Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Beam Therapeutics as part of our 2025 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 well. Great to be here.
Great, great, great. Long list of questions here, but let's start big picture. Can you just maybe talk at high level what progress has the organization made over the last few months and maybe what's importantly, what's next here for Beam?
Yeah, so it's been actually quite an action-packed period for Beam. We're quite excited about how things are going. We are entering the period now with multiple franchises in our base editing portfolio, fully de-risked clinically, and with clear, we think, paths towards registration and reaching patients. The platform obviously becoming increasingly de-risked and successful, and then also our delivery and manufacturing capabilities. Very, very pleased. As a reminder, of course, we're using base editing, which is this next generation version of CRISPR that doesn't make double-stranded breaks. It makes more precise single base changes in genes. We're applying that ex vivo as well as in vivo, ex vivo with sickle cell disease, BEAM-101, where we showed, I think, quite compelling data in December showing a differentiated profile relative to what others have been able to achieve for severe sickle cell disease.
That is enrolling very quickly now. Talk more about that, moving rapidly towards potential filing. In vivo just showed, of course, our first in vivo data with the Alpha-1 Antitrypsin Deficiency program , BEAM-302, where again, we reached a clear therapeutic threshold in terms of raising total Alpha-1 levels, correcting the fundamental underlying gene that is mutated in that disease. It is a single letter change that we are turning back to normal. That program also now, you know, accelerating. Behind that, many more programs coming, including to have just dosed our first patient for BEAM-301, Glycogen Storage Disease Type 1a , the RD3C mutation. It is a very exciting time, I think, for the company and lots, lots more to come. We are well financed.
We just did a very successful capital financing, so cash into 2028, which gives us the resources we need to drive all of these forward in parallel.
Great, great, great, great. Super helpful of you. Let's talk about the FDA, right? I mean, lots of changes. You know, Dr. Prasad now, you know, head of CBER, you know, historically has been pretty outspoken against, you know, gene editing for PCSK9, the approval of Sarepta, and maybe in general, the use of surrogate biomarker when you think about like some of his commentary around MRD as a surrogate biomarker for multiple myeloma, which is more kind of his bread and butter given his background. I think most investors would probably argue that the bar now is higher at CBER versus before under Marks. Do you have a different view?
Yeah, it's a great question. We're all watching this very closely. I think there was one world where people were, I think, very alarmed at, you know, the DOGE and, you know, are we going to just dismantle the entire federal government? Are we going to have an FDA? Right? I think we're clearly not there. Even some of the scariest scenarios, like, are we going to mash CBER and CDER together and hope for the best? You know, that's clearly not happening. I think if you step back, we actually have an FDA leadership that's now in place that is, you know, a new administration. They have new ideas they're going to bring to the table, but this is still the FDA. This is still, you know, regulating drugs and they want to bring medicines forward for patients. I think that's all good news.
I think that if I listen carefully to what I'm hearing from Makary, from Prasad, and others, I think that yes, in a way, I think there will be a more stringent perspective on some kinds of drug development. I think you mentioned some of the examples where maybe the approvals were built on not as much hard evidence, right? I think that that's a fair question. Frankly, maybe that's a good thing. On the other hand, I think when we have drugs that are really clearly working, right, and are fundamentally addressing the root cause of the disease for patients who have few other options and are very sick, I think if anything, what I've heard from them is as much, if not even more excitement to try to work with companies and bring those forward.
I think that at least for us, I feel that we're actually right in the lane of what I hear them talking about wanting to do. I think that's great news. We aren't afraid of a high bar because I think we've got, you know, these CRISPR cures at base editing that are fundamentally fixing what's wrong with patients who are very sick. I think that we can meet any bar that you throw at us.
Yeah, yeah, no, for sure. Clearly, especially some of the commentary from Marty Makary, pretty favorable overall for rare disease. I think this is something pretty close to the president's heart when he thinks about like right to try and whatnot.
Secretary Kennedy has talked a lot about, you know, fixing the root cause of the disease. He was out talking about a new CMS initiative to speed up reimbursement approvals for sickle cell disease gene therapies, which he's talked favorably about in his confirmation hearings. I think up and down the administration, I think there's pretty good symbols of alignment here.
Yeah, yeah, and pretty good, yeah, plausibility of the mechanism of action and whatnot. Let's talk about DNA editing versus RNA editing. That's kind of a never-ending debate. You guys obviously have shown really, really good proof of concept. Some of your competitors also in the RNA editing have shown some initial proof of concept there. I think the believer of the RNA editing just makes the argument that, you know, you can revert to pharmacology in that case and maybe there's no risk of bystander editing. What would be your pushback to that?
Yeah, I think the, I mean, I think those points I don't think are going to hold much over the long term. In bystander editing, there's no tolerability concern there or toxicity concern. We've shown that before. You're just editing in the region of the gene. You're not going to cause any systemic issue. The question is, do you get successful edits out that are functional? And we do. That is, I think, fully resolved. You know, I think RNA editing certainly talks about, you know, the ability to stop dosing. I think, I mean, the main question for DNA editing will always be, do we have some long-term side effect that people are worried about? The off-target biology that we have now is so sophisticated.
We literally know with deep sequencing at every position of the genome exactly what's happening when you put this into the body. We wouldn't move something forward if it had any risk of that sort of thing. I think as we reach a decade of follow-up and more for the CRISPR field, which we're coming close to in this decade, those concerns go down a lot. If you think about something like Alpha-1, you know, patients are quite eager for a one and done, right? That is a big goal they have. I think that can go in favor of DNA editing in general. I would say beyond that, there are a bunch of other reasons where DNA editing, I think, has actually more potential power than RNA editing.
Not to say this on a role for RNA editing. I would not say that. You know, because we are fixing it at the root cause of the disease, now that gene is only creating normal mRNA, which then creates normal protein, which then will not hurt the liver and will help the lung. This is this dual mode of action where we help both sides of the disease. I think that is a, you know, a fundamental big advantage. Also, when the patient gets sick, it will be regulated normally so that you can turn the gene on and you will get more of our normal mRNA. With RNA editing, you are doing something different. You are trying to patch the diseased mRNAs in flight and correct them, right, to adjust the levels.
All of your corrected mRNAs are constantly being degraded and the gene is constantly creating new mutant form of the gene that you have to keep up with. There is a kinetic issue. In fact, in preclinical studies, most of these RNA editing systems kind of have a cap to how much they can keep up with that process. They cannot go above that. You know, usually about half of the RNA pool is what we see. With DNA editing, that is not the issue. We can edit every allele ultimately if we choose to. You know, it just is a lot more efficient to kind of fix the problem at its source. I think bottom line is I think I continue to believe that RTPP will be the superior one, both potentially more effective and more preferred.
At the end of the day, of course, this is also just about data. I think the RNA editing companies have not put much out yet. We would wait and try to see what they can deliver. In the meantime, we have already put out clearly, I think, the strongest data in the field by far. We have patients lining up to join the trial. There has been a lot of enthusiasm in the community. I think our operational lead actually at this point is growing, not shrinking. You know, our goal is to maintain that.
Got it. Got it. That's actually super helpful. How should we think about dosing? Obviously, you have a higher dose. We have yet to see that data. You know, maybe there's an argument to be made that, you know, Wave have shown somewhat similar total level of Alpha-1 at their lowest dose versus you guys are already kind of your third dose. Like, how should we think about that dynamic? Like, what do you think is going to be the contribution of the higher dose? Can you actually drive the level of Alpha-1 closer to 20s or like high teens? Or like, how should we think about what you're trying to achieve with a high dose here?
For sure. I think a couple of points. One is, I think, I mean, Wave is at a low dose on their multi-dose, but remember they did a single ascending dose first, right? I would not say that that is a low dose. More important to me in the RNA editing world is where are they relative to that peak, that cap of activity, right? Are they already there? Are they, you know, like, because if you can only edit half of the RNA transcripts, you are only, you are going to have a limit to what you can do. That is where I think we just need more data from that side of the field. For DNA editing, we do not have that kind of concern. For sure we can go higher.
The way I think about our activity levels is the most important chart in our data set is the fold change from baseline. Because patients will either have low or high baseline. They're probably low or high after treatment. It's just all going to be higher. You know, what we have achieved is sort of 1.6x at 15 mg, 1.9x at 90 mg, and then 2.8x at 60 mg. What I'd like to see from the 75 mg dose is that that goes, keeps going higher. Can we get into the threes now, you know, in terms of fold change? It would seem plausible to me. You know, that would put a patient with Alpha-1 levels of four to six up in the 13-18 range, right? There's nothing stopping us from keeping on going.
Back to the point of DNA editing, you can in theory edit every allele. I am pretty convinced that already we would never be able to show a clinical difference between patients at this level and at higher levels because we're already in the world where carriers, you know, heterozygous people live. They do not have progressive disease. They do not have Alpha-1 deficiency. It is not clear I could ever detect the difference. That said, as long as we're still tolerated, which so far we have been, we're absolutely going to continue to push it and see how it can go.
Got it. Got it. Super helpful. Let me just talk briefly about safety. We're still getting questions from investors on that side. Can you just talk to some of your, you know, lipid nanoparticles, some of the differences between your molecule and Verve, obviously Verve running into issues for the first generation? Like, what are the differences and similarities between your molecule and their molecule? And how are we thinking about it?
Yeah, I mean, hopefully that the question starts to go away and we've put it to bed. I mean, it's a fundamentally different LNP. It's a different lipid. It is licensed from the same vendor, but it's a different lipid from what Verve one-on-one was. I mean, we did all of our own formulation and process and manufacturing and quality control. It is a completely different LNP. I think you saw from the results that it is very well tolerated. It's a very clean LNP. I think that speaks to the strength of both of all of those components. I think Verve one-on-one, I think it was just an outlier in terms of maybe both lipid and kind of the process that was made to make it. That's why Verve pivoted, which made a ton of sense. I think we're thrilled with the safety profile.
It gives us a lot of flexibility to keep pushing dose, to be confident that we're going to have a really safe and tolerated therapy long term. It is de-risked now for the rest of our platform, right? Certainly the GSD program, BEAM-301, exactly the same LNP. These same kinds of principles can now be applied to future programs, which we're already thinking about, right? What is our next in vivo play? That will start to be, I think, a progression of programs that take advantage of this and that should theoretically all have the same high probability of technical success for achieving a certain level of editing in the liver that we've already shown with Alpha-1. That is the beauty, again, of these CRISPR-based platforms. Base editing is no different.
That once you've done it once, if you're not changing a lot of things, it should work again. You get a lot of leverage out of that initial investment going forward.
Sure, sure. Super helpful. Let's maybe talk about regulatory. Like, how are you thinking about the path here going forward for accelerated approval? I think that probably the comp here should be what in hybrids, right, was asked by the FDA, right? Obviously potential approval on a surrogate, which is Alpha-1 levels in the serum. However, maybe superiority to the current standard of care. Is that the right bogey for us to think about it? Maybe a refined question, like, should we think about levels at peak or trough versus current standard of care? Just walk me through all that.
Yeah. Maybe that last point makes a point that I'll make here, which is, it's important with augmentation, it's important to remember it's just a completely different thing, right? It works differently. You're going to add as much as you can when you dose, and it's never going to go up again. It's not being produced by the body, and it's going to be washing out constantly. Augmentation has to think about, okay, I need to overdose and then land at a trough that is more than the body would ever need if you get sick, okay? That's a complicated piece of math to do. By the way, the body is still creating Z, and the liver is still full of Z, and the circulating Z is there, and that can interfere with the M.
Like, there's all totally different dynamics here. What we're doing is totally different. We are again fixing the disease at its root cause. We're going to now create normal M, which is also functional, but at the same time we've dropped Z. We're eliminating Z from the circulation. Our 60 mg cohort was 12.5 total micromolar. More than 11 of that was M, functional M, right? Just one is Z now, right? We've already moved so significantly in the right direction, and it's going to be normally regulated. Our levels are a floor, not a ceiling, okay? That's really important. When the patient gets sick, we know it will turn on and you'll get more.
You do not have any of the concerns you have with augmentation of where does that trough live and how does it relate to what I might need, you know, we kind of make that in. What we do is you think about the clinical genetics, right? Who are the people who look like the biomarkers we are showing, and they are carriers, right? They are MZ carriers or SZ carriers that have just one copy of the disease gene allele, and they live in the double digits for total Alpha-1 levels. It is all functional. They do not have much Z circulating, just like us. They do not have disease, right? I actually think, as much as possible, I actually think we are not going to try to build on augmentation as a precedent. We are trying to start a new conversation with the FDA.
Because augmentation is just so different, and there's lots of history there. I think at the end of the day, we have an opportunity to say, for the first time, we're doing something fundamentally different in this disease. We're fixing it at its root cause. We have all these biomarkers that go in the right direction to therapeutic thresholds, total AAT, functional AAT, lowering of the MZ ratio. I think that opens up the door to have a fundamentally new conversation with the FDA about what is the path to approval for this agent. In terms of what that might be, I think, you know, it's too early to say exactly, but I think clearly with this data set, we feel we are already in what I consider to be looking for some accelerated form of registration.
Now, what exact flavor that takes will depend on the conversation we have with the FDA. You may have seen we just got RMAT designation. This is the kind of breakthrough therapy for advanced technologies. That is beautiful because what it allows us to do is to engage early and often with the FDA about this conversation. You do not have to go in for just one big conversation. You basically say, here is what we are thinking. You hear back from them. You can follow up subsequently, you know, pick up the phone, you know. It is going to be quite enabling, given that, as I said, we want to have a sort of a new conversation about the pathway here, but throughout be exploring different options for accelerated pathways to market.
Sure, sure. That's actually helpful. If I can follow up, I mean, everything you're describing is essentially a biochemical response in the serum, right? You're going to have like total levels going up and, you know, obviously Z going down and you have the wild type going up as well. Like, do you think a biochemical response in the serum is sufficient or you will ultimately need to show some function at least for accelerated approval? If so, if it is, you need to show some function. What are the endpoints that you're considering?
Yeah, so I think there's a spectrum here. I think that, you know, it's not like these are novel biochemical signals we have picked out of the data and are kind of advanced, right? This literally defines the disease. You have Alpha-1 antitrypsin deficiency. You now have more Alpha-1 antitrypsin protein. You know, that is pretty corrective. And much like LDLC, like we kind of understand the causal role of these sorts of proteins in the disease process. I think we have reason to believe that these are going to be pretty solid. All of them together, again, I think it's more of a composite view here that we can lean on, not just any one of those things. All that said, we're definitely going to look at these other things.
We will, even in this part of the trial, in the liver patients we test, be doing biopsies. We will start to measure aggregates. We will be measuring fibrosis change. You know, some of that science has evolved. In the lung, we will be doing bronchoscopies. You can measure inflammation level. You can measure, obviously, local concentrations of these things. Longer term, I think for lung function, you know, that is another sort of area that the field has been working on. We generally favor CT densitometry, which is where I think the Alpha-1 Foundation and the investigators are generally there. Europe is there. The FDA had been resisting that and being more focused on FEV1 for stroke reasons. I think that we really understand that is not the right way to measure the disease. FEV1 in this disease drops and then plateaus.
It's not a good measure long term of function. So, but CT is there and, you know, lots of trials are doing and that database continues to grow. I think we'll be doing all of those things. We'll want to generate that data set over time. The question is, are those a confirmatory trial? Are they real-world follow-up? You know, like what is the kind of format in which we'll be gathering that data? That's the dialogue we'll have to have together.
Sure, sure. When is your next conversation with the FDA? You have disclosed it and what's on the agenda for that conversation? Again, given the leadership and all that, how are you thinking about it? Now you have the data in hand. Like, walk me through that part.
That's right. So we've had, I guess, you know, three interactions with the FDA so far. One was the pre-IND meeting we had. And I should say even then we're having some of these conversations. Of course, not guidance yet, but they didn't close the door to these kinds of accelerated ideas even then. Then, of course, we submitted the IND and that was approved on the first cycle. That was very exciting. The third interaction was, of course, after our data, we submitted that for the RMAT and they have approved it, right? They've obviously been paying close attention. I would say also the approval of RMAT happened pretty quickly, you know, as well before their sort of statutory clock was up. They're clearly, you know, following this closely. Next is you start to bring in the data for live conversations, you know.
We'll have probably a series of meetings with them where we share the data. We talk about these kinds of issues in terms of endpoints and path to market. We get some feedback. You know, we will not give, you know, guidance on like meeting to meeting. That'll be way too granular. I'm also cautious to give too much in terms of what we're hearing from the regulators because, you know, if we're going to give that guidance, we want it to be really, really certain. This is a dialogue. The FDA evolves and they have to think it through. I think companies get themselves in trouble if they go too quickly to try to say what they think the FDA is saying and maybe they didn't quite hear it correctly.
I would say that generally, I think over the next 6 to 12 months, we will probably figure most of this out, is my guess, over a series of meetings. The reason that's important is because we basically have to start figuring out what's the next step in the program. You know, if it is an accelerated format of some kind, then I would expect one possibility is to take the current phase one two trial and say, how can we leverage that, right? Do we expand it? You know, do we add a larger cohort? What is the size of that cohort? You know, these are the things we have to work through with them. At the same time, if we're talking about some of these other endpoints, you know, is it controlled or not controlled? Is it historical control?
You know, what does that trial look like? These are all things that have to get sorted out because ideally you're operationalizing those things next year.
Sure, sure.
In the meantime, I can say there's tremendous enthusiasm from patients and from investigators for this program. We are eager to meet that. You know, one of the things I think the FDA is looking for is signs of that demand. I think we will actually add more patients to the protocol in terms of some of these cohorts that we're actively doing now, just to try to increase the overall n and gain more experience with the drug. All of that puts us in an even better position for whatever comes in 2026.
Sure. I'm probably pushing my luck, but will you apply for breakthrough?
I just heard this morning somebody had done both. I don't actually know why you ever would. The benefits are identical. There's no reason to. If you read the guidance, RMAT is basically described as all of the benefits of breakthrough designation, you know, and I think there's some other stuff around the manufacturing, you know, because these are complicated cell therapies and gene therapies. We wouldn't get any benefit from doing that.
Got it. Got it. Okay. That's actually very helpful. Maybe last one on Alpha-1 and then maybe one last one on SICO. How do you think about part B for Alpha-1? I mean, obviously these patients are going to have a different liver involvement. And, you know, there's some questions around lipid nanoparticles and, you know, patients that have liver involvement and all that. Does that keep you up at night or how do you think about it?
Great question. It doesn't keep me up at night, but it's something we wanted to do just thoughtfully. As a reminder to people, we're doing this trial in two parts, part A, part B. Part A is basically all Comer Alpha-1, but if they have a heavily involved liver as tested through FibroScan or LFT levels, we exclude them. That takes out, you know, it's probably 15%-20% of total. It's not the majority by far. The reason is because then those patients, they have a heavy liver involvement. We're dosing the liver. We just didn't, if we were seeing any liver toxicity, we wouldn't know, well, was it the liver of the patient or was it our drug, right? Now we have a very clear idea that, oh, our drug is quite quiet.
We don't have a lot of liver action at all in these lung patients. Now we'll go back and treat the liver patients. Our goal and expectation would be that we actually can bring them back together again, you know, so that by next year we're doing, you know, all comers, right? These are patients who have more heavily involved livers, but if you look at, you know, there's so minimal evidence of LFT rise in the patients, even at these higher, medium high doses in the lung. Patients with liver involved Alpha-1, you know, they're not at LFT grade 2, 3. They're at LFT grade 1, 1.5. I think if we don't add much to that, I have every expectation that it'll work.
From efficacy perspective, pharmacology models, we have done that in preclinical studies in animals with very advanced disease and we see no difference in efficacy.
Got it. Got it. Very helpful. Maybe sickle cell disease quickly. You guys obviously have some very exciting data and you're also thinking about what's step two in this evolution, right? Would ESCAPE. Want to look kind of big picture of the launch of the Vertex and CRISPR's product, as well as some of the decisions that we've seen for sickle cell disease more broadly, including Editas, which honestly had some reasonable data, but ultimately decided to discontinue that program. Is there a version of the world where at one point you may pivot and just go from first gen to next gen and maybe not even continue to invest capital in the first gen? Or how should we think about that dynamic?
Yeah, it's a great question. I think most likely not, but we'll see. We're data driven. We are, of course, watching the Vertex launch carefully. We have time, so we can see how that plays out over the next, you know, six, six months into the next year. You know, nothing that's happening in Vertex is surprising to us. It's a complex operational procedure. You've got to get it up and running. You know, just go back and look at the early days of CAR-T launch, right? It was just as complicated. Last year, CAR-T, autologous CAR-T is a $2.8 billion category. And this year it'll be $4 billion. Okay? These things take time, but once they're built, the system is built and there's actually tremendous stickiness. It actually is quite hard to unseat them because they're so effective, right? With CAR-Ts, we thought about AlloCAR T.
We talked about bytes and T-cell engagers. And so far, they're sticky, right? The same thing is going to happen here. I think these wave one therapies are very effective. And for the most severe patients, they're a great option. You know, we do see an opportunity there for one-on-one. I think Editas had good data, but it wasn't nearly as differentiated as our data, I think. We do still feel confident there. Nonetheless, we're investing in these next gen, both ex vivo and in vivo. I think that as those come online, the first thing they will do is expand the market to more addressable patients without unseating wave one, okay? Only when they can get to equally effective as wave one, will they then also cannibalize wave one?
In our minds, the way to do that is the ESCAPE technology, which lets us select and drive chimerism even higher. That is certainly a big part of our long-term play, but I think there's plenty of room for one-on-one and wave one and then for the future of ex vivo and in vivo to come along after.
Got it. Got it. Super helpful. John, I have a lot more questions, but no more time. Thanks again for joining us today at RBC. Thanks everyone for joining. Yeah, we'll talk soon. Thanks again.
Yeah, absolutely.