Capital market. Today it's our great privilege to have Beam as part of our 2026 Global Healthcare Conference. Representing the company we have John Evans, Chief Executive Officer. John, thanks so much for joining us. How are you doing today?
Doing very well, thank you, Luca.
Great. Long list of questions here, but maybe before we go into specifics, it would be great if you can maybe start a little bit big picture about what progress has the organization made recently, and kind of what's ahead here for Beam.
Great. It's great to see you all. Beam Therapeutics is a next-generation gene-editing company. We're working on a new form of CRISPR called base editing. This allows us to make single letter changes in genes on a permanent basis, without needing to make a double strand 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. 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. Here we are correcting the single letter misspelling in the Alpha-1 gene, back to normal. 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 in due for better therapy. Following onto that and building on that platform, will be a variety of other liver programs. We have BEAM-301 for glycogen storage disease, Ia. That'll have data this year.
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. We're thrilled with the early progress. The data has been very much confirmatory of the way we think base editing should work. The beautiful thing about this platform is it's very predictable. Right. 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. In some ways, we've made a lot of progress.
In other ways, I feel like we're just at the starting line.
Sure
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. That's a super helpful overview. Maybe let's double-click on Alpha-1 antitrypsin, maybe just remind us what data you have seen so far. 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 mg, either by doing a 75 mg or the 60 + 60. I think that experiment maybe didn't pan out the way you were hoping for, but maybe what are the lessons learned from going higher, and then we can go from there.
Yeah. The first data we showed a year ago was after three dose cohorts. We went from a low, to a medium, to a sort of medium-high dose, and that was 60 mg. As you recall, that was shown to be a potential functional cure. We had reached the threshold of efficacy we were looking to get to. At 60 mg, we achieved over 11 micromolar of Alpha-1. That's the sort of magic threshold people talk about. 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. Anyone who has the disease, who has progressive lung and liver damage, generally they're below that line. They're in the single digits. We had gotten all of our patients up there.
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. You have one shot at that. What we basically said is, okay, 60 is clearly a possible dose, then we want to do some experimentation around that, sort of pushing the dose higher, trying two doses, and doing more 60s just to confirm where are we on the curve in terms of our maximal PD effect. 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. 75 didn't add much of anything, it was still well-tolerated, which was great. The 2x 60 didn't add much either.
The second dose was not as well-tolerated as the first dose, clearly that's not getting anything. The bottom line is we confirmed that 60 was where we want to be. That larger data set showed 60 mg to deliver an average Alpha-1 level at 16. 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%+, which is in excess of what a carrier would have, an MZ person. Z had been reduced by 84%. Okay? 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 patients in a position where they shouldn't have any progressive disease going forward.
Got you. That's actually super helpful. I think you already alluded to it, but I think this is important for kind of broader field of gene editing. Why was the 60 + 60 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 eight weeks apart from each other, so you would have thought that the first kind of lipid nanoparticle would be kind of completely washed out from the system. Why was that maybe not as well tolerated as the first dose?
Yeah. It's hard to know. I think, certainly it's true by the preclinical data, eight weeks should've been enough to have kind of a clear background, right? Yet we did see a little bit of response. That said, these are not normal livers. This is Alpha-1. Alpha-1 livers are different in terms of their physiology, their macrophage biology is different. There's all sorts of things that may have sort of retained some sensitivity given that time period. I don't have data on this, but I feel fairly confident that just a longer time period would probably resolve that.
Just to note that the things we saw were not show-stoppers. We saw higher infusion-related reactions, so more like grade twos, where you're giving MOTRIN to handle some soreness. We had basically one patient who'd gone to a grade three for AST/ALT. It was asymptomatic. They never went to the hospital. There was no bilirubin, and it resolved very quickly. Right? 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 pharmacodynamic outcome, there's no reason to pursue it. I think for the field, nobody should draw from that conclusion that redosing LNPs is not possible. It clearly is.
Sure.
Moderna does it all the time. Intellia has redosed patients successfully. I expect we will as well. In fact, we still intend to go back and redose the patients in our trial at the 15 mg and 30 mg level, who received subtherapeutic doses and will need to get the full dose at some point soon.
In that case, you're not going to go higher than whatever is the 75 mg, or is that the idea?
No.
The patient that received 60 are going to get 15, or is that?
No, usually what you do is you say, once you've sort of settled on the final dose, in this case it would be 60, then at some point you would go back and just give them 60.
60. Okay. Okay.
We wouldn't do anything. Go higher than that.
Okay. That makes sense. Maybe one last one on safety, if I may. I just think this is super important for the broader field here, given that you are obviously pioneering this space. 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.
Yes.
What can you tell us about what you've 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, this is a complex indication. There's the liver manifestations, there's the lung manifestations, so whatnot. Just maybe walk us through the kinetics and how the magnitude of the elevations compare between the two buckets.
Yeah, it's a great point. I want to make sure people understand. We're all learning about LNPs in real time. There has been this concern from a couple of the programs. There were really 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? 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 signal is just it goes up fast and then it comes down fast. Right?
It's really the kind of mass action of putting a lot of lipid into the liver all at once and the liver gets inflamed. The key is you want to see them within days coming down rapidly, and you want to see no bilirubin change.
Sure.
Right. Because that shows you the liver function has not been affected. It's still processing bilirubin, et cetera. That's exactly what we saw, right, in this case. I think nothing out of the ordinary, just a sign that the liver was still sensitive, I think of it, and not fully reset.
Sure. Sure. Okay, that's helpful. Maybe let's talk about bystander editing. That's something comes up in every conversation we have with investors. Maybe remind us what kind of work you have done to really make sure that not only you have this 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. 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, and 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.
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. 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 six, seven, eight different variants you can find in people. The one that we're making is found in people and not associated in disease. It's just a permissive sort of surface residue on the protein. I think the most important data we have shown is that when we showed the functional data, we showed that we had very high levels of functional data consistent with what you would expect to see if it was just the M and ours was the mixture of M and M variant. 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.
Yep.
Very dramatic drop, very quick by this Alpha-1 sort of mixture that we're creating. Again, showing you it's clearly functional.
I forget, have you disclosed the ratio between the variant and the wild type?
It's comparable to what we see in preclinical models. You see some amount of M and some amount of M variant.
Okay. That's helpful. Maybe let's talk about going forward, the pillar 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. The higher is the Alpha-1 at baseline, the higher is the boost, and appreciate at the end of the day, you need to have as many patients as you possibly can above this level micromolar. Can you enrich this study in some capacity to stack the odds in your favor and try to maybe enroll or maybe exclude patients to have baseline level below certain thresholds, or how should we think about that part?
Yeah, it's a great point. I think you're probably thinking about this correctly. I don't know exactly how hard and fast a rule it is, but generally, my read of our data is that yes, there is a spread. It's true even at the baseline. Z patients live anywhere from four to six or three to seven. It's kind of a range. If you were low on that range, then you get edited, you're probably low on the resulting range. If you're high on that range, you're probably high on the resulting range. 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.
The great news is that is what we're seeing. Right? Now, could you game that? Yes, of course, you probably could. We're certainly not excluding any patients on the basis of their AAT levels, so we take them all.
Got you.
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. Your ability to play those games goes away with larger N.
Sure.
We've already converged on-
Sure
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. Super helpful. You guys came forward early this year about alignment with the FDA and a path to accelerated approval. You guys have talked about biomarkers and maybe you haven't offered the specifics, but we can all think about total Alpha-1 and MZ and the whole nine yards. How do you feel about that, especially in the context of the never-ending headlines around the FDA? We've seen companies obviously complaining about them moving goalposts and whatnot. How do you feel that the FDA is fully on board, everybody's on board, both the reviewers are on board, and the top of the house are on board and not top of the house changes? 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 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 where that's going. 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. Hopefully that stabilizes, and I expect it will. I think the good news in a way for Alpha-1, and it's true of Sickle as well, is we're not doing anything unusual here, right?
Our Alpha-1 path is not reliant on the Plausible Mechanism Pathway, right? Nor I think hopefully will I have to worry that somebody's going to rug pull us at the end, right? I think it's just this is a classic accelerated approval.
Sure.
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. 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.
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. That should be enough for an accelerated approval. The FDA has seemed very amenable to that. The main pushback they pushed towards us was to have 12 months of follow-up because they know that Alpha-1 levels can bounce around. They want to make sure they have a good longitudinal series, perfectly reasonable. We'll enroll 50 patients, follow them for a year, and then bring it in.
Got you. That's helpful. I think one of the components here for the accelerated approval is like, yep, I am going to drive a level of Alpha-1 above certain thresholds. There's a little bit of debate around augmentation therapy now with this data with Inhibrx and Sanofi that kind of a little bit of raising the bar on the total level that can drive in the serum. There's a debate around trough versus what you achieve. 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 is actually there.
Yeah.
Can you maybe speak about some of the endpoint that you're now doing? Obviously, biopsy will be invasive, it'll be difficult to enroll patients and whatnot, at least for now. What are you measuring to actually prove that in addition to emphysema type of potential benefits, you also have a liver benefit?
Oh, for sure. First of all, on the Inhibrx program, yes, they do achieve these high levels. Of course, as you note, because it's a chronic therapy, you have to worry about the trough level.
Sure.
It's also not inducible, right? That trough is as good as it's going to be when you really need it when you're sick, right? Our trough is different. It's really a floor, and when you're sick, you get more, right? It's a very different kind of dynamic way of looking at the numbers. Equally, the inhibitor is not a natural protein. It is an Fc-bound set of AAT proteins. What is the biodistribution of that? Does it show up in the right places? Is it fully active? I think there are probably a lot more questions there, right? For us, everything about our situation, you can rely on the MZ genetics to tell you what that should be. I think we have just a higher background credence, and probably less to prove on some of these ways.
All that said, 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. We're clearly doing that. We're getting Z levels down to or below what an MZ carrier might have. Again, they don't generally have progressive liver disease of any kind. How will we show that? We are doing biopsies in the Part B patients.
As a reminder, the great news of Part B was that so far all the Part B patients have tolerated the drug the same as Part 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. In the Part B, we are doing biopsies before, and then six m onths and 12 months. 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. 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 maybe the trials are too short to actually show a benefit by MRI?
Yeah. It's an emerging field. This has been pioneered a little bit by Takeda with the RNAi drugs, which are, of course, liver only in their benefit, potentially. That endpoint work will be applicable here. You can do some imaging. There's FibroScan, there's other things there. I think biopsies end up being important to kind of directly measure fibrosis as well.
Sure. The primary point of that Takeda Arrowhead trial is biopsy, right?
Exactly.
It kind of makes sense to me. Maybe just quickly, I know early days, but kind of fun to start talking about approval and maybe pricing.
Yep.
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, will payer appreciate the longer term pharmacoeconomic value of doing one and done, or they will rather pay less for something that I got to pay for one year?
Yeah.
I guess because I'm assuming that you're going to ultimately price higher, what's the price of augmentation therapy for one year, given it's one and done? Will the payers get it?
Yeah. It's a great question.
Yeah.
There's no question we will price higher than the one year of augmentation, right? I mean, the whole one and done model has to do that. Payers are very sophisticated. They want to deliver cures and great medicines to their patients, and they do the math, right? I mean, that's kind of what the business is. They're really good at math. Generally, when we bring them a great value story with strong pharmacoeconomic argument, they can understand it, and they will get behind it. We've actually seen this play out in sickle, right? 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 lost productivity and, of course, the hospitalizations.
Even ICER, Institute for Clinical and Economic Review, which is a fairly conservative body, said over a $2 million price in sickle cell disease made sense. As far as I know, there have been no rejections on price in the sickle cell disease market.
Working on speeding up authorizations and things like that, but ultimately that's a price that the payers have said they're willing to pay, and that includes CMS and Medicaid, right? Alpha-1 is basically similar, right? We've published some data showing that lifetime cost for an Alpha-1 patient can be anywhere from, depending on their course, kind of the $4 million-$5 million to $8 million over time. Certainly we think that's suggestive of genetic medicine pricing. Of course, it's too early to talk specifically about that. I do think that we feel strongly about the pharmacoeconomic value of what we're doing and the value to patients. Of course, relative to augmentation, we would have more sources of value as well, right? Not just the one and done.
Sure
Obviously the liver plus the lung, more of a deep resolution of the situation. 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 see a lot of transactions and whatnot there. I guess give us an update on your ex vivo approach, and what's the latest on thinking to pivot to in vivo?
For sure. 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 four months, which means we can treat patients quickly and with high predictability. Part of that's base editing, part of it's the manufacturing. 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. That's a multi-billion dollar a year opportunity to bring an exciting product forward, and that's what risto-cel will be.
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. They'd be a great fit for something that is in vivo and more scalable. We're also working on that, of course. 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. Now people are also getting to T cells pretty well. We think HSCs are coming.
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. With preclinical studies, it's always important to see did they disclose the dose? If they didn't, you have to sort of see how close to the finish line they really are. I think it's going to happen. I mean, we're quite active there. Of course, we have the ex vivo capability with risto-cel. Of course, Beam is also an LNP company. We're an in vivo company. Everything else we're doing is in vivo. I think we've got a lot of tools in the toolkit for that one. 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. On that note, I have a lot more questions, but no more time. John, appreciate you joining us. Thanks everyone for joining us here at RBC Conference, and we'll talk soon. All the best.
Thank you, Luca.