Good morning, everyone, and welcome to day two of the Cantor Conference. I think you'll be rewarded by a wonderful presentation to kick off the day. So appreciate everyone getting up early. My name is Eric Schmidt. I'm one of the Cantor analysts, and we're delighted to have with us today Beam Therapeutics. We've got John Evans, the company's Chief Executive Officer, and Sravan Emany, the company's Chief Financial Officer. It's going to be an eventful, certainly next 12 months, but it's already been a pretty eventful 2026. John, maybe you can just start us off with high-level state of the company.
Great. Well, it's great to be here. Thank you for having us. Beam is in a really important phase where we're executing really across a number of different key initiatives in a portfolio that continues to grow and starts to have line of sight to real commercial franchises in gene editing across a number of diseases from sickle cell disease, alpha-1 antitrypsin deficiency, PKU, GSD1A, and others. As you know, of course, we're working on next-generation gene editing technology with base editing. This is a CRISPR 2.0 capable of making single base changes in genes without making double-stranded breaks. We're delivering this ex vivo in sickle cell disease, that's risto-cel, which is on its way to our first BLA filing, and we think has a high probability of success to get approved and be a best-in-class product in sickle.
Then, of course, we do in vivo with lipid nanoparticles delivering to the liver. There, generally, we are taking mutations and turning them back to normal, which is a first-in-history achievement. That'll be BEAM-302 in alpha-1. It will be BEAM-301 with data later this year. PKU, another big indication headed to the clinic soon.
Just in terms of the pipeline, obviously we've heard of generation one, generation two, maybe now with prime editing, some generation three technologies. What does it take to be successful in the whole gene editing platform space?
Yeah, it's a great question. I generally think of it as gen one was sort of CRISPR right out of nature. You use it in its normal way, which is it binds to a certain spot. That targeted binding is a real breakthrough, and it's programmable with the guide RNA. But once you get there, it does its normal thing, which is cut, and you end up scrambling the genome. It's very good at turning things off, but not so good at fixing them. I think this next generation of tools, of which base editing is the first, you mentioned prime editing, and there are others, generally do the precise targeting that we learned from CRISPR, but we turn off the cutting. Instead, when we get there, we're going to do a more precise, controlled change.
In base editing, you do a single base change chemical reaction. In prime editing, you're doing rewriting with the reverse transcriptase, and again, there are others. I think the power of these next gen approaches is now we can really rewrite, reprogram the genome. Now within that class, obviously base editing is the most validated. We've been working on this now for years. We're clear leaders in the field, and base editing works really well. It's highly efficient. It's very predictable. At this point, it's been working in multiple diseases, as we have shown in our data. The next technology with prime, some of these prime systems, we're still waiting for more data. We have some ex vivo data from Prime Medicine, which obviously looks good. In vivo, we're still looking to see some data there.
I would say the validation level of that technology is lower, but hoping to see some more data soon.
How important is delivery?
Delivery is critical. In genetic medicine, these are not pills. You cannot take them and get it to every cell in your body. But we have solved delivery for certain key applications. Obviously the cell therapy process where we take the stem cells out of the body, edit them, put them back in. In sickle, that is now well-validated. We have taken that to a very high level with our manufacturing process. On the in vivo side, lipid nanoparticles, very well understood, but tricky. You have to still have a lot of capabilities and get them right, that is to get to the hepatocytes. A next -generation that we will talk more about in the coming years is targeted lipid nanoparticles. This is where we take an LNP, we de-target the liver, and now we retarget it using binders to different cell types.
We have done this for T cells, and we are very hard at work doing this for blood stem cells, which would be the foundation of our in vivo sickle program, which is a next generation program we have in sickle. Bottom line is you have to get delivery right, and you cannot talk about delivery unless you also talk about manufacturing. Beam has spent years building out manufacturing, a full -stack. It is all internal. We have a large facility in North Carolina, a tremendous team there. They do all of our cell manufacturing for sickle. They do all of our mRNA production, all of our lipid nanoparticle production. Beam has really built a fully integrated capability from the design of delivery, the design of the editing, to how we manufacture that deliver to patients.
I think that has created a real platform and a flywheel now because we can apply those capabilities over and over again and go faster and faster to diseases two, three, four, five and beyond.
Okay. Let us get right into what I think most would consider your lead program. I know it is not your most advanced program, but BEAM-302 for AATD. I know we are coming off the ERS meeting just last weekend, and we will probably talk about that update. But perhaps just set the stage on this program. Why is it of interest?
Yeah. Alpha-1 is a very large unmet need in genetic disease. You have patients who almost uniformly, over 95% of them, have the same genotype. They have a single misspelling in their SERPINA1 gene, which is for this protein, alpha-1 antitrypsin. It causes a mutant form called the Z form of the protein. We call the normal form M. The Z protein does two things. It builds up in the liver in a toxic way, and it causes liver failure over time. It also is imperfectly secreted and also dysfunctional, so it is not getting enough levels to your body where it is supposed to protect your lungs. When you get sick, your body mounts an inflammatory response. A side effect of that response is it can destroy your lung tissue and give you lung failure unless you have this protein present.
These patients do not have enough of it, and they start to fail with their lungs as well. This is a perfect indication for base editing. We want to go in, we want to land right on that mutation spot, use the base editor to change that letter back to normal, and literally turn a Z allele back to an M allele. We have done this. This is, again, the first time in history we have shown direct correction, a rewriting of a gene to a functional state. Obviously, that has been source of the great enthusiasm for the product. There are 10,000- 15,000 patients diagnosed in the U.S. alone with this disease, all of whom would be a fit for this product. From there is up to 100,000 total patients.
Many are undiagnosed, so that is going to be a second part of the market where we want to go find them. The beauty of BEAM-302 is it does all of the things that these patients are hoping to have done. It literally changes the mutant gene back to normal. It does this with a one-time therapy, and the benefits, as far as we can tell, are going to be with you for life, and you never have to be treated again. You are creating the normal protein, you are eliminating the toxic protein, and you are getting alpha-1 levels to those protective levels that they should not have any progressive disease anymore.
Okay, at the European Respiratory Society meeting, just this past week, we saw a few more patients, a few more months of follow-up, but what are the key take-home conclusions from the program at this stage?
Yeah. This was our first academic conference, so this is our chance to start to bring a wider group of investigators and patients into the story. There has just been incredible enthusiasm about the profile that we are showing. At this point, we are showing, first, durability. The effects that we have been measuring are quite durable. This is what you would expect with base editing. Nonetheless, it is good to see. We have patients at lower doses who are at 18 months plus at this point, and the change in their AAT levels is rock solid. Obviously, at the therapeutic doses, 60 mg is what we are going with for pivotal studies. Patients are out nine to 12 months, and again, very, very stable.
We have also shown exactly what I said we wanted to do, which is we have really converted these patients from a disease phenotype where they have ZZ genotype. They are all making 100% of Z, and they are generally in the four, five, six micromolar range. That is clearly where you get this progressive lung and liver damage. We have taken them to over 93% M in serum. You have converted almost all of the circulating AAT to that normal form, and we have taken everybody up into the double digits. You are at 11 or above. 11 is the famous protective threshold, and we know that is protective because we know that there are no patients who have those numbers, and people who have those numbers do not have the disease. We know all of that from clinical genetics, and so we were able to show that as well quite convincingly.
The last piece of data, a series of other pieces of data that I think are supportive, one is we showed, importantly, that the gene is still normally regulated. When you get sick, your alpha-1 levels go up, and this is just part of your normal physiological response. We want that to happen here, and it does. Because we fixed the gene in its normal location, it has the normal on/off switch. When you get sick, you get even more. The way our drug works, you end up taking patients from, let us say, a four, five to a 14, 15. They have a new set point. That set point should be protective. But then when they get sick, they go into the 20s. That is the dynamic nature of fixing a gene in its normal place. We saw that.
We saw that with a patient with an upper respiratory tract infection. We have also shown now a variety of pharmacodynamic markers. We want to say, is the AAT that we are producing functional? We can show that, and we have shown that through neutrophil elastase binding, neutrophil elastase inhibition. That is great to see, fully functional. That is something the FDA cares about. We have also shown inhibition of neutrophil elastase in serum, and reduction of Z polymers. The Z protein is bad for your liver, but actually, it is also bad systemically. It forms these polymers. They are inflammatory when they land, and they can actually frustrate the ability of normal AAT to protect you. Getting rid of them is really quite important.
I think at this point, the translational data set has started to get quite mature as we see all of these different biomarkers and measures telling us that we have truly changed these patients from the disease phenotype to a normal phenotype. That bodes well for clinical benefit over time.
This is amazing data, biologically, clinically, game-changing in many ways. If you don't mind, I'm going to pick on the edges around the data.
By all means.
Obviously things that we've been hearing in the marketplace. Stock was down earlier in the week. Maybe the first topic is the grade three liver enzyme elevation and what to make of that.
Yep. Yeah, so basically what we do when we measure LNPs is one of the main things we look for are these LFT elevations, and when you put a bunch of lipid into the liver, you are going to see some of that. The key is it transient? Is there any impact on liver function? Obviously, what kinds of changes do you see? In alpha-1 antitrypsin deficiency, it is an important question because these are patients who have some level of background liver burden. Their livers are already struggling through with the Z protein. Generally, these patients live at the high end of normal as sort of their baseline. Then we also categorize patients in our trial. It was part A and part B. Part A are the primarily lung patients.
Part B are more lung and liver, kind of where their livers are sicker, and they are sort of our sickest liver patients. Those patients can even live above normal, that you can get up to about 1.5x as just your baseline. By and large, the LNP has been extremely well tolerated, and I think we continue to see that. We have seen almost only grade one sort of changes, which is really a minor change right around the threshold of normal, with this one exception. In the single-dose regimen, we saw one patient who was one of our liver patients, so they had the sicker liver, and they got a grade three. It was a fairly low-level grade three. Their AST/ALT never went above 300. Normal is about 50. But it went up, and then it came back down.
The key point is it was transient. It is a lab abnormality. We have heard some people mistaking the idea of, oh, does grade three mean hospitalization? No, it does not. This is just a lab value. Grade three just means it went up more than 5X from baseline, and then grade four is 20X. The bottom line is, I think, this is why we do the phase I. We kind of see when these things happen. Obviously, in this patient, this is one of our sickest liver patients, and it is not super surprising to see this. I can tell you the investigators see this sort of thing even in daily living for some of these patients. Bottom line, we are not changing anything about the trial. There is no monitoring required. There is no change in our conduct.
I think overall, we continue to be really thrilled with the safety profile and tolerability of the drug.
Thank you for addressing that. I think the only other really question I've been receiving on the data in the last couple of days is dosing and what the appropriate dose is. You went up to 75 mg, but it does appear that 60 mg actually performed a little bit better. I don't know if that's noise or not. How do you know that you're kind of maximizing the editing efficiency that you have with this product. This, of course, has competitive repercussions as well.
Yep. Yeah, so I think we feel pretty clear that 60 mg and above is clearly saturating the mechanism for what we're achieving here. You're right, there's a little bit of an inverse trend at 75 mg. I think this is stuff that we'll study over time. But in both cases, you're getting clearly the therapeutic effect. Anything 60 mg and above is clearly therapeutic. We ultimately chose 60 mg just because it gives you a well-studied dose. It's got a solid safety margin, and it is the best performing dose we have, and that's obviously very attractive. The key point here is what does the TPP need to do. Are we getting patients to the protective threshold?
Are we getting past what I would say carrier levels of the M to Z ratio of lowering Z, carrier being someone who's normal, a parent of the patient who does not have the disease? The answer is we are. So I think we feel very good now about where BEAM-302 sits. It's now been in 30-plus patients. We're getting pretty good data set, and I think that we feel we've studied it adequately, and that's what gives us the confidence now to push forward. Patients are waiting, and we got to get this to market as quickly as we can.
No doubt you have a very substantial lead time advantage, which we'll talk about in a moment. But in terms of the competition, let's say your product profile is at baseline about a 15 micromolar or so serum AAT concentration, and others maybe in the future can do better than that. What's the importance or lack of importance, if that is the case?
Yeah. There's no question other competition will come. We've sort of shown that this is a highly valuable place to be. In general, because our drug does so many of the things that you would want to do, there aren't that many places to try to differentiate, I think. What next-gen programs are generally trying to do is push potency, push maybe can we get a little higher AAT levels, and can we take it from a 15 to an 18, 19, 20, something like that. We'll see. I think there's always room to do sort of second-gen, third-gen things. Is there any clinical impact of that? I think the answer is clearly no. What we know is patients below 11 have disease. Patients above 11 don't. There's no difference between 15 and 20 or 18 at that point.
We hear some of our competitors talking about getting to normal as well. I talk about the carrier threshold. Well, normal folks in this room would be somewhere in the 20- 50 range. The average would be about 30- 35. I feel pretty confident that I don't think people are going to get there. The reason is because these livers have lived with ZZ disease their whole lives, and I think that the dynamic range is not as great as it used to be. So we don't see ourselves getting there. I don't think others are going to get there. The good news, again, with a genetic disease, you don't need to get to normal. You only ever have to get to the carrier threshold to end the disease. We've all been given two copies of genes for a reason.
There's redundancy in there. So if you lose one, you're normal, and that's exactly what we're doing at alpha-1. So bottom line is, I think competitors have a very thin ledge to walk where they have to push to try to argue for some incremental level of AAT and argue that that's important. The reality is there won't be any clinical difference between what they can show and what we can show, and there's so many other things that matter where there won't be differentiation potential either, which is the M/Z ratio, the reduction of Z, the pharmacodynamic effect, the inducibility, safety. I think mostly I now focus on the operational lead, which is we've got a drug. This clearly is getting patients to a functional cure. We're two-plus years ahead of our competition.
We're definitely going to have our foot on the gas and keep going fast here, and because patients are waiting, the faster we can get there, the better. We're pretty convinced that the FDA is working with us on that, and they see the urgency, too.
You have started your pivotal trial. You say you are two-plus years ahead. I would agree. Talk about the advantage, either in terms of competitive clinical development or commercial opportunity being two years ahead.
Yeah. It is really all of the above. On the clinical side, we get to work with the FDA first to establish the pathway. We have now done that with an accelerated approval pathway that we have arranged with them. We have a lot of insight into how they are thinking about this disease, that helps a lot. We have built a really incredible investigator network. The enthusiasm from doctors and patients for this drug and its profile has been incredible. We are at 16 sites now in six countries around the world, and adding more. That is a big advantage. It takes a while to build that up. All those different regulatory engagements, we know how to get now through those. The reason to do all of that is because then you get to the filing sooner, and this is absolutely a first-in-class will have an advantage situation.
This is an easy dose. It is a vial out of a freezer, and you sit in the chair for two hours, and you are cured. Obviously, as soon as we can get to market and start treating people, they are done. They are not in the market anymore. They get to go off and live their lives. There is a huge first-mover advantage there. Then for sure, dealing with payers, setting up contracts, being first to establish the market is another big advantage, and just the relationships that we can establish. I think we have been in this community now for nine years. We have been meeting with the alpha-1 Foundation since 2017. Actually, thinking about this is one of the first diseases that was on my list when we were starting the company originally.
I think all of that leads to a kind of classic first-mover advantage, and we are not going to sit still. We are going to make sure we are also maintaining our best-in-class edge on the competition. We have got a huge amount of platform resources to do so. I think that we are clearly leaders today, and I think we can stay there.
Is there something else you are trying to improve upon or solve for with the next in class?
It is mostly just we have a long-term commitment to the field. We have an incredible depth of science. Anything that we can learn or think about over time that patients need in this disease, we are going to make sure that we are supplying it over the next five, 10 years.
Okay. Should we continue with PKU? What would you like to talk about? We never talk about PKU.
PKU is great.
Why don't we talk about PKU?
That sounds great.
You've got BEAM-302. Just remind us why PKU, what is the unmet need here, given we do have therapies.
Yes, we have therapies. None of them, as far as I know, are cures, and we want to go farther. Here, as with alpha-1, we're going to be looking for point mutations that we can correct, turn back to normal. We think it's a perfect indication for base editing. One edit to the liver to fix a point mutation, you're now going to restore normal phenylalanine metabolism. You should see that dropping in these patients once you've done that. You can think of it like a bathtub that is clogged. If we get in there and we remove the clog, all of a sudden, all that phenylalanine can just drain out. It's the high levels of phenylalanine that cause cognitive damage, cognitive defects, executive function decline. It's a very severe disease.
To deal with that, you take these horrible diets that are very tough to manage that literally don't have the protein in them. A lot of medical foods and avoidance of foods. Even then, patients are not controlled, and they suffer from this. We have shown in vivo data on two mutations. One of them is the most prevalent, the R408W mutation, where a very low dose, 0.1-0.3 mg per kg, can fully normalize Phe levels permanently in these animals. We expect to try to do that in humans. The other really nice thing about PKU, it's obviously a big indication, up to 20,000 patients in the U.S., and a lot can be treated here. We're starting with the classic PKU, which is a more severe form. The development pathway here is very straightforward.
This is going to be a dose escalation study where we test safety, make sure the LNP is working normally. Obviously, that can also generate proof of concept, and as with our other drugs, we would expect proof of concept to be pretty clear early if we're going to get it. Then you go pretty much straight into an expansion cohort, and the endpoints here are phenylalanine lowering with some diet normalization, and that should be full approval. There's a lot of precedent for that. This is one that will go pretty fast, and I think if there's maybe something to think about with Beam, it's really the fact that we are set up for this rhythm of commercial entry. We're going to have sickle cell first with risto-cel. That'll be on the market latter part of next year. Then alpha-1 coming out of its accelerated approval push.
PKU won't be far behind it, I think, if it goes well, obviously, and if everything stays on track the way I've just described it. All three of those are blockbuster franchises.
Okay. I called it 302 before, but it's 304, of course.
PKU is BEAM-304. Alpha-1 is BEAM-302.
Excuse me for that. On BEAM-304 and PKU, what is the target product profile? What is something that is game-changing here?
I think it is very simple. We want to normalize phenylalanine. The threshold for treatment is getting phenylalanine consistently under 360. Normal is down around 120, so this is one where as low as we can go, we would like to go. We would like to do that with a single dose. Can redose if we need to, but the bar here is fairly low for editing, I believe. We want to allow people to normalize their diet on top of that. That is really it, and all that for a one and done that is an LNP, easy to deliver, well-tolerated, and provides this lasting effect.
Update us on your progress to starting a study and getting maybe that proof of concept data.
Yeah. We opened the IND in middle of this year, and this is quite an innovative IND. I think that's something also to appreciate. This is going to be a novel platform approach with the FDA that it's actually going to open the door to doing this a lot more, I think, in other liver metabolic disorders, particularly, where they've said, "CRISPR is so elegant. If you change the guide RNA, you can now treat a different mutation, but the acute tox, the manufacturing, all of that is the same, so you don't have to rerun that stuff.
In fact, if you show me a few of these mutations in the clinic and they're all working the same way, I may not even make you rerun it on the commercial market when you add more editors into this IND." So right now, we have an IND that contains two different editors for two different mutations as the same product, and we have the ability to add more over time. If you've heard of the plausible mechanism pathway, this is very much in that sort of world of guidance from the FDA, where they're trying to work with us to make this kind of thing a reality, which is very exciting. We should kind of watch this space, because I think there's going to be a lot more of that to come. But bottom line is I think we're open now.
This is going to be a large academic site, so it takes a little longer to get through their processes. So that's going to be the second half of this year. Dosing will be around year-end, early next year, I believe. But once we initiate dosing, then it's just three-patient dose escalation, get to an optimal dose, and then off to expansion.
You think you're starting at a dose that's going to be somewhat effective?
Yes. Ethically, you have to. You have to start at a dose that has some promise of impact for patients. As I noted, because of the low bar here, I do not think this will be four or five levels of dose escalation to get to a meaningful dose. It should be lower than that. We look forward to giving that data update. I cannot tell you when the data will come, but obviously, we will be generating data throughout next year. Again, once we show that data, I think it will be presumably data, if it works, that is pretty definitive on both safety and efficacy. You will see if it is a drug, and if it is a drug, we are already off into expansion at that point.
I think we should spend a minute or two on risto-cel.
Yes, please.
This is kind of the forgotten program, though, your lead program. These days, investors are not too keen on ex vivo cell therapies, especially in sickle cell disease. Why is that something that you can do better?
Sure.
Yeah. Well, thanks for the question. It's something we're really excited about. We think that there is a real market there for a therapy for patients that are some of the sickest sickle cell patients out there, which is about 10,000 patients in the U.S., or 10% of the overall sickle cell patient population. We think that the current therapies we have a best-in-class advantage over them, whether it's our ability to drive up the fetal hemoglobin levels and drive down the sickle hemoglobin levels to essentially the 60/40 level, which is where we think the carrier status is. If you were a parent, as John mentioned earlier, who has essentially one copy of the sickle gene, you're a trait at that point. We have resolution of the underlying anemia. We have the ability to have one mobilization cycle in our clinical trial.
That's, again, attests to our manufacturing capacity and capability and cell collection and ability to deliver for patients. And then lastly is neutrophil. The engraftment time frame was only about 16 and a half days, which just reduces the amount of time that a patient spends in the hospital. All of which allows a hospital system to treat more patients, allows a patient to get in and out of their therapy much faster, and is truly differentiated relative to the other therapies in the market. We've got real excitement from the facilities and the clinicians for our therapy, and we think there's potential class preference there.
This market is growing, but maybe hasn't yet achieved the success that others expect it to. What would be a successful launch for risto-cel? What would that look like?
Well, we think this thing has, as John mentioned, the potential to be a blockbuster. I think it's a matter of achieving that over time. Obviously, we think that takes a couple of years, but we think that we have the potential to do that for sure.
And then just last question, cash and cash runway.
Yeah. We have $1.2 billion of cash. We have cash into mid-2029. That should take us through the launch of risto-cel, essentially much of the pivotal activities for BEAM-302, maybe to BLA, we will see. But most of the pivotal activities will take BEAM-304 far along as well for PKU, and also just other development in our pipeline.
Great. John, Sravan, thank you so much for being here.
Thank you very much.
Appreciate it.
Appreciate it.