Sam Semenkow, one of the senior biotech analysts here at Citi, and it is my pleasure to be hosting Beam at Citi's 2026 Biopharma Back to School Summit. I am joined by John Evans, CEO, and Sravan Emany, CFO. John and Sravan, welcome, and thank you both for being here.
Thank you for having us.
Why don't we just start by level setting. You have made a lot of progress across the pipeline this year. Just tell us where the company stands today and what we can expect through the end of the year and beyond.
Yeah, great. Beam has made a lot of progress. We are moving very quickly now across a broad range of programs, all building off of this very dynamic platform that we have created using base editing, of course, next generation CRISPR 2.0 technology for more precise gene editing, but then building that into a delivery and manufacturing machinery that is now quite mature. D oing both ex vivo cell therapy, but also now in vivo lipid nanoparticle programs, and manufacturing all of that internally. I t is a very significant capability we have built. The programs are now moving very quickly. R isto-cel, our sickle program, is really awaiting its final data cut from a now fully enrolled and dosed BEACON trial, that will become a BLA filing right around the end of the year, which will be our first BLA.
T hat will be an update we are excited to share, t hen in the in vivo programs on the liver, we have BEAM-302 for alpha-1 antitrypsin deficiency. We just have shared new data there showing really dramatic consistency of that program as we continue to add patients. That's now in a pivotal cohort. We're enrolling patients. We dosed our first patient in July. By the end of the year, we hope to significant progress on enrolling that 50-patient cohort, and continue to move that program forward towards patients. Behind that is BEAM-301, which is a program for glycogen storage disease 1A, the R83C mutation. There we'll have first in human data this year on a couple of dose cohorts for that program, another metabolic type of mutation that we're going to try to correct. Finally, also in vivo PKU, BEAM-304.
We now have an open IND, so we're now opening sites as we speak, and hope to begin screening patients towards the end of this year, and obviously then that'll become a clinical program to follow. L ots going on, lots to talk about, but we're seeing this flywheel continue to gain momentum on both the payload technology and our delivery and manufacturing capabilities.
Yes, absolutely. As you said, lots to get into. Why don't we start with AATD? Y esterday you did share new data at ERS, an updated data cut, and our takeaway, kind of what you said, is that it seems to be quite durable and that the level of AAT and M-AAT induction that you're achieving just continues to be within the range of that protective MZ phenotype. Maybe it would be helpful just to hear a little bit of the feedback from ERS. Walk us through how physicians are viewing the data, how impactful they believe achieving these levels of AAT and M-AAT are for patients.
Yeah, it's a great question. T here's been a lot of enthusiasm, and I'd say ERS is no exception. We're hearing from physicians around the world, certainly our investigators, but more than that this looks like the profile they've been waiting for. This patient community is really overdue for some better therapies. When you ask them what is the ideal outcome, they will say, "Well, we need something that raises our AAT above the protective threshold," which basically means into the teens, because that is the place where there are no patients who have those kinds of levels. We want to raise it by creating M, the normal protein, which we know is functional and will protect their lungs. At the same time, we want to be reducing Z as much as we can.
That is a toxic protein both for the liver, but we have learned a lot more recently about its disruptive effects systemically, causing inflammation and interfering with the protection of normal AAT. You want it to be inducible. When you get sick, it needs to go up, and we have shown that. Then, of course, you want it to be durable. These patients have been on chronic therapy their whole lives, taking weekly augmentation. They are very hungry for a one-time cure, and that is what we believe we are offering. Lots of excitement, I think, across the physician and patient community, and we continue to see that operationally in our BEAM-302 trials.
One thing we heard after the presentation yesterday is maybe a little bit of confusion on the assay used to quantify AAT and M-AAT. It can make cross-trial comparisons perhaps a little difficult, and maybe even comparing your own data cuts difficult. Maybe just talk about whether turbidimetry or LC-MS is the better assay, why you are using both, and maybe clarify if we are seeing a decrease in AAT levels or if it is just an assay difference.
Yes, great question. There are multiple assays available, and I think the important point is to step back and see that they are actually telling the same story across the board. We do change back and forth between them a bit. Turbidimetry is the classic in the field. This is literally taking protein in liquid, shaking it up, and seeing if it disrupts light scattering. I it is a fairly crude sort of old assay, but it is used by the clinicians very frequently.
T hat is the standard. If you are going to get diagnosed with AATD, you are going to use turbidimetry to do so, but they do not check AAT levels very frequently. It is kind of a one-off. For our first academic conference presentation, which was yesterday, we thought turbidimetry makes sense because it could be familiar to the clinicians, and they would fully understand it. LC-MS is different.
That is, of course, mass spec, and we need LC-MS to discriminate between the kinds of AAT. If you want to see how much M you have, how much Z you have, turbidimetry cannot do that. So, we need LC-MS at least for that. You have seen some of our LC-MS data. It is reporting that. Our expectation is ultimately even things like total AAT level for the FDA, they will also want LC-MS. W e have been bridging our way over to that assay. I expect you will see more of that from us in the future.
Right now we are validating it for pivotal stage, but it gives fairly similar answers. There is definitely for these assays, there is a 10% wiggle as you think about sample to sample. Also AAT levels themselves drift up and down for these patients on that order of magnitude. I definitely don't see, there's no change in our levels, I think that you should interpret here, between 16, 14.5, it's all basically mid-teens. As we have seen, it's quite durable. Once you see those set points, I think you'll see them sustained.
Right. Okay. Yeah. What patients tend to achieve is what they tend to keep? I see.
Exactly.
Then looking forward, there's a lot of competition in AATD. The space has quickly become quite crowded. You remain well ahead of competitors entering pivotal studies. O ther companies are also developing gene editing therapies. How do you see BEAM-302 positioned outside of being first to market against all the competition?
Yeah. I think the success of BEAM-302 is definitely going to invite competition. They will be coming. We have the fortune of being well ahead. We've been up against some different classes of medicine. RNA editing is one that we've been facing. I think we're now moving past them in operations. We're now into pivotal trials. RNA editing is still in more of the early stage of development. By and large, the numbers they've produced have been positive, clearly for patients, but maybe numerically not where we're at in terms of both levels of AAT, amount of M-AAT being produced, amount of reduction in Z. Then you look to the DNA editing field, as I said, I think the DNA editing is maybe more where the ideal target product profile lives for the patients and for the community.
BEAM-302 is in pivotal trials. We will have a clear first and class advantage. We are about two years ahead of our most advanced competitors, but there are going to be others. By and large, it is not clear to us where the opportunity for differentiation clinically really lives. There will definitely be a competition around who can maybe have the higher AAT level, and that will be something that people focus on. The reality is all of our patients are already above the protective threshold, so there is no evidence that there is any clinical difference once you get to that state or going a little bit higher. It also is not clear to me exactly how much higher you can go. I think we will learn as we see some of the competitor data.
I think it is clear to me that editing a lot of the liver in these patients, you can get patients to that protective threshold. You can get them into the teens. I do not think it is going to be possible to get people to 30, which is kind of where normal would live. Again, it is all good because patients are protected now. Beyond that, I think BEAM-302 is doing everything we need it to do. I think we are looking forward to pressing on the accelerator, and staying certainly ahead of the competition and bringing a new product to patients as quickly as we can. All that said, competition is good for patients. We are always welcoming of more entrants. They certainly deserve more options.
Just to maybe double-click on that a little bit about the AAT level. Do physicians recognize that it is going to be difficult to show clinical differentiation, say, if you have 20 AAT versus your 14 AAT, 16 AAT, depending on the assay? How do you think it will be viewed by physicians when they are trying to make treatment decisions?
Yeah. I think it is actually quite well understood. These physicians have thought a lot about the clinical genetics here. ZZ is the profile of a patient. They live in the 5- 6 range in terms of their alpha-1 levels. Their parents, the people who are carriers, who maybe have one copy of Z, but the other is of M, they are in the teens, and this is called MZ. A n alpha-1 expert intimately knows what a ZZ patient is like versus an MZ carrier. Then, of course, MM is the normal. There has been extensive literature that these community groups have done to understand what is the relative risk of each of these groups. It is a very settled question that MZs do not have progressive disease. They are perfectly stable.
Where they may have a little bit of higher risk is if they are heavy smokers, for instance. If you have a second hit, you can see a little faster decline, but that's really the extent of it. I think at the end of the day, I think if we're all in sort of the MZ neighborhood or better, I think that that's going to be a wash from a competitive perspective.
Got it. Okay. How important is it to lower Z levels? Does Z have its own pathologic effects?
It does. I think that is actually an increasingly important part of the story here, where, of course, we want the total alpha-1 levels to go higher, and then we like the fact that it's inducible, so when you get sick, it goes even higher still. I t's really the quality of the AAT that is being produced in the body. Meaning, in our case, we're getting 93% M circulating and only 7% Z, and that's because we have lowered Z by about 84%. That's really helpful. It's helpful obviously to the liver, because Z is the thing that's building up in the liver and causing toxicity. I T's increasingly clear, and Dr. McElvaney, who was on our call yesterday morning was speaking to this, that Z is a bad actor systemically.
It causes polymers, and those polymers are basically inflammatory, and they lodge in tissues, and they cause a lot of local inflammation. They can also bind to and actually inhibit the natural AAT from doing its job to stop neutrophil elastase. T hey can actually frustrate M from doing its job. I think there are lots of sort of emerging ideas that the less Z you have, the better systemically. O ur ability to do that is an important part of the product profile.
How is enrollment going in the pivotal cohort? I feel like you've commented that it's going quite well. I'm wondering if you just speak to some of the engagement that you're hearing from your investigators based especially on the back end of this updated durability data.
It is going well. I think we have great enthusiasm. We're at 14 sites across six countries now. We've been adding more sites in the U.S. in response to demand. As I noted, almost each site has a list of patients who are interested and are willing to travel for this therapy. I think it's very clear we've gotten on the map with the community. Nothing more to say other than we feel confident in the enrollability of the cohort, and it's moving quickly.
How long does it take to get a patient off the list and into the trial? Is that site dependent on their capacity, or is it your ability to be able to dose them? How does that work?
The site obviously has capacity. They have to work through it. The patient has to go through screening. That's probably the biggest thing. We just have to make sure they meet the inclusion criteria, that they're stable, and all the right medical things are checked. You then have to wash them out. They're generally on augmentation, particularly in the U.S., and we are washing those patients out. You want to get the augmentation out.
That then gives you a clear view of their true baseline in terms of alpha-1 levels, all Z, of course. Then we take a baseline phase. Then we're going to take a series of measurements to make sure we have a good average of what their set point is. Then you can treat. I think there are definitely a few steps to go before the dosing. A s I said, we are already in the dosing phase. We had our first dose in July, so this has all been ongoing now throughout 2026.
I t is a little early to maybe start this conversation about the commercial strategy, but how are you thinking about initial launch strategy? Where are these AATD patients typically treated? Are they concentrated in centers of excellence, or do you need a community referral program, or are they all of the above? How are you starting to think about actually targeting this in a commercial way?
Yeah, it is not too early at all. I think we actually think about this a lot. T here is probably at least 100,000 patients in the U.S. who are ZZ genotype. That is our target population. Of those, we know about 10,000- 15,000 are diagnosed. Okay? So it is a largely underdiagnosed disease still. O f the 10,000 - 15,000, maybe 9,000 are on augmentation, something like that. T he large majority are taking therapy, but everyone is pretty educated about their disease if they have got the diagnosis. T hat is your initial addressable market, a nd that launch will be primarily through the academic key opinion leaders, the AATD treatment centers. These are specialists. This is still a rare disease, and that is clearly a very biotech-friendly kind of launch. We know these folks. We are working with them now.
They are partners with us, s o we feel quite capable of moving there, and that is a large addressable market, right, if you think about 10,000 - 15,000 patients at gene therapy pricing. From there, though, we are not done yet. Th en you have to think about how do you find the other 85,000 - 90,000 patients who are not yet diagnosed. Now, some of them may be ZZ but not yet symptomatic.
T hat would be a group that we would want to find and treat before they get the disease, but many are symptomatic. T hey have just not completed the diagnostic odyssey. T hey may be living in a respiratory clinic, may have a COPD diagnosis. They may just be primary care and be complaining about fatigue. There is an awful lot of that out there, and so that is more of a diagnostic campaign that would happen over the subsequent years. I think of the analogy to like ATTR-CM, right, where you have to go find those patients, educate them, get them to the right centers, and then you can treat.
Got it. Okay. That makes sense. That is a really large opportunity if you can improve those diagnosis rates over time, à la ATTR.
Yes.
Okay. You have alignment with the FDA on your path to accelerated approval. Just wondering if you could just walk through your engagement with FDA thus far and overall regulatory strategy and thoughts on the confirmatory study as well.
Yeah, FDA has been great. I know it has been turbulent over there, and investors have had a lot of questions. I always remind people that the commissioner is not our reviewer. We have had actually a lot of consistency in our reviewers over the last several years in these programs. That is true for sickle cell and for alpha-1. I think by and large, as I have always experienced, I think the FDA really, if you bring them really good science and really good medicine, they are very eager to help and do it in a thoughtful way. You just have to find the way to help them satisfy their demands, which is they have a lot of statutes they have to live up to, and that is good. They have been great. They have been working closely with us for years now.
I think as an example of that, we got RMAT designation, which is sort of the breakthrough therapy for advanced therapies. We have this CMC program called CDRP, where we get also extra advice from them. I think they're clearly understanding that base editing is a very frontier kind of technology, so they need to be very proactive with us to help us understand how to get it ready for filing, and that's been incredibly helpful. As you noted, we're now in an accelerated approval pathway, and that, of course, relies on their guidance to say, "Yes, this could make sense," and we align with them on that path. Again, I think, this is not a big stretch to see this as an accelerated approval candidate.
Accelerated approval is an approved statute for the FDA to use when you have enough biomarkers and science to suggest you are likely to have clinical benefit, which can then be confirmed in a confirmatory trial. While here, we have any number of biomarkers all pointing in the right direction, all exceeding the threshold that would say, "This person should no longer have the disease." I think it's a very clear candidate for that. I don't feel like we got a special favor. I think it was actually right down the middle. We will have to come back and we are doing so to design the confirmatory trial, which will help them establish the functional outcomes that they will want to see in coming years, and that'll be the next step of the process.
Before I move on to the rest of the pipeline, is there anything else AATD related that you think is important to really highlight?
That's a great question. I think mostly, just to step back and remember what's going on here. This is the first time, as far as we know in history, that we have a drug that can not just intervene genetically, which has been the new wave of medicine, but literally rewrite a sequence of the genome back to normal. It's a profound event, and I think it's gotten a lot of interest.
As excited as I am about AATD, I'm equally, maybe this is a good segue, excited about that paradigm and our ability to now use what is effectively a platform technology to now march through mutation to mutation always in, this case, maybe the same organ using the same delivery technology, the same editing technology, to increasingly, predictably, and reliably make these same kinds of interventions for more patients. I think we're opening a door here to a whole new kind of medicine, which is very exciting.
It is a good segue because next I want to spend a little bit of time on PKU, and particularly, what you're alluding to is that FDA sort of pathway or platform multi-mutation sort of IND, essentially. Maybe talk a little bit about the PKU opportunity. You're nearing your phase I-II initiation later this year, and just frame a little bit how you're leveraging that regulatory flexibility specifically for here, and then maybe even expand it beyond in your plans for additional indications.
Yeah, you had asked before about regulators. This is an example where the science makes something possible, and the regulators are following that science. With LNP delivery, we have a synthetic, highly predictable delivery vehicle, and we have an RNA payload. If of a certain LNP, if we run the preclinical tox again and again, even when we're changing the order of the letters of the RNA, it doesn't change the acute tox. It's always the same, so it's highly predictable and repeatable. Then for the payload, the base editor, again, we can change the guide RNA around. You'll have different on and off-target edits, so you have to check those, of course. T he acute tox, the manufacturing, it's all going to be identical.
That's a true platform that allows us to have high confidence every time we do it the next time. Beginning under Peter Marks, actually, in the prior administration, he was really at the forefront of saying, "Wow, okay, this should enable a different kind of medicine." We should be able, as regulators, to sort of see one set of studies with one editor, let's say, and once it looks good, we should give you credit for that, and you shouldn't have to repeat all those studies every time. In fact, even more than that, you should be able to say, "I'm going to make the same genetic change, but just a different mutation," but that should live under the same program every time. This was sort of very forward-looking of Peter to start laying this out.
T hen some of the best ideas in government are the ones that survive administration change. Then we're now in the Trump administration, Dr Macri comes in, and he says, "This is amazing. Now let's take this to the next level and talk about plausible mechanism pathway," which is exactly this point. Which is, we know that if I'm fixing the PKU, the PAH gene, and I'm correcting a mutation that's causing high phenylalanine, it doesn't matter which exact point mutation I fixed, it's going to have the same effect. Therefore, if you show me once or show me twice that it works, the third, fourth, fifth time, I'm going to give you credit that you can just build on that same foundation. That's where we're living now, so very exciting new world. As you noted, we have an open IND for BEAM-304.
This is to correct point mutations in the PKU gene, PAH. We would expect, again, as with alpha-1, that a single dose ought to be able to fix enough enzyme that you can then metabolize phenylalanine normally and hopefully get patients towards a functional cure. This IND already has two different editors in it, treating two different mutations. They'll be slightly different patient populations, but all mixed up into one trial. As we qualify and bring forward new editors, we will then add number three, number four, number five, some of that in development, some of it on the commercial market. Again, it's a very new paradigm, so we're going to learn about this together with the FDA, but it's very much right down the middle of what they were trying to outline with the plausible mechanism pathway guidance.
When you bring a new mutation onto the market, let's say you're already approved with those first two, how does that work? Do you have to do just a very short study? Do you not have to do a study at all?
W e'll see. In theory, if you really read their guidance, it may not need clinical trial at all. I think we'll have to see. W hat I'm sure we'll have to do is you will need to show some amount of potency information, may or may not involve more animal studies even. A t least in vitro, possibly in vivo, and then in vitro off-target assay. You'll have to sort of make sure you've shown for this specific guide, here's the off-target pattern, and everybody's comfortable with that, and then you move forward. T he whole point is to avoid having to redo clinical trials. In fact, if you think about it, in the limit, where this is going is ultimately individualized editors. That's the end game. We call that N-of-1.
We have already seen that with Baby KJ that the Children's Hospital of Philadelphia team in Pennsylvania did. There, by definition, you cannot do a clinical trial on the commercial market because you would have treated the patient. There is no one left to treat. It is a unique mutation. I think in theory, this system is designed to not need the clinical testing every time, so long as you have a plausible mechanism for the effect should be the same every time, and you are seeing consistent effects, I think then the FDA will give you that runway and latitude.
Yeah. No, that is really exciting. Excited to follow that as you progress it. Maybe just to go back to PKU as an indication you have selected. What makes it ideal for a base editor to come in, outside of there are multiple mutations that you could target?
Yeah, it is a high unmet need disease. Patients are generally not controlled, despite available therapy. It is an extremely life-disrupting disease. You really cannot eat normal foods. There are all sorts of social impacts of that. In the many ways in which you are generally uncontrolled, it modifies your executive function and cognitive ability, sometimes very deeply. It is a really tough disease. There are some products that work okay for some patients. You have had these BH4 cofactor types of products, KUVAN, now SEPHIENCE maybe has a little bit more of an impact, but still you have dietary restrictions. It is not getting that all the way to a functional cure. We have tried gene therapies. They generally did not work. AAV has been a tough platform to see that come through.
At the end of the day, I think a one-time LNP containing a base editor, if we can fix enough of the enzyme, we ought to be able to open up the spigot and start the flux, metabolizing phenylalanine and just drain it out of the body, no matter what you have eaten. That is basically the concept, and that would be a one-time durable effect.
Right. Okay. A big change for those patients. We are running out of time, so I want to make sure that we talk a little bit about sickle cell, because you are nearing that BLA filing. Even with me, it feels like it can be overlooked sometimes. How are you preparing for commercialization? How should we think about that early launch? We have learned a lot from CASGEVY, but what can you do to really drive perhaps even a more successful launch than CASGEVY?
Yeah, great question. I am going to have Sravan cover this one.
First of all, thank you for asking the question. We always appreciate the focus on risto-cel. I would say a couple of things. One, and we are remiss to not acknowledge it. We just hired a new Chief Commercial Officer, Eric Foster, who just joined us from Ardelyx. Really excited. Lots of experience in rare disease. I would say from an overall organization perspective, we are very focused on the launch. It is a whole student body effort, right, to make sure this happens, whether that is building systems, processes, coming up with plans in terms of manufacturing from a capacity perspective, and a quality perspective. Every part of the operations aspect of the company is very much gearing up for the launch.
That is the back end. I think on the front end, I think we have increased the presence that we have from a medical perspective and from a field perspective. I think that ramp will continue into next year as we get closer. Operationally, also, we are very much focused on submitting our BLA as early as the end of this year. Maybe it slips a little bit into the early next year, but as early as the end of this year, with hopefully a quick review and launch.
I guess just from a total market opportunity, how should we think about that, just given what we know on the slow CASGEVY launch? You have a lot of differentiation in various parts of the process, but how should we be thinking about what that actually looks like in terms of revenue?
Yeah. I don't think our views on this have necessarily changed. We still think this has a blockbuster potential as a whole, and from a peak sales perspective for Beam. Our cuts for the patient population that risto-cel can treat already assumes some amount of selection. There's 100,000 patients that we think in the U.S. with sickle cell disease. We think about 10,000 patients are about the right patient population size for risto-cel, and that assumes these are the people that are willing to step through conditioning to get there. With respect to the competition, it's not just CASGEVY, it's LYFGENIA. I think what we've seen is coming in, being the third to market here, we get the opportunity to learn from their approach.
We also get to ride some of their hard work in terms of seeding the market, whether it's working with hospital systems to build contracts and sign contracts, processes within the systems themselves. Some of those things are now hospital systems across the country all have familiarity with this therapy, at least the ones that do treat the sickle cell patients and the ones we'd start out by marketing to. I think that from our perspective, we see the potential there. We think our differentiation will carry the day, whether that's our ability to get to a 60/40 fetal hemoglobin to sickle ratio, our resolution of anemia, our total time to engraftment being about two weeks, 16. 5 days. Just overall, I think we feel really good about what we have, and we think we have a potential for real class preference.
Yeah, looking forward to that. You've also prioritized in vivo as your next approach in sickle cell disease recently. I'm just wondering if there's an update or you could share just where that program stands. How close to moving this into the clinic as a quick follow-on for risto-cel is the company?
Yeah. Look, I think we wouldn't have made the decision we did or announced at the start of the year if we didn't feel confident that we have a path forward. I think we're in the process of making sure we have it right before we nominate it as a drug candidate. When we do feel like we're there, we'll come back to the market and share. I think it's at some point stay tuned is my response.
I'll work on my patience. Okay.
Yeah.
All right. Well, I think we've covered a lot here. Maybe just turn it back to you, John, for any closing remarks that you might have and to recap the runway and just the positioning that Beam has over the next 12 months.
Yeah. I t's been a great discussion. I think we've covered a lot. I'd maybe add to the near term that we will also have first-in-human data for another metabolic disorder, GSD1a, again, fixing a mutation here, R83C. That's BEAM-301. That'll be a couple cohorts of data, and that'll be this year. There, Ultragenyx had a recent approval looking at cornstarch reduction. That's an okay endpoint. We're also thinking about time to hypoglycemia. So, I think that's a near-term point. Long term, I think we have runway into mid 2029. We're well-financed. We will have a commercial sickle product by then. I think alpha-1 will be right around the market around that time. We haven't tightened that up yet, but we'll do so in the future. If you think about the speed with which we can get sickle launch, then an alpha-1 accelerated approval.
PKU is pretty fast, too. It is obviously entering the clinic, so it will be behind those, but not far behind. It is a pretty efficient development process. We think all three of those are blockbuster potential franchises where we can make gene editing into a real business and become a sustainable multiproduct company. All of that is using this same platform that is now built. As we talked about a little bit along the way, I think the opportunity to now exploit that platform and target it now at many other diseases and continue to grow on that base is just what is so exciting for us on the long term.
Well, lots to look forward to there. Thank you so much, John and Sravan, for the time. This has been wonderful, and I really appreciate it.
Thank you.