form of the protein. So we had about 11 micromolar of M and just over 1 micromolar of Z remains. So not only turning on a lot more AAT in the body, but it's all that normal functional M protein and much less of the toxic Z. So we think all of those components are important, both higher total levels, higher functional AAT in the body, production of M to a high degree and elimination of Z as much as possible.

The reason we think all those are important is because when you look at people who are carriers of the disease, they have one copy of the Z mutation, but their other copy is not Z, it's some other allele, they don't have the disease. okay? So they are not progressive. Their lungs are protected and function normally. Their livers are not getting toxicity, whereas in patients, the Z protein is both causing liver toxicity and failing to protect the lungs from progressive toxicity over time. And so our 60-milligram dose cohort looks like a medicine to us. It gets patients well out of that disease phenotype and into the zone where we would predict that they would not have any further progression.

From here, as you noted, we're going to do some additional dose exploration. This is our one chance to do it in the latter part of Phase I. So we're going to do a few different things. First, we're adding more 60-milligram patients because, again, we think this is a potential drug already. And then we want to push for more exposure to see, can we pick up more editing? Can we drive levels higher without sacrificing safety because the safety profile here has been very clean so far.

So we're basically following 2 axes on that exploration. One is to add more single dose potency. So we're going to go to a 75-milligram cohort. And then the second is to stay at the same dose but add more frequency on the schedule. And so do a 2-dose regimen of 60 milligrams each separated by 8 weeks. So this just tests different sort of pharmacodynamic ranges for the drug. What happens if you had more drug, what happens if you add a second time and see what we get in terms of AAT levels, transformation, creation of new M and then obviously, safety. Our goal is to bring all of that back by early '26 and get a read on where we think the optimal dose and schedule is for a registration push.

Right. Thanks for that overview. I do want to touch on safety because that's something that's notable from your data report. Safety has been very good with Grade 1 observations only. Could you talk about any specific design feature of your LNP that might account for this profile? What is your -- how about your expectation for tolerability profile with a second dose?

Yes. Thanks, and thanks for the invite, by the way. And so the LNP has obviously 4 components to it. And one of the components is ionizable lipid, which is an ionizable lipid that we have in-licensed from a third party, which is biodegradable. And the nature of biodegradability certainly helps to that tolerability component. But it's important also how you assemble the LNP together. And at the company, we have extensive experience actually of doing LNP from various prior lives as well as what we've been doing here. And so I think we paid a lot of attention actually making an LNP that we had introduced all the features and the manufacturing process that we felt was important to be able to do that. And thankfully, the data is backing that up and gives us the opportunity to do that.

So the second dose, actually, we're now expecting to see an additional tolerability component. And in part, in order to maximize that fact, we are going to give the second dose 8 weeks apart. And what that means and the reason why we've chosen the 8 weeks is because the -- by that time, by the time the second dose comes, the lipid from the first dose will be completely washed out of the body.

And therefore, the second dose will be a second first dose. So there will be no accumulation of the LNP. And so that would essentially -- our expectation is that it will behave just like the first 60-milligram dose. So -- and that was the opportunity, like John said, to explore situation in which you increase the AUC, the area under the curve without pushing basically the max higher. And obviously, with 75 would be pushing the Cmax as part of that. I think we've already disclosed that with 75, we've seen some initial tolerability data, which is as good as the 60, so grade 1 or below. So I think it's really behaving as one of the best LNP, frankly, that I've seen.

Got it. Thanks for that color. And then let's talk about the 12.5 micromolar because that's something you highlighted. Obviously, you could get even higher with further studies, which remains to be seen. But just wondering for this level, you said it's a therapeutic level already, right? In your interaction with physicians or patient community, what's the sense and they're feeling towards this level as an outcome?

I think the patient and physician response has been overwhelming. I think there's a lot of enthusiasm for what we've shown. This got picked up in the New York Times, and we got patient e-mails from around the world. I can tell you that the physicians have never seen something like this, right? So the field to date has really only had augmentation therapy, right?

And augmentation therapy, you're basically adding some extra M protein into the system. That's the normal protein. But it is going to gradually wash out of the system. It isn't regulated normally. It doesn't turn on when you're sick, which is what your gene will do. So our numbers are, in some ways, a floor. They will go up when the body needs more. With augmentation, that doesn't happen. And you aren't affecting Z. The body is still making a lot of Z. So the liver is going to be sick. It's going to interfere with lung function, et cetera. So it's a good option for patients, but it's not perfect. It's not a cure.

And so this BEAM-302 is the first time that the field has seen a potentially curative fundamentally addressing the root cause of the disease medicine. And so I think you can see in our enrollment rate, which has been very swift that there's a lot of people signing up. We have waitlists. We have a lot of investigators who have been eager to get involved. And when we do informal and early market research, we do test these sorts of profiles. And I think it seems clear to us that the target product profile that we're showing of a onetime correction that gets you into these carrier ranges that is raising your M and eliminating Z, and you only take once and you're then freed of chronic therapy is very popular.

Got it. Got it. Could you be a little more specific in terms of in your market research, when you put forth the profile into the carrier range, did you give a specific micromolar number? And then also from that research, do you get a sense of the proportion of patients who will be pursuing the therapy?

Yes. I think we -- I think it is a significant proportion. I'm not going to give specific ranges or numbers, but it is not only a large proportion, but we think it's the winning proposal. It's the winning TPP when you kind of compare it across different options.

Now in terms of levels, I think there's obviously a lot of debate about that. Physicians in the community, they are used to numbers in the mid-teens, let's say, for augmentation therapy, right? So the augmentation gets you to about 16. But it's really apples and oranges, if you think about it.

So that is a number that will not go up when you're sick, right? Whereas our numbers will go up to that and higher when people are infected. So they operate differently. And the 16 is really about 11 M on top of a remaining 5 Z, right? So the Z is the baseline. That's already there. It's still being produced by the body. The augmentation just goes on top of that. You haven't corrected the toxic protein. So in our case, we're really substituting and replacing toxic protein with normal protein, really turning it into 11 M and it will go up on therapy.

So I think that, that's really where we get the confidence to say we're already in what we believe is a functional curative range. It's not to say that we can't go higher. I think we probably can, and we'll be exploring that and pushing on those in the ways that Pino mentioned. But back to the clinical genetics, we know that a person with the profile that we have just produced using this drug would not have any progression and wouldn't have the disease.

Got it. Got it. Speaking to potentially also getting even higher levels, you did dose 3 patients at 75 mg cohort. Of course, the data will come early 2026, along with the data from this double dose 60 mg cohort, which you haven't dosed a patient yet, I assume. But just on the patient you dosed on 75 mg, I think you did mention something about dose response in your -- you haven't given any detail, but you did mention dose response. Can you give us a little more color on what that means and how to think about that?

Yes. So in addition to the safety that Pino mentioned, we also do see signs that as a fold change, so how much -- what percentage does the alpha-1 level go up for a given patient after therapy. We do see that 75 may be giving us more than the 60.

That 60.

That's right. But I think it's early days, and there's a lot of follow-up still to do.

Got it. Got it. Very helpful. Definitely looking forward to the early 2026 data. Then your competitor reported data yesterday. This is the RNA editing approach. This obviously had -- there's a lot of investor discussions. So I was curious if you could comment on your thoughts of that data. Yes, please.

Yes. I think the data sort of indicates and support the profile that we've already disclosed with our program is frankly superior to what has been shown yesterday. And I think what we were talking before is very important is that quantity is only one aspect of what we need to look about quality and quality by quality means how much M you actually have is really the critical data point here.

And unfortunately, for Wave, what was disclosed is that the total level of roughly in the same ballpark as we are, but actually the amount of M is -- or actually, I would say the amount of Z that is retained is significantly higher than what we are seeing. Depending on whether it's the 200 mg or 400 mg there, I think it's between 40% or 60% of Z that is residual. So a significant component of those 12 is now actually Z and M is only a fraction of that. I think it's between 4 and 7 micromolar, if I remember correctly, the data.

So that is the issue because Z, in my view, is the offending protein. Ultimately, what you want to eliminate is that Z because Z is not only a clear function of an accumulation in the liver because obviously, there's going to be more Z in the liver than what you see in the blood because the Z is not secreted that well. But also Z in the blood in itself actually contributes to inflammation of the lung. It is actually a chemoattractant for neutrophils, for example, it forms polymers. And so the elimination of Z has a direct impact on both liver and lung disease. And so you really want to eliminate that from the system.

And the other aspects of the data, at least from my interpretation, seems that already a 200 milligram of antisense oligos, the system that they're operating seems to have hit a saturation level. And so it remains to be seen whether additional dosing may unlock that, but at least that's from the initial data that they've disclosed.

Yes. Maybe I'd add only one thing to that, which is we talk about total levels. There's another key readout, which would be functional AAT, right? So in functional AT, you directly measure the concentration you're getting of protein that is effective at inhibiting neutrophil elastase and binding to neutrophil elastase. That's the role of AAT to protect you from infection. And so we've quantified that.

And so in our case, with the 12.5 micromolar, you're getting 11 micromolar of M and our functional is right around 11, right, or more. So it's nearly all functional at that point. So the issue with having a lot of Z left over, Z is much less functional, right? You get a little bit of activity from Z, but not much. And so it wasn't quantified in the data set, we would predict the functional AAT readouts would be lower as a result.

Maybe one additional point to add is that, to some extent, if you look at the preclinical data, it's probably what we are seeing could have been predicted. They seem to have reached a 50% editing sort of ceiling that they couldn't break through. And so maybe as a consequence of the mechanism of action, in that case, the production of Z mRNA is left untouched. So you have a continuous production of Z mRNA. And so then now you're asking the system to be able to take care of all of that amount in a meaningful way so that you actually see the overall reduction of Z. And it seems that, that may be difficult to achieve with that approach.

Got it. Got it. Maybe let's switch to regulatory perspective. Congrats on the recent RMAT designation for BEAM-302 in AATD. Does it allow you to interact with FDA on a frequent basis? Is the dialogue starting? Or has it started? When could we hear some updates from there?

Yes. So it does. And we've had a lot of interactions with the FDA. We often get questions about is the FDA still open for business? Is everything on track there? We think it is. In fact, the RMAT designation for alpha-1 came in early before it was even due. We have many of the same reviewers all showing up to all the calls. So I think it's all on track. We won't obviously give much specifics in terms of when we're interacting with the FDA or exactly what the dialogue is like. But that is certainly something that is ongoing in parallel.

I mean one of the reasons I characterized the kind of late-stage dose exploration that we're doing in Phase I as this sort of bake-off between these different sort of possible doses and schedules is we want to finalize that because we want to move forward to a registration path. And so in parallel to that, we need to align with the FDA what that is. And so part of the early '26 update that we're planning would be not just data, but we would expect to be able to give some color commentary on what are we hearing from the FDA, what is the path to market and what is the way to get this filed.

I think the -- our expectation of a drug that is working on the fundamental mechanism of the disease in this way and has the dramatic effects like this is having is that we may have access to some sort of accelerated pathway, based on levels, the total AAT, functional AAT, production of M, reduction of Z. Those are all independently predictive of clinical benefit in their own way. And of course, altogether, we've shown really correcting the pathophysiology of the disease. So we'll see.

We have to work through that with the FDA. But I think that remains our sort of base case assumption. And the alternative would be we have to go do a randomized trial. Those are also doable in this disease. That would take a little longer. But I think a drug that is this dramatically active early in development, in my experience, tends to be a candidate for finding a faster path to patients and then following up, of course, with longer-term studies to build out the data set.

Right. That's super helpful. And I certainly think one of the investor focus is whether -- as you were saying, whether FDA would be okay with using serum AAT as a surrogate marker for accelerated approval. You did mention the clinical benefit and that's going to be the key rationale for FDA to agree to use this pathway. I was wondering, could you elaborate a little bit more making a case, I guess, if FDA is awaiting this information, you would need to present the case why this is the appropriate biomarker. Could you give us a sense of how you will make this case?

Yes, maybe I can take that. So first of all, the important thing that I want to stress is that the data that we are able to generate is not just serum AAT level, which clearly is an important thing. But it's the demonstration of M going up, Z being reduced, the functional activity are all consistent to basically the gene function that is what we are restoring.

And the reason why that is important is because that has never been possible to do before. Enzyme replacement therapy does not do that. It does not take care of Z, right? It does not -- and by the way, upregulation is also what we expect to see because the promoter region is exactly the same. So it's really that totality of data package that demonstrate the restoration of the gene unquestionably, frankly. And I think even the data that we've already generated demonstrates that. And there is a very strong understanding of the relationship between the gene function or the Z protein and why the disease is progressive.

So the science basically is absolutely well described in the literature and for many years that if you then now are restoring the functionality of the gene to the extent that we do, particularly when you are recreating essentially an MZ profile as we are doing with 20.5%, but importantly, 90% of that being M and potentially even greater than that. I think it's going to be difficult from a scientific point of view to suggest that, that's not evidence of restoration of the gene.

Now will they accept that, that may be supported additionally by some clinical evidence. It's possible. Our most optimistic would be that gene function restoration should be sufficient or could be sufficient for a full approval. Should that not be the case, it's probably -- we would expect that at least an accelerated approval on the back of that should be certainly scientifically valid and supportable.

And then at that point, you may support some confirmatory trial data potentially with some clinical endpoint. And in that case, we think that actually CT densitometry is the way to do it. And there is -- it's not yet completely endorsed by the FDA. It certainly endorsed by the EMA, but there is definitely sort of a hint that they are considering that very strongly. And the body of evidence of CT densitometry is the way to characterize the alpha-1 is becoming so overwhelming that actually, I think they would find it difficult not to accept that.

And in that case, CT densitometry, there is publications already available with natural history data that looks at untreated individuals, you should be able to see with 100 or so individual over a period of 2 to 3 years already see the benefit basically that the dose would do, particularly with the strong data that we've already generated. So the effect size is fundamentally huge in this. So I think that's our position, and that's really the argument that we're going to be making.

Great. Thank you for laying that out for us. It is a very convincing compelling series of agreement. I appreciate that insight. Obviously, the company -- we touched upon it multiple times, you will have an update early 2026. I was wondering 2 things. One, could it be as early as the January conference, for example? And I was also -- can you also give us a sense of the data, what it would look like at that time?

A curious question given that you talk about the importance of the M level can go up at the period of acute phase reactions. Any potential that you can capture an event like that by the next update?

Yes. So I would say I wouldn't look to the health care conference. That's the very beginning of '26. I think guidance is really early. So you can think of that as the first quarter thereabouts. So I think in terms of what we would share, we'd like to see, obviously, all the same things we've been looking at here, right? So you want to see total alpha-1 levels, you'd want to see functional levels, you'd want to see how much M is being produced, how much is Z being reduced.

We would have quite significant durability at that point across all of our dose levels, of course. I think the -- obviously, very earliest patients would be out to a year or so at that point. And even some of the 60 mg patients would be maybe half a year or more. And then, of course, less with the more recent cohorts. But I think that would give a good sense of durability, which, again, we expect to be rock solid given its gene editing. And then yes, we will be looking at inducibility. That's -- that one, you have to get a little lucky. It was nice to see in the data set from Wave yesterday that there was inducibility shown with a fortunate or unfortunate, I guess, medical event, but they got a good reading on it. So we're definitely looking to see that. But that's exactly what would be expected from these editing modalities.

When the gene turns on, you're going to create a lot more transcripts, right? And in the case of RNA editing, you edit a similar proportion of those transcripts, and that was what was seen by Wave. In our case, of course, all the transcripts would be corrected. And so you would just be generating a lot more M. So I think that would roughly give you a -- I guess the last thing that would be part of that data set, we will be dosing patients in what we call Part B of the trial. So recall, most of the patients we've been talking about to date are in this Part A, where it's the majority of patients where they are primarily liver disease -- I'm sorry, primarily lung disease with maybe some liver. And we have been excluding the patients who are -- really have sick livers, right?

It's probably about 10% to 15% of the population where liver is actually the leading symptom more than lung. And so we're going to bring those into this second set of cohorts. We talked about initiating enrollment already in that. We're going to start at 30 milligrams. Drug has been safe enough. We don't have to go back to 15 the way we did with Part A. And so I expect to have some number of patients dosed as well and give a read on the safety in those heavy liver involvement patients at that time as well.

Got it. Got it. And what about the 3 to 6 patients for the double 60 mg dose? Do you expect most or all of the patients with data there?

Yes, we expect to include those patients, obviously, will depend somewhat on recruitment, but we think that, that should be part of that data package. So you would have 60 mg, 6 people, 75 mg, 7 people -- 6 people and then some of the Part B. So we intend to share all of the data that we would have available at the time.

And importantly, also maybe greater clarity on the regulatory impact as part of that, which I think is obviously of interest and important as part of that. And as far as inducibility is concerned, we obviously -- we're measuring CRP as well, just like you've seen from -- and I don't know, we're hoping on the flu season coming up. So we'll see how it goes.

Interesting. Lastly, I was wondering if you are able to comment on the Prime Medicine's move to develop a Prime editing treatment for AATD.

Yes. So in this competitive landscape, you've obviously got RNA editing. I think there are multiple players out there. The preclinical packages look comparable, right? And so we've seen, obviously, one of those from Wave. Let's see more. It's a big disease. So it has room for a lot of different kinds of modalities, although, again, we feel quite good about where BEAM-302 and base editing stack up.

You have next-gen augmentation therapy coming, which is interesting. There, again, you're not going to be regulated normally. You're still leaving Z in the system, but you might have longer-acting, less frequent dosing for the M that you're adding. That's interesting as well.

Then there will be certainly other gene editing approaches, right? And so there's a few of those. Prime is one. So we actually are partners with Prime. We have exclusive rights to Prime editing for making transition mutations. So that's a place where there's actually an ongoing legal dialogue with them over that program in terms of their rights to advance it relative to our development in alpha-1.

So obviously, we'll let that play out. But there will be other gene editing players come forward. I mean it's not going to be an edit 1. I think the real question is really for BEAM-302, is there anything we have left unfixed, right? Is there really unmet need. I think if we can edit the entire liver, if we're creating M, if we've really eliminated Z, at that point, I'm not sure how much room there is to improve with additional gene editing plays. But again, patients benefit from having more options. And ultimately, that's a good place for the field to go.

Great. Great. In the remainder of the time, let's discuss sickle cell. You completed enrollment for the pivotal study, and you dosed 30 patients as of July and plan to provide an update at year-end '25. What will be the focus for that data? What is the -- at what point do you plan to discuss the regulatory path with FDA? And do you need -- like how much data do you need to start the filing?

Yes. So we think that the regulatory path has been described already through the Casgevy approach, and our approach is very similar. So that's where the 30 patients' data package is really very similar to what they have done. So we think that there is already a path to that.

Incidentally, we've also announced that we started to dose adolescence. And so we plan to incorporate some of that as part of that. So we -- in terms of when we look to interact with the FDA, we'll be -- we don't provide the dates in particular, but we have basically the data package already to start some meaningful interactions with them. And so very -- as soon as we have greater clarity, we'll obviously disclose that. But we're very confident about what needs to be as part of that BLA package in order to support the licensure and because there's a precedent basically.

Yes.

And you had mentioned ASH. I think that we'll have an update at ASH that really starts to show expanded durability, right? You have patients -- a number of patients out past a year. And obviously, we would hope to see the same signs of strong differentiation we've seen previously, both in the process, a few cycles of mobilization, faster time to engraftment than what has been seen previously as well as the hematology parameters, higher levels of F, lower levels of S in terms of eliminating sickle protein and resolution of anemia.

Got it. Got it. Great. I think that's all the time we had today. I wanted to thank the team for a very wholesome discussion and all the insights that you provided for our audience. Thank you for being here.

Thank you.

Thank you very much.

Thank you, everyone.

All right. Good afternoon. My name is Sam Semenkow. I'm one of the Biotech analysts here at Citi, and it's my pleasure to be hosting Beam Therapeutics for a fireside chat. I'm joined by CEO, John Evans; and CFO, Sravan Emany. John, Sravan, thank you so much for being here.

Thank you for having us.

Absolutely. So why don't we just jump right in then. Tell us a little bit about Beam. Tell us a little bit about some of your programs that you have going on, and then we can just dive deeper into each of them from there.

Wonderful. So Beam is working on next-generation gene editing using CRISPR tools. Specifically, our lead technology is a technology called base editing, which allows us to precisely target the genome similar to other CRISPR companies. But once we get to the target site, we make a much more precise edit without needing double-stranded breaks and generally create a single base change. So this is useful in a lot of different contexts. We have two major franchises under our control.

One is in hematology, working on sickle cell disease, lead program BEAM-101 for severe sickle cell disease. We think a best-in-class option for patients with this disease, followed by some next-generation versions, which attempts to deliver that same functional cure, but in increasingly accessible ways, dispensing with chemotherapy in the case of non-genotoxic conditioning or just in vivo delivery directly to the bone marrow. That's hematology.

Then on the liver side, we're doing direct LNP injections to treat liver and edit the liver. Lead program is alpha-1 antitrypsin deficiency, BEAM-302. And that program also has shown very strong evidence of correction of the causative point mutation for alpha-1 and restoring patients to sort of a therapeutic range. And I'm sure we will talk a lot about that program, followed by BEAM-301 for glycogen storage disease and then what we see as a real scalable franchise of additional liver targeted genetic medicine programs behind that.

Of course, many other places we can take this platform over time, but those are really the focus areas for now. Very well financed with $1.2 billion in the bank. That's cash into '28 and certainly sufficient to do a lot of different things with that pipeline through some really meaningful milestones.

Perfect. So you're correct. I would love to talk a little bit more about the AATD program. So there's some competitor data out this morning, but maybe let's just go ahead and start first with what you've shown to date and some of the context you've given even around some of the higher dose cohorts that you've run. And just maybe a high-level overview to level set.

Yes. So what we're trying to do with BEAM-302 is to correct and edit the causative point mutation in alpha-1. This is called the Z mutation. So this is a single base change where you have a G where there should be an A in the gene for this alpha-1 protein. And your body should normally be making alpha-1 in the liver. It then is circulating around the body where it will protect your lungs from degradation when you get infected, but also is being secreted out of the liver quite efficiently.

When you have this point mutation, two things go wrong. One is that you have a mutant form of the protein that builds up in the liver and causes liver toxicity. And because it is building up in the liver, it is no longer secreted, so you have low systemic levels and that causes the lungs to be unprotected and they become degraded over time. You get emphysema and eventual lung failure. So our job with BEAM-302 is to go in and make that single letter change, the base editing is so good at and turn that Z mutation back into the normal, which is called M. So the normal is M, the mutation is Z. And that's exactly what we do.

And so what we showed in March was our initial data out of our Phase I trial. It was over nine patients, three different cohorts, a dose escalation as we give larger and larger amounts of the LNP. And indeed, at the third dose cohort that we tested, which was 60 milligrams, we saw striking evidence of therapeutic correction of this gene. We had seen it at lower dose cohorts as well. There was a dose response. It was quite clear. Specifically, what we saw was total alpha-1 levels get up to about 12.4. And of that total alpha-1, 90% of it was M, was this corrected form and only 10% was Z. So very strong production of M and reduction of that toxic Z, the Z was down about 80%.

So -- now why are those numbers important? Well, we know that patients with this disease, what we call ZZ patients, they have two copies of that bad gene. They generally live in the total alpha-1 level range of about 4 to 6, right? So they're mid-single digits. There are no ZZ patients who live in the teens, okay? So that's quite clear. And of course, it's all Z. There's no M. And so the fact that we've taken these patients into the double digits or higher, that it's almost all M.

We look much more now like what I would consider a carrier, somebody who maybe had one copy of the bad gene, like the parent of a patient, okay? But those people are normal. They don't have the disease. And so that's how we know that the editing that we have produced has gotten patients to a therapeutic zone. On top of all of that, we also showed, of course, that the LNP we were delivering was well tolerated. The base editing was well tolerated. So the safety looks really good. That continues to be the case. And of course, this is a onetime durable correction. So we literally could treat the patient once and have them have a lifetime of benefit. And of course, that's something we're following now.

That's good overview. In the higher dose cohorts as well, you have a 75 milligram. You qualitatively have talked about how you're seeing a dose response there above the 60 milligram, and you've also expanded to do a multi-dose cohort for the 60 milligrams and you've added some more patients. How are you thinking about what the ideal dose could be for 302?

Yes. So building on the idea that we're clearly in the therapeutic range, and we think 60 milligrams could very well be a great dose. We still want to push and explore, particularly because we've been so safe, we think we have the latitude to do that, and we wouldn't want to leave efficacy on the table. And so what we're really doing is what I consider sort of late-stage Phase I development where you have one opportunity to really get this right.

We want to thoroughly explore dose and schedule parameters even while we think about what the next step is towards registration. So that's going to take a few different forms. So we're expanding on the 60 milligrams. We're adding more patients there. We have initiated -- and then there's sort of two axes we're going to explore. One is to go higher on single dose, and that is the 75 milligram dose, and we're adding six patients there. And the idea there is you're now going to push higher on the Cmax of the LNP, which can potentially penetrate the liver a little bit more.

And then the second axis we're going to explore is AUC. So what happens if we add a second dose, but there's still 60 milligram doses. So now you see your Cmax' will be the same, but you're adding more total exposure separated by 8 weeks. And again, preclinically, we see that, that does indeed add editing. So a little bit of an empirical experiment, but it will help us really understand that relationship, I think, of safety, dose and efficacy.

As you noted, just the early sort of qualitative read we gave at our last Q was that as we're dosing, we do continue to see good safety and tolerability, including the 75 milligram cohort. And yes, we are seeing signs of dose response where especially we measure this as sort of a fold change above baseline. We do see that climbing up at the 75 milligram over the 60 showing that there is still some editing still to be done in this liver.

So all of that is going to come together. We're going to plan to give a data update in early '26, where we can hopefully present all of that data together along with dosing some of the -- what we call Part B, some patients with liver involvement and just check to see that the safety is the same in those patients. That should altogether give us a very clear idea of where are we going to be for future development as we push towards registration of what we think is clearly a drug.

And how do you think about -- or is there a way to sort of get an estimate of what editing level you're achieving so far with the 60 milligrams? Because you noted that clearly the 75 is showing you that there is more room to go. How much more editing could you achieve within the bounds of the clean safety that you're currently seeing?

Yes, it's a great question. It's something that until we do liver biopsies, we won't be able to know for sure. And we actually are going to do some liver biopsies in the liver patients that we're testing both as part of a safety test. Also, we can potentially look at editing. And of course, you're going to look at Z protein aggregates. This is what builds up in the liver and then hopefully see some of that resolve over time, which we expect it will. But until we do that, we're really looking outside in. So I think that there's good evidence that we are -- we've edited a lot of the liver. I think we're clearly north of 50%. If you look at our MZ ratio, for instance, right, we're 90-10 MZ.

A person who is a carrier, as I said, that threshold for not having the disease, they're generally at an 80-20 ratio, right? So we're north of that. On the other hand, there's still some Z around. And so clearly, we have not edited the whole liver yet. So being more precise than that, I think, it's probably impossible at this point. I think frankly, we'll learn a lot this year from these additional dose cohorts that we're adding to see how steep is the further dose response? Are we -- where do we start to see plateauing? Or is there still a good dynamic range ahead? That will tell us how much left of the liver there was to edit, and we'll learn a lot from that.

Got it. And in the update in the first quarter of next year with the Part B, specifically the liver patients, what doses are you starting at? And what doses do you think we could -- would it be more than one dose that potentially ends up in that data readout? I'm curious because you mentioned about the biopsies. So I'm wondering if we can get a feel for that editing level at a couple of different doses in that readout.

Yes, great question. So just stepping back, so everything we've done to date has been in what we call Part A, which is patients who are primarily lung. And basically, what we've done is we've excluded the minority of patients who have really heavy liver involvement. Like livers are really sick. We wanted to get a sense of the tolerability of the drug without that factor, then go back and dose those patients. So those patients are in what we call Part B. It's really just a clinical experiment that we wanted to do to get a clear signal in both populations.

We don't anticipate much of a difference. These patients have sick livers, but we have dosed LNPs to animals with heavily involved livers. The field has dosed LNPs to people with sick livers before, and it has been tolerated. So I think we're quite hopeful there. But that's a check that we want to do. If that's successful, I'd say the goal would be then to bring everybody back together again. So we don't check for liver status as we go forward. That's probably the base case expectation. This is probably 15% of the patients who have this kind of liver involvement.

So in terms of biopsies, I think it would be unlikely that we'll have biopsy readouts by the early '26 sort of update. That would probably be some pharmacodynamic data we'd have to bring subsequently. But I do think we will have some number of patients dosed, and that will give us a sense on the safety question and how we're treating that population going forward. Part B is going to start at a higher level than Part A did. So we'll start at 30 mg. And from there, if that's tolerated, we'll likely go to 60 mg or something like that, and that may be...

Got it. Okay. And I wanted to talk a little bit about the Z protein. Obviously, you're decreasing it less than 10% of total. When you're seeing any level of Z in the plasma, it's not available anymore to become an aggregate in the liver. Is that correct? And then I guess the follow-up question would be, if you're seeing a higher percentage, let's say, closer to 50%, 30%, so anything above 10%, is there -- what is the risk then that you could still have Z aggregating in the liver?

Yes. So Z, we do think of Z as the bad actor here, and it poses risk both in the liver and systemically. So you can think of this almost as an analogy to in sickle cell disease, the sickle protein right? Which is, again, the bad actor there. You want not just protective fetal hemoglobin, but you want to get rid of Z as much as possible. Really, the same thing is happening here in alpha-1.

We want to get as much M fully functional, normal protein as we can, and we want to eliminate Z as much as possible. Now Z in circulation, I don't believe, is going to go back into the liver. So I think at that point, the risk of the liver is gone. But the Z in circulation you see is the small amount that got out. Any sign of Z, that's already after a whole lot of other Z got stuck and was creating toxicity and aggregating and causing a lot of harm.

So certainly, any significant amount of Z is a sign that the liver is still potentially threatened and may still be sick, particularly when you get sick. And systemic Z has problems for the lung. So you can actually aggregate in circulation, right? So these aggregates can be inflammatory and they can travel around the body in bad ways. And it can have a kind of dominant negative effect on the function of the protein, right?

So you're trying to inhibit neutrophil elastases, but it's less effective at doing so than the normal M protein, but it's getting in the way, right? And it can interfere. So people think of Z canonically as sort of causing that liver toxicity, but really, it has -- there's a lot of evidence that it has negative impacts on lung as well. And so the bottom line is, to the premise of your question, our goal is to get Z down as far as possible, both in the liver and systemically, and that will have its own benefit in addition to raising M as far as we can.

Okay. That's helpful. And then on the M piece, for the 60 milligram, you've above 11 micromolar on average and all patients were above that threshold, I believe you've said before. Is that sufficient to -- for one, regulatory perspective? But also, I'm curious about if you need to go higher? Like what are your thoughts on the benefit above 11 once you hit that 11 threshold?

Yes. So this is where we keep going back to the clinical genetics because that's nature's experiment, right? We can -- we know so much because there are tens of thousands of people who have these sorts of genotypes, and we know how healthy they are, right? So it's not that there's a magic number like 11, although that's been used in the field a lot, and we think it's a reasonable sort of benchmark to look at. It's not that there's a magic number. It's more that we know that patients who have liver disease, who have steadily declining lung function and who may ultimately get themselves into lung transplant, liver transplant kinds of situations, they live in the 4 to 6 range for alpha-1 levels.

They do not have 9 or 10 or 11 or 12 or higher, right? So it's just not what you see. So I think the fact that we've gotten the total AAT up into the teens that we've gotten the M level up into the double digits. We also test functionality of the protein, right? And the functional AAT is a sort of very important assay, and our functional level was also about 11, right, about the same as the amount of M we were producing, which makes sense.

So all of that, I think, is very strong evidence that we're already in a therapeutic zone. So then you say, is there benefit going higher? The answer is maybe. We're certainly going to go higher if we can and as we can so long as it doesn't cause any kind of safety questions. We love the safety profile of the drug, and we want to keep it there. It is not clear to me that you would ever be able to detect the difference clinically from, say, where we are with 302 at 60 milligrams and going higher.

Because if you look at the genotypes, again, you have MZ, which is the carrier. You actually have one called SZ, where S is a kind of rare intermediate allele. It's not quite as active as M, but it's not as bad as Z. So if you have one of those and then one Z, even those patients do not have progressive lung deterioration, okay? So it's a pretty steep curve where if you can get out of that ZZ place, SZ patients with total AAT can live in the 8 to 12 range or so and maybe a 70-30 ratio.

So anything there or higher, we think will be stable effectively. And so we're already there, and we think that we'll be able to show that. You would also finally ask the question about regulatory bar. I think there, again, I don't think there's a magic number on any one of these parameters that the FDA is looking for. There's, of course, history with augmentation therapy and other types of development efforts in this space, which we can build on. But fundamentally, we think we're doing something totally new, right?

Nobody has ever had a drug like we have, which is fundamentally correcting the root cause of the disease and is causing a renormalization of the physiology of the entire AAT system across the whole body between total levels, M levels and Z levels across the board. So that, we think, opens a lot of doors because all of these changes are predictive of clinical benefit and will be lasting.

Got it. And so one of the things that came out from a competitor this morning was, I think, the first evidence that we've seen of a patient having an acute phase response. And it was interesting because we had a nice increase in both total and M. So thinking about what that data showed and about your product, how do you think that patients that have had BEAM-302 would respond to an acute phase? Because at the end of the day, protecting the lung during those inflammation events is the goal, right?

Very much so. So one of the beauties of our approach is that it will -- the gene that is corrected will be under normal regulation. And so when it wants to turn on -- when you get infected, it will turn on. And that is a very, very important paradigm shift because when you think about what we've had in the past, which is augmentation therapy, right, there, we're just putting in some exogenous protein. It is not produced by the body, so it's not regulated by the body. So basically, however much you put in, it's sort of washing out over time, you get to some sort of trough and then you have to redose, okay?

And you're also not affecting the Z protein that is already being produced by the body. The body is still completely producing Z, we've added some M, okay? So that's augmentation. And that is somewhat effective. It has some benefit, but it is clearly not ideal from a bunch of different perspectives. So in our case, we will be regulated. And I think it was exciting to see the upregulation data that was shown by WAVE today showing that in an acute event, the levels do go up, and that is proof-of-concept that, that sort of thing is possible, and we expect the same is happening with us.

Now in their case, they have a large proportion of Z still, and that's sort of a feature of that data set. So it went up to about 20, but about 10 was Z still and 10 was M. In our case, as -- if we get that induction event, it will be almost all M, right? So that's an important distinction. But it does highlight this point that unlike augmentation, where the levels you have are sort of your average and your trough, right? For us, it's really a floor, okay? So levels that we report are kind of your baseline and then when you need, it can go up higher. And that's -- it's just a fundamentally different sort of way to think about the numbers once you're in the sort of gene correction paradigm.

Right. And WAVE had, well, I guess, the experience of having a patient that have an acute phase pretty early on in their study. I think it was patient 2. You have shown us nine patients, I think, so far. Have you -- are you able to say if you've seen one of these events yet? Or do you think it's likely that we could see something -- some type of event like that in the data set in the first quarter of '26?

Yes. So we're monitoring it. I think we have seen evidence of regulation, I think. I won't give you specifics in terms of what you might see in early '26, but we're certainly confident that our mechanism is going to work in the same way. These are tricky events to catch. You have to really get patients at the right moment. But again, I think, it's a fundamental advantage of our approach, which is that we're correcting the gene in its normal location. One, that will be a permanent durable change. And second, it will be regulated normally by the body, including turning on.

Great. Okay. And then maybe we just talk a little bit about competition. You have yourselves -- I think you've definitely reported the most data, I would say, most advanced dosing data at least. WAVE now has a considerable amount of data, at least for the first dose. We also have another with Prime editing in the mix. We have some other RNA editors, obviously, small molecules that do [ very ] different things. Where do you see your BEAM-302 really fitting into this from a commercial opportunity?

Yes, great question. So -- and this is evolving, of course. But we've had historically augmentation therapy, where you're just, as I said, exogenously putting in some more protein and then trying to maintain that trough level, but it's not regulated in an endogenous way, and you're not affecting the Z.

Z is being produced normally. It's still circulating both in the liver and systemically. So there are new versions of augmentation coming, right, that we're interested to see those advance but fundamentally, that same profile will be there. You've then had us and probably RNA editing or the other kind of current sort of modalities that are most in view. So for RNA editing, I think, in general -- and we've seen some data today, right, from WAVE and there's others coming, where you clearly can create some amount of M.

You're taking the pool of Z, effectively mRNA, the body is producing and you're editing it at some point so that now some of it is mRNA and then that will produce M protein. And so you basically get a mixture of Z and M. And look, I think it's great to see multiple mechanisms coming forward. I think it's good news for patients to have this much development activity, and it's such a big disease with so much opportunity, there's room for a lot of players.

I think when I look at the RNA editing preclinical data, and I think it's, in some ways, reflected in the human data that was just released this morning. With RNA editing, you do get to a sort of a ceiling of effect in terms of the amount of mRNA that can be edited, the amount of M that can be produced and still having a fairly large amount of Z left over, right? And all for getting to total levels that are sort of comparable to what we've been seeing.

So I think fundamentally, it's good progress, but I do think it leaves BEAM-302 in a strong position as a potentially best-in-class option where we're driving that M protein more strongly. We're really eliminating Z much more thoroughly. And of course, the most simple comparison between the two classes will be that RNA editing has to be redosed for life, right? Because it will wear off because you're only editing the RNA pool.

With BEAM-302, you're editing the DNA. So it's a permanent onetime change that you benefit from forever. So we think there's a lot of demand from patients. Again, they've been living with augmentation, kind of a chronic therapy that creates some M, but leaves them with a lot of Z for their whole lives. And we think that RNA editing is more similar to that profile. With DNA editing, we move beyond that to more of a onetime fixing the disease at its root cause sort of cure. Now to your other point, there will be more gene editing efforts coming on over the coming years. I think that there's a lot of enthusiasm for that. It isn't obvious to me yet what BEAM-302 leaves undone.

We're editing a lot of the liver. We'll see if we can get towards saturation. I expect that we can. And we're producing really strong functional M protein and eliminating Z. So we've got a big lead there. But again, more options for patients is always a good thing. But I think that we are feeling very good about the leadership position we have relative to competitors with this really breakthrough target product profile, which is a onetime cure addressing both liver and lung and the root cause of the disease.

One of the criticisms that I do hear for base editing is the bystander edits. Can you just remind us what you've seen in terms of functionality, both preclinically and in the clinic for those bystander [ edits on them. ]

Yes. Yes, so this is a point that gets brought up by our competitors a lot because it's sort of a place where they can focus. So with base editing, what happens in, I'd say, a rare case, but in this case, it does happen, is in addition to the target edit where we're correcting the disease-causing mutation, we can, in some cells, create an additional edit nearby. And that is -- basically creates a variant of the M protein. But it's still M. That's the most important thing. And this is very predictable.

So it happens in some cells. And so what you do in that case is you basically characterize that protein. You want to make sure we fully understand it. And this has happened over 3 to 4 years over the last year where we've published on this. And the bottom line is that variant protein is still functional like M, right? So it is still secreted. It still inhibits neutrophil elastase. The structure is comparable to the M without the variant. So those are the same.

And really, in all ways, we can detect, it is silent. It's actually also a position where there's a lot of basically polymorphisms in the human population, including the one that we make. So it is observed in humans, and there are others as well that have been observed. So bottom line is we think it's basically a silent ineffectual kind of effect. So -- and I think that's been clear with the patient, and physician community, it's clear with regulators as well. So although it is something that competitors can talk about, we don't see any unmet need there in terms of the profile and the outcome of the drug.

Understood. But then when you think about just from a patient and physician perspective for base editing therapies, permanent change, I think that can, for some people, be something that they need to think through very carefully. In your conversations with both patients and physicians, what has the appetite been for a permanent change wherein presumably if you were to get approval, we might not have enough or what everyone talks about, which is 10 years, 10 years of long-term safety data quite yet. So how do you think that the community will balance that?

Yes, it's a great question. I mean this is very much a spectrum that is dependent on the disease, right? So if you have no disease, no risk, right, then yes, people are going to be a little more cautious about things that are genetic. For instance, GMO foods, right? It's like they're not as enthusiastic about that in some cases. Once you start to be sick, right, you're motivated. And the sicker you are, the more urgent it becomes. And so in alpha-1, this is a very serious disease, right? You are declining constantly.

And it's inexorable and you can't stop it, and you're literally losing your lung function as you age. And the end of that is you're on oxygen, you may need lung transplants, you've lost all your quality of life. So these patients are very motivated to get help and to get a cure. And unfortunately, they haven't had options that were actually that effective to date. And so I think for the most part, we hear from patients a lot of desire for this kind of curative approach.

In addition, as I noted before, they've been given augmentation therapy, which again is a great option for them, but it's a chronic therapy. It's quite burdensome on their lives. They have to kind of get it constantly and mold their lives around getting the augmentation therapy. The idea of a one-and-done, therefore, for this population is very appealing, okay? Now in any population, there will be early adopters and late adopters.

I think that's totally fine. But there are so many patients here, we have a lot to work through as we go. So if you think about it, there's over 100,000 patients in the U.S. who are ZZ genotype. Of those, 10,000 to 15,000 are diagnosed already and are quite well educated, quite up to speed on everything that's happening and quite motivated to get care. So that is a very large population that we can think about curing over a period of time.

From there, we'll then have the diagnosis campaign to identify the rest of these patients. They're mostly living in COPD clinics or even primary care, where they're just not getting followed up and no one's thought to do the genetic test. But as with other conditions, once you have therapies available, once you have a reason to test, we think we can certainly drive that and start to uncover those patients over time. So I think that, that will really help.

The last point you mentioned about follow-up, you're right that by the time we're reaching market, the specific follow-up on this drug will not be 10 years, but it will be many years. We're already a year plus into this. And so is it 3, 4 years by the time we're really treating patients. That's pretty good.

And patients, again, are quite eager to see more of this. But then you put that in the context of the whole editing field, right? We'll have sickle patients on base editing out 5, 6 years by then, and there are CRISPR Gen-1 patients out a decade or more. So I think given the severity of the disease, the urgency and the motivation of this patient population, I think it will be a lot of strong demand. And in fact, we're seeing exactly that on the trial. We see a lot of demand. There's a waiting list for enrollment. Patients are quite motivated.

Got it. That's helpful. Is there anything that I didn't ask about that you wanted to talk about for 302?

Maybe the last comment would be path to market and filing. This is an area that investors are quite focused on and rightly so, partially because I think we've checked the box that we have what we all think, I think, is a credible medicine here that could be quite important. But alpha-1 is a field that has been sparse in terms of therapeutics. That means you don't have that many things to build on in terms of endpoints and trial design and things like that.

So I can't give you guidance yet because this is still to be worked out, but we are thinking hard about how we will get this to patients. And one thing I've said frequently is that I think a drug of this profile where it's so clear what it's doing and all of the different changes are going in the right direction and start to look like a carrier for somebody who doesn't have the disease, and it would be very predictive of clinical benefit. We really should lend itself to something that's more on the accelerated side, right?

And whether that's a full approval or an accelerated approval with a follow-up, there's lots of details to work out. But certainly, that is our goal. And I would say, to a degree, my base case assumption. I think a downside scenario would be if the FDA says this is really exciting, but we want you to go do a randomized controlled trial before reaching market. If so, great, we have endpoints for that as well.

And there's been a lot of progress on that front. Those trials are very doable. So one way or the other, we'll figure out what it needs to look like, but we are certainly thinking about this as how fast can we get this to patients. I think they're ready. I think the drug signal is quite clear, and we're looking to work with regulators to identify that.

And I recall that we should get some sort of guidance for what that could look like or at least an initial update in early '26.

Yes, that's certainly our aspiration is that part of that early '26 update is to give, obviously, the data, the dose information comparing all the dosing schedules that we're doing, but ideally give a clinical update as well, what's the next step in the trial. And ideally, that has a lot of regulatory input included in it for sure.

Absolutely. All right. So 302 has monopolized a lot of our time, but let's spend our last couple of minutes on 101 and sickle cell disease. I love -- I think we're all kind of familiar with your data. I think we all know that it looks better than Casgevy. But I'm curious on just the market for Casgevy and how that's progressing and where 101 would fit in when and if it were to get an approval?

Yes. So it's an unusual market, right? So -- it's so operationally complex, and we've always said this, that we've never felt we were going to miss out on the important first few years of the market. In fact, we think there's a lot of building to do that is currently happening that we will benefit from, right? So some examples of that are the treatment centers learning how to schedule these patients and move them through the Apheresis Clinic and then into the transplant.

Reimbursement. Reimbursement today is still happening on a lot of what we call single case agreements, right? So importantly, it's important to note, and this is going to have read-through to sickle as well as to alpha-1 and other places. Nobody is quibbling on the price, right? So the $2 million to $3 million price, it gets headlines and it's a large number. But society, Dr. Oz, who runs CMS said this publicly, right, that, that is a price worth paying because you're going to then not pay many more millions of dollars over the life of the patient in medical care hospitalization and other therapies that are used chronically.

And ICER, the cost-effectiveness body of the U.S. said the same thing. So that said, you still have to make the reimbursement process more smooth, and that is not there yet. So in fact, there's a -- most patients on sickle are on Medicaid, about 50% to 60%. The Medicaid process to approve that reimbursement is just coming online. That's the CMMI CGT access model. And again, Dr. Oz of CMS is banging the drum, how excited he is about that, but it isn't even in place yet.

So I think this is just an example of it is going to take a few years for these sorts of things to become more and more smooth. And again, I continue to draw on the CAR-T analogy. CAR-Ts were first approved in 2017, 2018, right? And the first few years were slow as the hospitals got oriented to it and the payment models got worked out. But now it's a multibillion-dollar a year category. We're doing 5,000 CAR-Ts a year, and that line is just going up. So we remain quite bullish about it. I think we obviously are watching the Vertex launch carefully to sort of learn what are some of the things that are real roadblocks that we need to work on.

What are some of the things that maybe we're already going to improve upon relative to what is happening in the market, things like smoother manufacturing process, fewer cycles of mobilization, that faster time to engraftment. Some of those differentiation features also make it smoother for the hospitals to treat more patients. And what are things that are just going to get better over time and every year are going to be smoother and more predictable.

Let's talk a little bit about the ESCAPE program as well because that one is moving along, the CD -- I think it's 103, CD117 entering the clinic at the end of this year. When does that come online? If you can -- if you're able to provide some sort of estimate post 101 approval and commercialization? And how does that improve the market?

Yes. So in addition to 101, which we think is clearly a best-in-class relative to the field of kind of what we call WAVE 1 gene therapies where you're still using chemotherapy for transplant, we're equally interested in these next-generation versions, first of which is ESCAPE, we call WAVE 2, you're still ex vivo, but you're now adding an edit, which allows us to use an antibody to condition, that's BEAM-103 to get rid of old sick cells.

And then your graft will grow, but it is ignored by the antibody because antibody no longer binds that graft. This allows us to independently use a non-genotoxic conditioning agent like an antibody while the graft takes hold. So as you noted, BEAM-103 is that antibody that is on track to dose this year, in normal healthy volunteers, just a quick single-dose PK/PD study. And from there, we would be in a position to think about filing a patient IND for the clinical experiment, which we're quite excited about. So very important opportunity to expand and bring functional cure to more patients who aren't in that sickest population where chemo is a no-brainer. They're happy to do that. Lots of patients are just over that threshold where they would really rather not have the chemo.

The third wave then moves all of this in vivo. And that's really bringing the threads of our two franchises together because now you're going to use lipid nanoparticle technology, which we do all of our liver delivery with, like 302 for alpha-1. And instead, we're going to retarget it to try to go to the bone marrow and now reach those long-term hematopoietic stem cells in the marrow. That's an area of really intensive research right now. And I do think seeing some positive signs of progress in that field, we're quite bullish on targeted LNPs just in general, reaching a variety of non-hepatocyte targets within the body and HSCs is, of course, top on our list.

So that one is coming as well. You'd ask about timing. I've generally said in the past that this is a life cycle plan. So it would be -- as 101 reaches the market, it would be several years before ESCAPE, WAVE 2 reaches the market and then potentially several years after that for in vivo. In vivo is moving quickly now. So we'll kind of see how that timing plays out. But I think next-gen versus Gen 1 is still a several year gap, and that's why we're developing both fundamentally.

Right. I'm looking forward to hearing more about the in vivo piece moving along nicely in our next conversation, but we're unfortunately out of time. So John, I just want to turn it back to you for any closing remarks that you have.

No, it's been a great conversation. We're -- we couldn't be more excited about the progress that we're making. Obviously, the technology is working. We're helping patients. Enrollment is going very swiftly and smoothly. Despite all of the uncertainties and noise, the regulatory interactions actually have been clockwork and quite predictable. So I think gene editing generally is a field that's working and is growing. And we do think ourselves positioned to be a leader here with some really significant commercial franchises that bring this technology to patients who really need new options.

Great. Well, thank you so much for being here. It's a great conversation.

Thank you.

Good afternoon, and welcome to Beam Therapeutics conference call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request.

I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

Thank you, operator. Good afternoon, everyone, and welcome to Beam's conference call to review updated data from the BEACON trial of BEAM-101 in sickle cell disease presented at this year's European Hematology Association 2025 Congress. You can access slides for today's call by going to the Investors section of our website, beamtx.com.

With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Giuseppe Ciaramella, our President; Dr. Amy Simon, our Chief Medical Officer; and Dr. Ashish Gupta from the University of Minnesota. Our Chief Commercial Officer, John Lo, will join for Q&A.

Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as well as results of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change.

With that, I will turn the call over to John.

Thanks, Holly. At Beam, we are reimagining what's possible in medicine. Our bold vision is to provide lifelong cures for patients suffering from serious diseases. We are pioneering a new class of onetime curative therapies, treatments designed not just to manage disease but to potentially eliminate it at its source.

Today, we're excited to share with you updated data from the BEACON trial of BEAM-101, which we believe has the potential to be a best-in-class option for people living with sickle cell disease. A pointing example of our vision and action can be found in Brandon's story. Brandon grew up with severe sickle cell disease and spent much of his childhood in and out of the hospital continuously with pain crises. In sixth grade, he had both of his hips replaced because of the damage caused by sickle inflammation. By 17, he was having life-threatening acute chest syndrome attacks where the sickle cells were blocking blood flow to the lungs, causing Brandon to miss his entire junior year of high school.

In 2023, Brandon became the first person to receive BEAM-101. Since treatment, he has been healthy enough to experience many firsts that were previously unattainable due to his disease, graduating high school, his first job, planning for college and exercising like a normal young adult.

Beam has established a strong leadership position in the gene editing field, enabling us to pursue our vision of providing more of these kinds of outcomes for patients like Brandon. There are multiple factors that set us apart, including our clinically validated base editing platform with fully integrated manufacturing, 2 core high-value franchises, a dedication to rapidly executing our priority clinical programs and an exciting 2025 with multiple anticipated key catalysts.

Underpinning this work is the strength of our balance sheet with $1.2 billion in cash, cash equivalents and marketable securities as of the end of the first quarter, which we expect to support our operating plans into 2028. Within the last 6 months, we have now established clinical proof of concept for base editing as well as our ex vivo and in vivo delivery approaches spanning both of our franchises.

With consistent translation from preclinical models to the clinic, we have now provided strong evidence for the power and versatility of our platform and our internal GMP manufacturing capabilities have directly contributed to our clinical success.

On the clinical and regulatory front, we continue to make significant progress in activating new sites in new countries, ramping up enrollment and dosing in our trials and securing key regulatory designations to support the continued advancement of our programs.

Our 2 core franchises in hematology and liver genetic diseases each feature highly differentiated and potentially best-in-class lead programs. Our liver genetic disease portfolio represents a high-value strategic pillar of Beam's long-term growth. Our lead program is BEAM-302, a potential onetime treatment for alpha-1 antitrypsin deficiency aimed at addressing both lung and liver manifestations of the disease under normal gene regulation.

Earlier this year, we established clinical proof of concept showing that BEAM-302 addresses the root cause of AATD. And operationally, we've made significant progress, having received IND clearance as well as RMAT and orphan drug designations from the FDA. In addition, we dosed the first patient in the Phase I/II study of BEAM-301 for glycogen storage disease Ia. Looking ahead, we anticipate multiple clinical catalysts in 2025 with the potential to further validate our approach and unlock significant value.

Turning to hematology, which will be our focus for today. We believe we have a high-value franchise with potential best-in-class programs for sickle cell disease that have generated strong execution and momentum. I'm happy to report today that enrollment of both the adult and adolescent cohorts in the BEACON trial of BEAM-101 are now complete with dosing progressing swiftly. Our next-generation ESCAPE antibody for non-genotoxic conditioning is also on track to enter the clinic later this year.

So now to go deeper, let's step back and revisit our long-term strategy and commitment to developing safer, more effective and more accessible treatments for people living with sickle cell disease. Sickle cell disease is a genetic disorder that affects hemoglobin, which delivers oxygen to cells throughout the body. People with this disease make abnormal hemoglobin molecules called hemoglobin S or HBS. This abnormal HBS can force red blood cells into a sickle or crescent shape, blocking the flow of blood and oxygen throughout the body and causing pain crises, organ damage and early mortality. Our vision is to bring functional cures to all patients with sickle cell disease with a series of complementary technologies forming an integrated life cycle strategy. Our Wave 1 approach is BEAM-101, a genetically modified investigational cell therapy administered via hematopoietic stem cell transplantation with busulfan conditioning.

We believe BEAM-101 has the potential to be a best-in-class option for the roughly 10% of sickle cell patients who have severe disease despite receiving standard of care treatments and are considered appropriate for a chemotherapy-based transplant.

Wave 2 uses the same BEAM-101 edit and incorporates our escape technology to enable non-genotoxic conditioning with antibodies. If successful, ESCAPE would eliminate the need for chemotherapy condition, which we believe is 1 of the main hurdles for patients considering a transplant-based therapy and thus meaningfully expand the patient population for ex vivo gene editing by 3 to fourfold.

Beyond this is Wave 3 where we are using our leading capabilities in lipid nano particles to explore the potential for in vivo base ending for sickle cell disease, which would eliminate the need for transportation. In vivo delivery of base editing could be a maximally scalable delivery platform, enabling even broader patient access to these kinds of curative therapies, both here in the U.S. and around the world.

In 2023, the first gene therapies were approved for the Wave 1 market, aiming to revolutionize the treatment paradigm for the most severe sickle cell patients. Because they involve complex ex vivo manufacturing and transplant, these products will take several years to following operational lines.

However, we remain incredibly bullish on the commercial outlook for the Wave 1 market in the U.S.with peak annual revenue potential of $3 billion to $4 billion. This aligns with CAR-T benchmarks, another complex cell therapy that took several years to operationalize, but where today, 10% to 20% of clinically eligible patients receive these therapies and the fast has grown to a multibillion-dollar annual market.

Unlike CAR-T, however, in severe sickle cell disease, existing pricing is around $2 million to $3 million per treatment, meaning that each patient is profitable and the reimbursement landscape is strong. To date, there have been no reported prior authorization rejections and a new CMMI access model now covers 84% to eligible Medicaid patients. In addition, infrastructure is scaling as qualified centers are gaining experience with both therapy and reimbursement.

Patient experience metrics like mobilization hospital stay, safety and efficacy will shape provider capacity and therapy choice, and we believe BEAM-101 is uniquely positioned to differentiate in each of these categories. And already, there is evidence that demand is outpacing supply.

To illustrate that last point, patient and site demand has been lab and far from our market research, where KOLs have indicated significant interest from dozens to hundreds of their eligible patients, some of whom are on years long waiting lists for their chance to cure.

The current landscape is also such that no single player can meet this demand on their own, and this makes our work to develop BEAM-101 all more important. We expect this market to continue to mature as operational improvements across suppliers, providers and payers take effect, creating an opportunity for bean to enter a much more established market in the coming years.

Our goal has been to bring forward a product with a highly differentiated profile. Based on data to date, including our updated data now presented at EHA, we believe we are achieving this goal in part due to the underlying technology as well as our ability to make and deliver this medicine quickly and efficiently.

BEAM-101 uses base entity. A next-generation CRISPR technology that allows us to make more precise single-base changes at specific locations and genes, resulting in predictable edits in all felt without needing to damage or make double-stranded breaks in the DNA. The central hypothesis behind beam is that this breakthrough could provide a superior way to modify genes and the clinical experience of BEAM-101 to date exemplifies the best-in-class potential of this approach.

Without a double-stranded breaks or viral insertions in the DNA, we're seeing healthier cells and faster engraftment of the new edit itself. We also observed high levels of editing and the uniformity of these edits within cells results in higher hemoglobin at production and lower residuals.

Using this next-generation approach to gene editing, our goal for BEAM-101 is to achieve a deeper correction of the hemoglobin profile that is at least on par with or even better than that of a typical person with sickle cell trait, a carrier with only 1 mutation who is typically asymptomatic.

As shown on Slide 14, total hemoglobin for a person with sickle cell disease has 100% HbS in circulation. The disease threshold is exemplified by people with sickle cell tree as these people generally have about 60% normal hemoglobin and only 40% HbS. This is a threshold that has not yet been achieved in the field of sickle cell gene therapy.

Today, we're pleased to share that consistent with data presented in December at ASH. All patients treated with BEAM-101 to date continue to achieve this profile with HbF levels above 60% and HBS levels below 40% and meeting or exceeding levels seen in sickle cell trait. We also observed full resolution of anemia and markers of hemolysis and oxygen delivery were normalized or improved in all patients.

In addition, our data continues to suggest the potential for needing less time in the hospital with fewer average cycles of mobilization and rapid engraftment of edited cells following BEAM-101 treatment. Beyond efficacy and safety markers, differentiation of BEAM-101 extends to our manufacturing process, which benefits from the scheduling flexibility of controlling our own facility, high yields enabled by base editing plus a highly automated process.

Pete will review our manufacturing process performance in more detail later in the call. Altogether, our goal is to deliver a high-quality product and improves the patient experience throughout the transplant process.

Now to review the latest pinnacle data in more detail, I'd like to introduce Dr. Ashish Gupta. Dr. Gupta is an investigator in the BEACON trial and a pediatric blood and marrow transplant physician at the University of Minnesota Health Masonic Children's Hospital. Dr. Gupta is also an assistant professor in the Department of Pediatrics and a faculty member in the division of Blood and Marrow Transplantation at the University of Minnesota Medical School. Dr. Gupta, thank you for being with us here today.

Thanks, John. Ashish Gupta, I am as a associate professor in the Division of pediatric blood and marrow Transport and Cellular Therapies at University of Minnesota.

And I'll be presenting the updated data from BEACON trial, which is a Phase I/II single-arm open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with sickle cell disease with frequent and severe vaso-occlusive crises.

As we know, there is an unmet need in sickle cell disease for effective gene therapies that address the full spectrum of disease. BEAM-101 is an autologous stem cell-based therapy that uses a novel base editing mechanism to enable precision editing of HbG 1, 2 promoters without requiring double-stranded DNA breaks or disrupting downstream BCL11A pathways in order to upregulate fetal hemoglobin in patients with sickle cell disease. Preclinical data have demonstrated that base editing results in highly efficient and predictable generating outcomes, leading to a more uniform induction of hemoglobin F and corresponding reduction in hemoglobin S, resulting in fewer sickle cells.

The BEACON study is a Phase I/II single-arm open-label study evaluating the safety and efficacy of this product. The study is ongoing with more than 40 patients, past screening and enrollment, and here we present the data as of February 2025. The key eligibility criteria for the study include patients age 12 to 35 years with sickle cell disease and history of 4 severe VOCs in the previous 24 months.

Key safety and efficacy endpoints include proportion of patients with successful neutrophil and plated engraftment, the time to engraftment and the patients -- proportion of patients who are severe VOC-free for 12 consecutive months.

We also evaluated the markers of hemoglobin and RBC function. Further details about the RBC and hemoglobin function are on poster 1155 which will be presented on June 13, and in the post efficient one. The BEACON study involves 4 stages shown on this slide, that can span from about 6 to 8 months prior to dosing with BEAM-101.

After confirming the eligibility, patients undergo mobilization and leukophoresis to collect their hematopoietic stem cells. This is done with the help of plerixafor without any GCSF in the mobilization -- these HSBCs are subsequently base edited ex vivo and then administered back to the patient after mylobrative conditioning with busulfan. Following engraftment, patients are discharged and follow-up for up to 24 months on study before entering a long-term follow-up study.

The baseline demographics and characteristics of patients treated with BEAM-101 are displayed here. 17 patients have been dosed as of February 28, 2025, with a follow-up of between 0.2 and 15.1 months. The mean age of study participants is 22.9 years and all but 1 patient has BSPS. Median investigator reported severe VOCs in the 2 years prior to the start of study is 9.

On this slide, we present the mobilization and IFRS characteristics of BEAM-101 patients. 11 patients required only 1 mobilization cycle, 4 required 2 cycles and only 2 patients required 3 cycles for sensor mobilization. During the mobilization 4 patients were noted to have a reduction in platelet count, while 3 each had hypervalemia and hypomagnesemia, A median of 3 total mobilization days was required for drug product manufacturing.

Patients who received BEAM-101 were noted to have rapid neutrophil and plated engraftment with few days of cveneutropenia. The median time to neutrophil engraftment in 16 out of the 17 patients was noted to be 16.5 days. The duration of seveneutropenia was noted to be 7 days. Of the 17 patients, 14 patients achieved created engraftment by the time of data card.

The median time to platelet engraftment was noted to be 19.5 days. Of note, 7 patients out of these 14 did not require a single platelet transfusion going through the process. In terms of the safety data, the BAM study was consistent with busulfan conditioning, auto transplant and underlying sickle cell disease. There were no serious treatment emergent adverse events related to BEAM-101, and there were no AEs leading to discontinuation of the product.

One death was noted from respiratory failure approximately 4 months after BEAM-101 dosing, determined by the DMC not to be related to BEAM-101 and was likely related to busalfan conditioning. The common AEs reported in at least 3 patients included stomatitis, fibrin neutropenia and other AEs as reported here.

The swimlinplot here describes the VOCs pre and post BEAM-101 in patients who receive the infusion. The gray bar here represents a baseline period and each star represents a vasoclusive events that these patients had prior to infusion of BEAM-101. The blue bar on the right represents the RBC transfusion period while the navy blue represents the post-infusion transition period.

Of note, no patient was noted to have a severe VOC or a VOC post engraftment. Also, all patients achieved rapid and durable increases in hemoglobin F to greater than 60% with a subsequent decrease in hemoglobin S as well.

As noted on these parts, the navy blue ones are the hemoglobin F induction while the teal bars are the hemoglobin S. As one can see that hemoglobin F over F+S, which is defined as the hemoglobin F percentage of the untransfused blood was noted to be about 67% at 1 month in 13 patients, which remain consistent throughout. It was also noted that other than the rapid and robust increase in total hemoglobin as well as hemoglobin F, this increase was durable throughout the follow-up.

This hemoglobin F was also noted to have a pancellular expression, and it was observed even following the elimination of the transfused blood. Additionally, mean hemoglobin F reached a predictive threshold by month 1 and was sustained throughout the follow-up period as noted on the bar on the right bottom.

Also of note, the erythropoietin levels were markedly decreased to normal or near normal indicating adequate oxygen delivery to the tissues. Further details are on posterior which describe the RBC Health and function post BEAM-101.

We also looked at the hemolysis markers, which normalized or improved following BEAM-101. The graph here shows a decrease in haptoglobin or normalization of haptoglobin, LDH, reticulocytes and Indirect bilirubin. So in conclusion, the safety data from BEACON study supports continuation of the trial and demonstrate robust and sustained increase in hemoglobin F expression and resolution of anemia in patients with sickle cell disease.

Again, further details about the efficient collection and manufacturing process on poster 1165. As we talked about before, there was a rapid and robust neutrophil in platelet engraftment that was noted. There is the ongoing safety data is consistent with busulfan conditioning and auto transplant. There were no severe VOCs or any VOCs that were reported by investigators post engraftment.

There was a rapid and robust increase in total hemoglobin as well as hemoglobin F with a pan solar distribution and which was maintained through the steady follow-up. In parallel, there was a rapid and robust decrease in hemoglobin S, which was noted with resolution of anemia and the markers of hemolysis normalize or improved in all patients.

With that, I acknowledge all the study participants and their families and thank them for participation on this critical trial as well as their caregivers and the study investigators for their contributions. Now I will hand it over to Amy.

Thank you, Dr. Gupta. In addition to our primary BEACON clinical trial abstract, we're pleased to share data from an additional poster presentation that details the impact of BEAM-101 treatment on exploratory biomarker assessments of red blood cell hemoglobin expression and function from patients in the trial.

As shown in orange, the presence of hemoglobin as in red blood cells results in multiple functional abnormalities in the cells due to polymerization of the oxygenated hemoglobin S which leads to changes in cell shape such as sickling, density, adherence to the vasculature, deformability or the ability of the cell to pass through blood vessels as well as life span. These red blood cell abnormalities underlie the pathophysiology of sickle cell disease, resulting in vascular occlusion, organ dysfunction and systemic inflammation.

Given that BEAM-101 treatment, as just shown by Dr. Gupta, decreased HbS to less than 40%, increased anti-sickling HbF to more than 60% and decreased hemolysis we wanted to explore the impact of BEAM-101 and other important aspects of red blood cell health and function as outlined in green.

Building on the initial data from 2 patients at ASH, we now have data from up to 13 patients treated with BEAM-101, demonstrating that post treatment, 98% of their red blood cells express hemoglobin F as early as month 1, with near complete elimination of red blood cells expressing solely hemoglobin F.

These HbS only cells are the cells which would be most likely to sickle under stress such as in states of low oxygen or decreased temperature, causing pain crises, vascular occlusion and organ damage. In addition, we evaluated the rate of red blood cell sickling. On the left-hand side of the chart in yellow, you can see that at baseline, the blood from these patients has a high rate of sickling compared to the amount of sickling seen in the blood from healthy control individuals shown in the dark blue on the right.

After treatment shown in green, you can see that there is a significant decrease in the rate of sickling in these patients compared to their baseline. Importantly, the rate sickling post-BEAM-101 treatment is comparable to that seen in the blood of pain from sickle cell trait individuals shown in light blue on the right.

Also, as noted here, there were other improvements in red blood cell function, including an increase in deformability and a decrease in the percent of dense RBCs. We also observed a decrease in systemic inflammation as seen by reductions in serum CRP and IL-6 after treatment with BEAM-101.

Shown on this slide is a striking visual of the impact of BEAM-101 on red blood cell number and morphology or shape. As you can see on the panel on the far left, this is what sickle cell red blood cells look like pretreatment with very few pale red blood cells reflecting the patient's underlying anemia, along with the presence of sickle cells and immature in the shape in red blood cells that look target-like or elongated.

In subsequent images, you can see the resolution of the anemia with increased cell numbers that are no longer pale in color and no evidence of sickle cells or other abnormally shaped cells posttreatment was seen. These data in up to 13 patients from the BEACON trial continues to suggest that treatment with BEAM-101 restored RBC health and function.

In summary, following BEAM-101 treatment, 99% of non-transfused RBCs expressed hemoglobin F with near complete elimination of RBCs expressing solely hemoglobin asked as early as month 1 post treatment. Reductions in multiple sickling parameters were seen and were comparable to sickle trait.

Cell adhesion was reduced to significantly below the critical sickle cell disease threshold indicating a reduced risk for VOCs. The percentage of dense RBC's RBC deformability and systemic inflammation all improved.

And finally, an increase in RBC cell number and resolution of abnormal RBC morphology was observed.

With that, I'll turn the call over to Pino.

Thank you, Amy. As John outlined, there are multiple autonomous gene therapies approved for sickle cell disease, which are administered using a fairly similar transplant process that Dr. Gupta described in detail.

This is a complex and time-intensive journey. And with BEAM-101, we aim to streamline this process in multiple ways. First, with internal beam GMP manufacturing, we can make it easier from the start with flexible scheduling of mobilization and CD34 isolations.

Second, once we have the cells in hand, we use a closed automated manufacturing process that has resulted in high yields that as high-quality standards. As of the data catalyst, our clinical experience shows that most patients require just on mobilization side.

Finally, as Dr. Gupta noted, post transplant, patients treated with BEAM-101 are engrafting rapidly, reaching neutrophil engraftment in just 16.5 days and platelet engraftment in 19.5 days. This has the potential to translate fewer neutropenic days and shorter hospital stays.

The result is a potentially more efficient, better tolerated and patient-friendly process that also puts less of a burden on hospital capacity. This could allow more patients to be treated over time and positions BEAM-101 as a differentiated and scalable solution in the gene therapy landscape.

The manufacturing data being presented today at EHA gives insight into the consistency and robustness of our manufacturing process and on the base editing mechanisms. Shown here are 2 example base points from the manufacturing poster presented today. In the left-hand panel, we show the robust and consistent clinical process performance that our team has achieved across 28 CD34 batches with a mean viability of 85%. On the right, we show the strong and highly reproducible on-target editing rates being achieved by BEAM-101 base editing with a mean of 92% from 28 batches.

Through the automation of every unit operation, we are able to ensure a robust and repeatable process performance and produce consistently high-quality drug product. This manufacturing process has also allowed us to move incredibly far. As John noted, we are now fully enrolled across both adult and adolescent cohorts.

As of today, I'm happy to report that we manufactured and released drug product for 34 patients with 26 of those receiving BEAM-101 already. All of this has occurred in just under 18 months since the last patient was dosed with BEAM-101.

We've also made regulatory progress, securing orphan drug designation for BEAM-101 just a few weeks ago. We are well on our way to build in a package for a future BLA submission for U.S. approval, and we look forward to continuing to update you along the way. Back to you, John.

Thanks, Pen. As you've heard from our team today, we continue to be energized by the emerging differentiated profile for BEAM-101, the efficiency of our manufacturing process and the progress we're seeing in the established gene therapy market for sickle cell disease.

We believe that we have a clear path to our BLA submission with the potential to enter what we think will be a more established and growing market for sickle cell gene therapies with a best-in-class product. We look forward to continuing to advance this program to patients as quickly as possible.

Building on the foundation of BEAM-101, we also look forward to advancing our suite of next-generation innovations in hematology, nongenotoxic conditioning with ESCAPE and in vivo LNP delivery to hematopoietic stem cells, which will further expand our sickle cell portfolio.

With the combined strength of base editing and both ex vivo and in vivo delivery capabilities, we believe Beam is uniquely positioned to realize our vision of bringing the promise of functional cures to all patients with sickle cell disease.

Everything we do with Beam is rooted in our mission to make a meaningful difference for patients. I want to thank the entire Beam team for their extraordinary dedication in advancing BEAM-101 from concept to clinic and for their unwavering focus on the patients who inspire this work every day.

We are especially grateful to the individuals living with sickle cell disease who have made this progress possible through their courage, participation and partnership. We also extend our thanks to the investigators, site teams, clinical and manufacturing collaborators and advocacy organizations who have stood with us in pursuit of a better future for this community. Operator, please open the line for Q&A.

[Operator Instructions]. Our first question comes from Rick Bienkowski with Cantor Fitzgerald.

And congrats on the data. So I wanted to ask about the manufacturing time that you're seeing in the clinical trial.

I do see that there's a median of 1 mobilization cycle, but I was hoping to get more detail around the actual length of time it takes from mobilization to dosing? And is this meaningfully different than what is being seen in the approved ex vivo products in the commercial setting?

Thanks, Rick, for the question. And I'll pass it on to Pino.

Rick, this is Pino. The sort of the time basically from -- as you know, from the collection of the CD34 cells that occurs in the clinic, the cells basically are immediately shipped to us. And the process from that moment on takes approximately 5 days until we then store them in free we put them down.

So that is really the internal process. I'm not sure about the time from competition, obviously, but I would suspect that it is not too dissimilar from what others have seen.

Our next question comes from Eric Joseph with JPMorgan.

Pretty forward-looking questions from us in terms of the commercial outlook. Just notwithstanding your comments, John, on access and reimbursement thus far with the existing improved products. We've heard anecdotally that some treatment centers have in trouble with commercial reimbursement going beyond the DRG limiting their utilization.

So I'm just wondering along these lines, whether you could talk about sort of relative manufacturing costs with BEAM- 101 and whether price flexibility might be something that could be leveraged in order to kind of facilitate access and also take share. And then I also have a follow-up.

Great. Thanks. Maybe I'll have John Lo, our Chief Commercial Officer, talk a little bit about what we're seeing on access in general. And then maybe Pino, you can make a comment on relative cost of goods.

Yes. Thanks, Eric, for a really great question. So with regards to reimbursement, we have heard about this as well, I think it's an evolving landscape as commercial plans as well as Medicaid plans start adopting processes. It will be state by state or center by center. I'd say for the most part, what we've heard from most of the major transplant centers is that the reimbursement environment is improving, where by the states or their commercial plans are starting to input -- implement processes. So they're going away from single case agreements to the more standardized plans. There are going to be some holdovers or some laggards as you had referenced.

We anticipate that over time that, that will all evolve. And in fact, sort of by the time we launch the reimbursement environment will greatly improve. One example of that would be the CMI roll out that John Evans had referenced earlier in the presentation where 84% of covered Medicaid sickle cell patients will be eligible for up to sort of down to 2 to 3 days reimbursed.

Yes. And Eric, this is Pino. On your question about cost of goods. Obviously, we don't comment on the very specifics because you can appreciate the competitive of information. But 1 thing that I could say is that we expect every patient to be profitable, particularly if the price point can be -- as you know, we stand 2 million actually super treatment or even higher, as you can see it.

Yes. I'd be willing to go a little part of that and just say I think I do expect we'll have a competitive cost of goods relative to others in the field, and we even have line of sight to continuing to make improvements on that over time.

Our next question comes from Michael Yee with Jefferies.

Great. Maybe I can get 1 question for the doctor and one for the company.

Maybe just for the doctor, in your experience or what you are seeing with patients who are getting treated with the commercial product has Casgevy, is neutropenia a mandating factor for people being able to leave the hospital. So therefore, is that a material differentiation potential for the newer products and something to really keep an eye on.

And then also for the company or from the doctor, perhaps on the hemoglobin F levels, I see that 1 patient #4 seem to be sort of an outlier a bit just because they had maybe 1 or 2 points lower on average hemoglobin F. Was there anything particular about that patient or anything to note there on that chart?

Michael, Yes. Sorry, I just jumped on quickly. So regarding the question for neutropenia, definitely, it does make a difference because recovery from neutropenia is something that keeps those patients in the hospital. And also Hughes with -- like some of the pain issues are gone as the neutropenia is healing. So that becomes a very important anchor there.

What we are -- what I would say is the focus is more on the duration of neutropenia rather than neutropenic engraftment per se, which we are very impressed with the BEAM-101 data where we are seeing a median of about 7 days of severe neutropenia. So that does get into that factor of how quickly you recover from the treatment.

Regarding the HbF level, are you talking about patient 3 or patient 4, I'm just a little -- I'm not sure if you're considering the 2 patients?

Before we're sort of a light blue one is about at hemoglobin F of about 8.

Can you hear me? Hello. Can you guys hear me?

Yes. So,I think Mike was saying it's the light blue patient #4 hemoglobin F around 8.

Yes. So that patient actually is 1 of my patients. And I -- I mean that patient is doing very well and matches all of the patients. So I don't have a particular reason like why that is a little bit down. But overall, like what we are seeing is that at a month mark, there is a very robust hemoglobin F induction that is already happening, which is like quite remarkable. And it is sustained with a follow-up.

Again, like we have if you see just a couple of patients at a 1-year mark on this data, but they are -- they continue to show the robust hemoglobin F induction.

Our next question comes from Kostas Biliouris with BMO Capital Markets.

Congrats on the data. One high-level question from us for the company. Generally, the pushback we get from investors on Casgevy is related to the lengthy process of treatment and delayed revenue bookings, given that BEAM-101 is also an ex vivo therapy.

Can you discuss high level to what extent it can meaningfully address the current investors kept about Casgevy and potentially how your follow-on treatments with a milder preconditioning and in vivo dosing can also address skepticism?

Sure. Maybe I can just handle that one. I think -- so for sure, it's a function of the ex-vivo therapies that they are a longer process to get going and then the revenue recognition comes on the tail end of that. That's primarily a dislocation, I would say, in market expectation on the beginning of the launch curve, and we're kind of living through that right now. And so that's obviously a focus area for investors.

But that will become -- that will work itself out and gradually catch up. So I don't think we -- by the time we're launching, we don't expect that to be as much of an issue as I think it is today. Certainly, we would be similar in terms of our process, notwithstanding the fact that our overall process from patient entry to dose may be faster based on some of the data we're seeing here, but it's still a process.

ESCAPE ex vivo would be comparable. It's still that excel process, again, probably more rapid than what we're seeing now, but still ex vivo manufacturing, in vivo course could go faster and that's one of the attractions to it. But all that you're doing is you're shifting the timing of the revenue. I think the magnitude is still a function of the severity of the patients in the Wave 1 market and then our expansion to many more patients as we move to wave 2 and Wave 3.

Our next question comes from Greg Harrison with Scotiabank.

This is Joe Thomas on for Greg Harrison. I just had a quick 1 on the biomarker data around oxygen affinity for patients treated with BEAM-101. Have you seen any quality of life observation so far in the trial of this increased oxygen affinity? Are patients able to be more active or do anything that maybe they haven't been able to do previously.

Thank you. Maybe either Dr. Gupta and maybe, Amy, do you want to add on?

I can actually jump on to that, and I can share some of the patient experience there, Joe. We are very like impressed with what we are seeing on the other end, just from the experience that we have with our patients, these are young men who are back to doing their work out, taking cold showers, which is like unheard of in sickle cell patients actually because that can precipitate crisis and back to work, actually.

So the quality of life, again, I don't want to comment like there is a whole other study that is going on that. But overall, we are very happy and impressed with what we are seeing in these young people actually who are living their lives now.

I'll just add just briefly across the study, and thank you, Ashish, that's wonderful to hear. We take cold showers for granted and some of the other things you said about going to work. So this is wonderful. I do want to say we have a pretty robust amount of different PROs that we're collecting throughout the trial that will look at things like fatigue, one of the biggest complaints of people who have sickle cell because of the anemia.

We also will be looking at different aspects of pain, looking at different pain medication usage and very kind of common PROs or patient-reported outcome measures that are used in sickle cell and in general populations.

It's too early given the duration of follow-up that we have right now to report on this. We will plan to report on this usually after people have 6 months to 12 months of follow-up is when you start to report out more data. So stay tuned, we're looking forward to seeing that data.

Our next question comes from Patrick Trucchio with H.C. Wainwright.

Congrats on the data. Just a follow-up question around the regulatory piece. I'm just -- I'm wondering what discussions have occurred with the FDA around the regulatory path particularly following recent personnel changes, including at CBER and how those changes in today's data may potentially impact the path going forward?

Yes. Thank you, Pino?

Yes. Thank you very much for the question. We continue to have very interactions, frankly, with FDA and I think even with the change of leadership, we are very encouraged by the comments that have been made with the new leadership there, continue to see the opportunity for frankly, transformative in curative therapies such as ours to really make a difference to -- meaningfully to these patients and generating data that very clearly demonstrated that's the case.

We haven't yet confirmed frankly, the path to the BLA yet. We plan to do that very shortly, but we have several interactions with them. They would suggest certainly, we already see a path with the experience of Casgevy and Lyfgenia example, being an example that we can follow.

Your next question comes from Alec Stranahan with Bank of America.

And congrats on the update here today.

Maybe 2 quick ones from us. First, has anything changed with the busulfan conditioning since the update last year, either in terms of target exposure limits or -- or monitoring. And as a quick follow-up to that, any comments around the range you're seeing for average AUC of busulfan? I think it range from maybe 50 to 90 in the latest update, which is which is a little bit wider than what we saw at ASH last year.

I'll comment first, Ashish, and then you can go.

We have not changed anything about our busulfan monitoring, which is basically very PK driven. And in general, as you know, we had an unfortunate event. Even that patient was within the kind of what we were aiming for as far as the limits. And so that would not have been predicted. So I feel like, again, all the monitoring is the same.

I'll have Ashish comment on the range and compared to what he's seen in his clinical practice.

Absolutely. So Alec, good question actually. The tricky piece with busulfan is that it is very center-dependent practice. Some centers would like to dose it once a day like us. Other centers would like to dose it every 6 hours and then the dosing has changed in real time based on the pharmacokinetics levels.

So that is where you see a lot of variability actually in the AUC for busulfan. I think the target is around 80% of AUC, which actually -- like if you're in that goal range, you are still able to maintain that target, which is a good myeloablative target. That's where you are seeing the variability on the AUC end, but how much it effects the clinical outcomes. Actually, it is on the cumulative AUC where you are able to still maintain within the range.

Like busulfan has a wide range for myeloablation, anywhere between like 60 to 90 is considered myeloablative. So until you're maintaining that range, you should be able to still get a good depletion of stem cells.

Our next question comes from Samantha Semenkow with Citi.

Congrats on all the progress. I wanted to ask about the early signals that you're seeing that demand is outpacing supply. I guess, based on your understanding of this demand, how much of it would you say or consider a bolus? Or do you think this is something that will be enduring and continue to be demand that is there for you to capture potentially upon your launch? Just any context you could provide there would be very helpful.

Yes. Great. So maybe I'll have Dr. Gupta to talk a little bit about what you're seeing yourself in terms of patient demand. And then maybe, John, you can expand a little bit on how we're viewing that market and the sustainability over time.

Absolutely. So Samantha it's a really good question. And like as -- as any new therapy comes to the market, there definitely is an issue -- there's an initial bolus demand. But this is an ongoing process as well. Like so at my institution, we do maintain a list of patients who are not meeting the criteria yet. But as the time goes by, we do see actually that some of these patients eventually meet the criteria.

So there will be an ongoing need for sure. As John earlier pointed out, is kind of like about 10% of the population, and we are -- we are still seeing a consistent flow of sickle cell patients. And again, different -- depending on the response to different standard of care treatments, they some of them will fall into this category of severe sickle cell disease.

So I do think that there will be a consistent demand. It's hard to assess that at this point, while we are still in that bolus space, I like that word. But I do think that there will be a consistent demand as we are seeing on the clinical side that there are patients who have severe disease continue to be there.

Yes. And just to build on that, we've -- and thanks, Dr. Gupta for your centers experience. We've talked to a number of the top transplanters across the country, and they would indicate that. I think 2 other points that just to make one, a wait list is being built in a number of different centers. So it's unlikely that, that would be depleted over the next x number of years before we launch.

The other one is we are only projecting for the $3 billion to $4 billion market size, a 10% to 20% penetration of clinically eligible patients. And that balances roughly around sort of the incident patient population that would sort of age into the addressable patients.

So we actually think there's a fairly long-term steady state that would also rely on sort of the referrals from other centers into the major transplant centers.

Our next question comes from Luca Issi with RBC Capital Markets.

This is Katie on for Luca. Congrats on the strong presence at EHA. And we also have 1 question for company and 1 question for Dr. Gupta, if that's okay.

So circling back on a prior question around the FDA. KalVista just announced that they will not need the PDUFA date due to heavy workload and limited resources. When was the last meeting you had with the FDA? And are you seeing any disruption there? Any color there much appreciated.

And If Dr. Gupta, could you remind us the way base mix per kg dose for plerixafor that you're using for FRS.

Sure. Maybe Dr. Gupta, do you want to answer that 1 first, then we'll come back on there to you.

I don't have the dosing on top of my head. If you want to answer the FDA, I can actually quickly get you the dose, if that's okay.

That's much appreciated.

And then Pino on the FDA.

Yes. Just from our perspective, we haven't seen any dysfunction as you've made. What I would note is that we have received several designation very recently, actually, even both some of the changes that have occurred we obviously mentioned that we have an orphan drug designation for BEAM-101 just a few weeks ago. And for our other program BEAM-302, we've announced that we have received both in RMAT as well as an orphan drug designation. And that occurred actually in some cases, even faster than the deadline that they normally we buy.

So our experience is all continues to move at the speed that it normally does. And so obviously, we'll continue to see how it goes in future interactions. If I could just finish that question up.

The plerixafor dosing is really based somewhat on the recommendations in the label which then if you go to the plerixafor label gives guidance when people are under 85 kilos. So you can stay tuned we'll be presenting probably hopefully at a medical meeting in the future a little bit more about the plerixafor dosing and the outcomes.

Our next question comes from Yanan Zhu with Wells Fargo Securities.

Great. Congrats on the data. A 2-part question for Dr. Gupta, if we may, when you enroll patients into the study, is there also a decision to be made whether the patient would like to undergo commercial treatment. Do you think the differentiation or data from ASH has swayed the patient decision in any way if that there is such a decision point.

And then just secondarily, could you comment on the total hemoglobin levels in these patients now that we have a few more patients. I think the earlier patients were on a higher end in terms of total hemoglobin, anything of note now that there are more patients data to look at?

Sure. Thank you for the question. So from a decision standpoint, the way we practice over here is that we do what we call as a shared decision making. So I'm a transplant physician and in consultation with the hematologist and the family we discuss all options. It's not just 1 modality of gene therapy, but whatever is available. And we discuss the pros and cons for each of the options and then make a decision.

Again, recruitment on the clinical trial is based on after multiple consoles with the patients and the families. And definitely, when that unfortunate event happened with -- with the patient on this trial, which was presented at ASH, we did have discussion with the families. And also, the patients were already recruited on the trial as well. And we discussed all the possibilities and how busulfan can play a role. And all the families and the -- I should say, all the patients because these were all others. -- consented on that, agreed and had -- we had a lot of decision around it.

So I think it is always very upsetting to see any negative outcome or like especially a death, but also you have to put things in context where like when you use a drug like this all kind of these things can unfortunately happen.

Regarding your other question, yes, it is -- we do have more data than before and the total hemoglobin as I say it is impressive actually where we have a good rapid induction of hemoglobin F.

Your question regarding the high hemoglobin, like we didn't just consider just the high hemoglobin, you have to see what is the erythropoietin doing, what are the other markets doing? And all in together, they are very impressive and they are where we want it to be.

Regarding the high hemoglobin, there are no clinically as we or clinical concerns actually that we have, like I have my patients actually who have high hemoglobin too. And they are doing fine. These are like young men who are like doing stuff that they were not able to do earlier on. And we are monitoring them.

But at the same time, it's like there could be multiple factors for high hemoglobin. And we are not seeing anything concerning on our end, while continue to monitor them.

Our next question comes from Sami Corwin with William Blair.

Congrats on the data. I was wondering if you could discuss your ex vivo manufacturing capabilities, specifically your current clinical scale supply what scale it might be necessary for future commercialization and how easy it would be to switch BEAM-101 manufacturing to BEAM-104?

Yes. Thank you very much for the question. The scale we are capable of supplying the clinical program pretty much fundamentally from North Carolina. The process is already pretty much a commercial process, so we can scale up very rapidly. And we have the ability to be able to satisfy the demand of the commercial setting from the North Carolina side. So we feel very well placed to continue to progress this program all the way to commercial.

Our next question comes from Mani Foroohar with Leerink.

We have Ryan on for Mani. Congrats on the update. Maybe pivoting over to the ESCAPE program. Wondering if you could just talk about what the regulatory pathway looks like for this post the healthy volunteer data?

And then piggybacking off that, just wanted your perspective on how mature this initial ESCAPE data has to be for you guys to feel confident reorienting your strategy around that approach.

Yes. Thank you. Thanks for the question. In terms of regulatory path, obviously, we need to continue to have the conversion with regulators, but we do plan for the health volunteer study that is scheduled for the second half of this year to provide a PK/PD analysis of the antibody and therefore guide a dosage in the patient setting that will come at a later time.

The important thing there, as you know, is that -- the other part of that product is essentially BEAM-101. And therefore, the clinical sort of learning that we can make it now will completely directly inform what we're going to do with the patients there.

In terms of the change in the pivot, obviously, we will want to see more clinical data eventually with that second in order to be able to determine whether that is worth a sort of consideration in terms of switching. For the time being, we do believe that BEAM-101, and that is obviously the product that's moving forward. And that, as I said, in any gain forms in the future for scale type product anyway. So there's a lot of synergy and we move in BEAM-101 forward as we are.

Yes, I'll just add to that to say the same thing, which is I think we don't view it as a reorientation. We view this as a single integrated life cycle strategy, where BEAM-101 opens up with the severe patients and then we look to escape to expand that to many more patients. And then ultimately, in vivo, of course, is the maximally scalable option across the globe.

So really, they build on each other, and they move together and they have been for years.

Our next question comes from Gena Wang with Barclays.

I also wanted to congrats on the very consistent data. So I wanted to go back to the patient 3. It's a very unfortunate event. When we look at the Slide 25, we could see the red blood cell transfusion period was very long. It was almost 4 months. Maybe any color there? And then also any color regarding the gene editing efficiency for that patient.

And if for doctor, I wanted to ask you if fast forward, all the 3 drugs on the market BEAM-101, Casgevy and Lyfgenia,how would you use these 3 drugs?

Great. Thank you, Gena. So I'll have Amy do the first question and then Dr. Gupta you can talk about across the 3 drugs.

Sure.

Thank you, Gena. So just to be clear about that patient unfortunately, had the untoward effect from busulfan, that patient had complete recovery and rapid engraftment like everybody else and was actually doing quite fine.

So in other words, stable hemoglobin stable hemoglobin F above 60%, normal platelets, everything was well until the patient was then hospitalized. So the transfusions and other things don't really start on that patient until after she becomes critically ill and is in the ICU. So she was not someone who, for example, failed to engraft had low hemoglobin S et cetera. She had that same percentile, the greater than 60% less than 40% and was doing quite well. And in fact, when people looked at an examine her bone marrow, et cetera, and other things, that was also in complete recovery.

So in fact, what you see with the transfusions, et cetera, is only after she became critically ill.

I'll also add here that this is unfortunately consistent with when you have some busulfan-related toxicity. We do see this all the time in allo transplants, where busulfan toxicity can put you in ICU, and that is where you require a lot of transfusions and stuff. So that is kind of like where you are seeing data consistent around that.

Your other question regarding the comparison. We are not there yet, but it will be a very interesting scenario. I would say that like this is a -- we are in the middle of a revolution where 10 years ago, we didn't have that many options for these patients. And now we are talking about potentially 3 options, plus throw transplant in the mix. That will be great. And it will be a good problem to have. I will just I'll just leave it at that.

And hopefully, we'll have more data from beam also, which would be very helpful to compare and see -- I mean, at one size does not fit all. So we have to see what issues the patients have and like what would be the best product. And again, as I mentioned, it's a shared decision making. So we do need to have all those discussions when we are there. But again, a good problem to have.

Thank you. I would now like to turn the call back over to John Evans for any closing remarks.

Great. No, I think great conversation. We really appreciate the engagement. I just want to thank everybody for your time and for your attention. I certainly want to thank Dr. Gupta for a great presentation, and thank you for all the help. And thanks as well to all the patients and investigators and families who have been a part of this journey. So we appreciate it and look forward to continuing to bring this product forward.

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.