Excellent, everybody. Luca is a Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Beam Therapeutics as part of our fireside chat here, representing the company. We have John Evans, Chief Executive Officer. John, thanks so much for joining us. How are you doing today?
Great. Great to be here. Thank you.
Super, super. We have a long list of questions here, but maybe, John, before we dive into the specifics, it would be fantastic if you can give us a little bit of a big picture, overview of some of the progress that your organization has made over the last few months, and most importantly, what's ahead here for Beam.
Yeah, great. So, it has been a really active first half of the year for Beam, maybe end of last year as well. So, as you know, base editing is our core technology, and we're bringing that forward to patients with a wide variety of diseases with what we think will be a best-in-class and superior technology offering to those patients than what has been possible to date in gene editing. So in hematology, and sickle cell disease is one of our lead program areas. BEAM-101 is our lead program there. We dosed our first patient at the end of last year. We've dosed two more patients over the course of the first part of this year. All of them were successfully engrafted, as expected, and that's all going well.
The Data Monitoring Committee has then given us the green light to go ahead with expansion dosing. We're gonna dose up to 45 patients total. That's now, you know, free and clear. So we have a lot of patients in the pipeline now, and some moving forward for dosing already. So very excited about BEAM- 101's progress. Behind that, of course, our next generation version of sickle cell disease, ESCP, continuing to make good progress as well. By the end of the year, we hope to have clarified a development candidate that could then start some of the preclinical studies that will move us forward towards the clinic there in our long sort of journey to create better and better options for patients with sickle cell disease and ultimately treat, you know, ultimately all of the 100,000 patients in the U.S.
Of course, millions globally who have that disorder. Then on the liver side, also doing a lot there as well. So our lead program is BEAM-302 for alpha-1 antitrypsin deficiency. Here we are open in the U.K. with an approval by the MHRA to proceed with dosing. We're in site startup now. That, of course, is a very rapid startup process. Execution's going great there. So we do anticipate dosing, and you know, imminently, over the next month or so. And that will be a classic dose escalation design. We can talk more about that, but we'll be exploring for the optimal biological dose of that drug that we really believe can be a game changer for patients with alpha-1, helping both their liver and their lung disease with a one-time therapy under normal genetic regulation.
Right behind that will be our second liver program. The beauty of some of these constructs is how modular they are and how you can begin to leverage the same infrastructure investment to create multiple programs. So BEAM-301 for glycogen storage disease Ia, the R83C mutation. That'll be a U.S. IND at the end of the first half of the year. So pretty imminent now. Teams are working hard on that already. And that'll be a U.S. filing, and then hope to get that open towards the end of the year, you know, and then start to look to those patients. Rarer disease population, obviously, than alpha-1, but you know, really exciting application as with alpha-1, correcting a single mutation that's broken in these patients to potentially give them a cure. So three, you know, really heavyweight, you know, core programs in view.
We also have BEAM-201, a CAR-T product that is in the clinic. As we announced in the fall, CAR-T is gonna be a lower priority for us long term, so we don't focus as much on that right now, but it's still in the clinic. We're treating probably a handful of patients this year, and I do expect that to show what base editing can do and hopefully help some patients, and so that it's moving along as well. We anticipate having data this year, probably second half of the year, on both BEAM-101 and BEAM-201. Obviously, with BEAM-101, a very high-profile data event where people are looking for us to be able to show what base editing can do above and beyond what has already been a really exciting time for the field. And then the liver programs, obviously, will be dosing patients this year.
You know, it's more likely a 25 data event, but, but not too far off in the future. So it's gonna be a a catalyst-rich period for us coming up, and, we're just, you know, very excited to be able to show what base editing can do in in in patients who have real need for more options.
Super, super, super helpful. Maybe if I may, we've obviously seen some toxicity from the Verve program, with, you know, grade 3 thrombocytopenia as well as ALT elevations. You know, I think the company makes a pretty good argument that that's ALT, and maybe that's related to the base. Now it relates to the base editing, because we're basically LNP, a lipid nanoparticle. What's your view of that safety event and any read-through for Beam?
Yep. Yeah. So I think there is really very minimal evidence that there's anything to do with the editing event in that case. I think Verve said that. We certainly agree with it. You know, the beauty of editing is it's really a transient exposure in the cell to some protein that goes to the DNA and edits it. I mean, you really have very little expectation of any acute effects at all, frankly, from it. And we actually haven't ever seen any. Obviously, the focus there is more the long-term effects. You know, are we specific? Are we safe over the long term? That's important. So no, the acute effects are mostly vector-driven, right? And in this case, it's an LNP. And so, yeah, so Verve obviously saw these signals.
I think, you know, I think I would say a few different things. I mean, one is, in general, they were not the most severe signals. I mean, it basically so any LNP is gonna give you LFTs. Okay? That is just a function of putting a lot of lipid into your body, right into your liver. And it's gonna kick off some of this. As long as it's transient and it resolves and the liver is fine, then, you know, this is an acute one-time therapy. You're past that, right? So, you know, they saw, you know, a medium to high level, you know, getting up there, but it, you know, we didn't think it really presented a safety risk to the patients particularly much. And then on the thrombocytopenia, same kind of point.
It was transient, you know, resolving in a couple of days. Didn't get down to levels that were of of safety concern to the patient. Our hypothesis there is actually something called sequestration. So at any one time, your spleen actually contains about 30% of your platelets. And spleen actually takes up lipid. It takes up LNP. That's one of the organs of of interest just beyond the liver. And so it's easy to imagine the spleen getting inflamed or getting, you know, containing a lot of lipid and basically temporarily having more platelets engaged. That's called sequestration. The key point is it resolves quickly over a couple of days, right?
That's what would make it different from something that would be more concerning, which would be an immune-driven thrombocytopenia, where there's an antibody response to your drug or to the platelets at that point, and then that would go on for longer, a week, two weeks, three weeks. And that doesn't seem to be what they saw. So I think on the whole, we actually view that the signal is somewhat benign. All that said, I think in our preclinical data, we have not seen those signals at those levels. So we have some hope that our LNP will give us an even wider window. Of course, we're treating patients with alpha-1 antitrypsin deficiency as opposed to cardiovascular disease. So, you know, very severe disease.
You know, I think these kinds of lab and safety findings wouldn't be a roadblock for us to move forward. And, you know, we have a quite potent drug product as well. So we certainly, you know, believe we can deliver efficacy well below seeing, you know, seeing these sorts of things. So we'll see. You know, our job is to go into phase 1 and generate that data. But, you know, we've done our own LNP work. It's our own process and formulation. It is an independent lipid. So I think if you put all of that together, we, you know, we don't see a lot of read-through to our program.
Got it. Got it. Super helpful. Maybe sickle cell disease, obviously last year, historic approval from a couple of your competitors. Obviously in the first quarter, I think Vertex commented on five cell collections, and I think bluebird bio one cell collection. What what was your read of that? What's your read of the initial launch for both of the players? And then in that context, I found it super interesting that Vertex really highlighted the opportunity in the Middle East.
Yeah.
We'd love to kind of pick your brain on both, how you're thinking about how the launch is going versus your internal expectations, and how you're thinking about market beyond the U.S.
Yeah. Great question. So I think, I mean, mostly what I've been saying on the launch is I think it is too early to be staring at very, very small numbers and trying to draw conclusions. That said, I can tell you that the numbers we're seeing across the board are in line with what we would have guessed. So I think it all looks like we would have expected so far. So I think that's actually to some degree good news. But we'll learn a lot more, I think, over the next 6 months and then particularly 12 months, I would say. But all that said, I think the leading indicators, if you will, are really positive, right? A lot of lives covered, a lot of payers signing up with agreements. You know, reimbursement looks like it's getting aligned.
Treatment centers are getting open, right? I mean, the system isn't gonna engage itself like that unless it's ready to deliver for a certain set of patients who have demand. And I think that's happening. So we're quite encouraged about that. The Middle East is absolutely a fascinating opportunity. We think that's a deal. We're watching closely. Our global strategy will be determined over time, obviously. We're starting in the U.S., but ultimately, we would like to go global. So I think we'll learn a lot over time.
You know, as a reminder, you know, our expectations for this sort of wave one of the market are that there is a meaningful market here, and that there, you know, it could be 10% of patients who, you know, at least, who wanna seek a therapy using this sort of chemo-based transplant that we have to offer today. But even that number, you know, could create a multi-billion dollar a year category, over the medium to long term. And so that's a really meaningful market. Nonetheless, that still leaves 90% of the population that we still need to go back and treat, with different regimens. And those are the slightly more mild to moderate patients for whom a chemo transplant is not quite something they wanna sign up for, even though they have, you know, a disease that's gonna cause really severe, early mortality.
that's where our waves two and three come in, where we wanna then, you know, create a regimen that is more accessible to those patients.
Got it. Got it. Super helpful. How should we think about the impact of these approvals to your enrollment and your enrollment pace? Are you starting to see more? There's already a lot of competition in sickle cell disease to begin with. There's a lot of companies, obviously, trying to develop therapies for in that space. But do you anticipate any impact from the availability of these commercial therapies in terms of your enrollment pace?
Yeah. We've said before that we don't anticipate it. I'd say we still don't anticipate it. I haven't seen it. Never would say never. But, you know, we aren't taking any chances. So we have a very broad site footprint. You know, it's probably a broader set of clinical sites than even our competitors have had at this stage of the game. I can tell you those sites include sites and investigators who have worked on the CRISPR-Vertex program, on bluebird bio and on the other programs in the field. So they know this very well. And they're excited about what we have. You know, they're excited about base editing. And that's a big part of it. So I don't anticipate an impact from that. We're very happy with the enrollment we're seeing. And there's a lot of enthusiasm.
That gives us a solid pipeline of patients, now we can put through the trial, which, of course, is the critical path to getting to market.
Got it. Got it. Super helpful. Maybe on 101, you just maybe remind us the molecular biology there. So, obviously, you're doing a very different approach versus what CRISPR and some of the others are doing. You're not knocking out BCL11A. You're obviously editing the promoters, the fetal hemoglobin. So, 1, tell us why you think that's a better approach. And 2, I believe, at the end of the day, you have to do 4 edits, right? Because they're on 2 different alleles. So do you have a sense of what percentage of the cells that you're actually infusing into patients have 2 versus 3 versus 4? Like, walk us through how should we think about that part as well?
Yeah. It's a great point. So, yeah, the targeting so we're targeting the exact genes themselves for fetal hemoglobin. That's the HBG1 and HBG2 genes. There are two of them. They're copied, duplicated. And then there's two alleles. So you're right. There are four different genes that are in play here. And we're able to do that more directly because we don't make cuts. And so we can go directly to their on-off switch and put in a single point mutation that turns them on. And these are mutations that are well validated in people as turning on these genes. And so I do think that is a differentiator. But I'd say the bigger differentiator is just having base editing versus not, right?
So what base editing allows us to do is to create cells where we haven't made that cut, the double-stranded break, right? So the CRISPR-Vertex program, the Editas program, and others, they're making double-stranded breaks. As those are repaired, they have errors. And so you're getting a random scrambling of the gene sequence at the cut site, to say nothing of the potential for larger-scale chromosomal rearrangements as well. And the more cuts you make, the more of that you will see. But let's even just put that aside for a moment. You know, just the scrambling, one of the issues is you end up with variable effectiveness of each edit for the nucleases, right? Some cells will get a really productive scramble, and some will get a less productive scramble. So you're gonna get some variability.
So with base editing, we have a bunch of advantages. One is we don't make the cut. So there's no genotoxic signal to the cell. It doesn't even know the editing has happened. All right. You see that in gene analysis. Okay? We think that's gonna create a cell that is healthier and more viable and doesn't have that viability hit. The second point is we get this very pure and consistent response. Every cell that gets edited will have the same exact allele outcome. And that will give us the same robust turning on of that gene, as opposed to kind of variability. The third is just base editing is really efficient. You know, it's chemistry at the end of the day. And so when we tune it right, you can get very high levels of editing.
So I, you know, as far as I've seen, we have the highest level of raw editing in the industry. So we've shown all of this preclinically, and we still feel very confident that we have the best-in-class editing profile between number of cells edited, you know, consistency and uniformity of that high level of F for all of our edited cells, and a higher level than we're seeing from others, in our case, over 60%, lower levels of S, as well, and all with no double-stranded break and no viral insertion.
Got it. Got it. Super helpful. How are you thinking about safety? I mean, bluebird bio has had a couple cases of AML and MDS. I think most docs we speak with believe that that's probably just a combination of the patients having a hyperplastic bone marrow and busulfan. That probably means that all the other players are probably gonna see some events along those lines. Does that keep you up at night?
It does, only in that it, you know, it's a random event that can slow you down. I mean, that's, you know, but, I would agree. I think there is at least a chance that it is busulfan-driven, but on the background of sickle cell disease, okay? And because you'll note that they we haven't seen that as much in beta thal patients who are getting the same busulfan treatment. So if there's a role for busulfan, it is only incremental. I think the bigger issue is in sickle cell disease, like when we talk about hemolysis, which is one of the big concerning things you see in sickle cell disease, the reason you're seeing hemolysis is those cells in the marrow are dying constantly, right? They get created, and they die off really quickly.
And so then the marrow revs up trying to get enough cells to overcome that, to overcome the anemia. All right? So you're basically aging your marrow and fast forward, if you think about it, right? Cancer, ultimately, is just the inevitability of errors in your genome. If you, you know, replicate enough times, you will accumulate some bad luck mutations. Okay? So if you have marrow that is aging much faster than normal marrow, you are going to end up with some sort of hematologic malignancy. And that is generally known as a risk in sickle cell disease. And that's one of the reasons why the depth of cure that we talk about, more cells edited, as much as possible, normalizing hemolysis, right? That's critical because you're gonna change the risk curve for patients for these kinds of things.
So I think mostly this leads me to believe that in sickle, we have to get as early and as deep a cure as possible to save patients with this outcome. Nonetheless, I would agree. I mean, whether it's AML or not, we know busulfan as chemotherapy has some low secondary malignancy rate. That's known already, and that's one of the things you have to weigh when you're considering a transplant. Now, again, if you have severe sickle cell disease, you're going to the hospital 2-12 times a year with a week-long pain crisis, and you're gonna die in your 40s, you are obviously still motivated to go get, you know, cured. And that's what the patients will be in wave one. But if we can get rid of busulfan, obviously, we would like to do that.
That would be one of the big benefits of that.
Yeah. For sure. And I mean, we can have a long conversation surrounding why we don't see those cases in beta thalassemia. These patients are obviously hypertransfused. So their bone marrow is not as hyperplastic as it is in sickle cell disease. And that's probably why we're seeing it in sickle cell disease and not in beta thalassemia. Maybe just a quick question on the data update in the second half of 2024. Obviously, first time we're gonna see your data. Just give us a little bit of a data preview at this point. How many patients are we gonna see? What should we be focused on in terms of endpoint beyond maybe reduction in VOC and ACS? Just walk us through a little bit of data preview in the second half.
Yeah. Great question. So yeah, this will be a big event for us, obviously. First of our clinical data, I think in sickle cell disease, unlike, say, an alpha one, where we're doing something for the first time ever, where you're trying to show correction of your mutation and the effect of that in the body, in sickle cell disease, it is a, you know, there are people in front of us, and they've set a high bar, right? So VOCs have been largely reduced by bluebird, certainly, and by Vertex. But as I've been sort of noting, if you look back to the AdCom with the FDA, and since then, you know, not everything is fully normalized. It's just not, all right? So you still have VOCs. You have some that have cropped up. You have both breakthrough VOCs.
Some of the newer patients have had VOCs. So there's still some threshold of exposure to that sort of pain breakthrough, which goes to depth of cure. You've had relatively slow engraftment times from Vertex, maybe a little faster for bluebird. You know, hemolysis is better, but it's not fully normal. I mean, hemoglobins are better. They're not fully normal. So we think there's a lot of room to improve. And so our job is to, you know, see if our preclinical data does indeed translate to improvements on some of these very important clinical parameters that are all signs of patient health and long-term outcomes. So that'll be the data update.
So yeah, second half of this year, you know, our guidance has always been, we don't wanna give just one patient data. We would like to see, you know, multiple patients across multiple of these parameters. And we'll try to give as full a picture as we can. And you know, if the, you know, the preclinical data, you know, translates to the clinic, which it has been doing so far, you know, then we continue to believe we can provide potential best-in-class profile for patients.
Got it. Got it. Super helpful. Maybe in the last few minutes, love to talk about alpha-1 for a minute. Remind us why you decided to file a CTA and not an IND, and what's the plan to get an IND over the finish line?
Yep. So, yeah. So the IND, we think there's a path at the FDA for sure. And in fact, our GSD program is going straight to the FDA. So that'll be an IND filing shortly. The for alpha one, it's actually an alpha one specific issue. So we want to do our experiment on a clean background where the patient has no augmentation therapy. So we wanna know, what are their background levels of alpha one, both normal, which should be none, and Z, which should be some level. And then on that background, we want to dose the patient.
And then within no more than a month, we will look and see, hopefully, upregulation for the first time of normal protein in this patient being made by their liver, and reduction of Z, because we've literally converted some alleles from the Z to the normal. And in the U.S., you would have to have a conversation with patients and doctors about discontinuing their augmentation therapy, washing that out. Then you go in and, you know, I think just given that that's it's a reimbursed approved therapy, I think it's more complicated. Whereas ex-U.S., it's generally not used nearly as much. And so that gives us a much easier path with some basically phase one PD data, I think we then come back to the U.S. and would open up.
I think U.S. will probably be, you know, during the phase 1/2 trial, you know, we will get that open.
Got it. So you wanna see level in the serum going up for alpha-1 before you approach the regulators in the U.S., which makes sense. Can you maybe just talk a little bit about competition in alpha-1? There's a lot of different approaches. And, you know, the Arrowhead's approach is maybe a little bit more orthogonal going after the liver. But then you obviously have the RNA editing players. We're gonna see data from the RNA players in the foreseeable future. Vertex hasn't given up on a small molecule. Like, walk us through where do you think your therapy could potentially fit in the current evolving competitive landscape?
It is a very, you know, in some ways, complicated landscape. But I would argue that it's complicated because people have had to take such indirect means to treat the disease, right? Because what they've been missing is what we're able to do, right? What you really wanna do is go to the liver to change that letter back to normal, in alpha one and simultaneously start producing normal protein and stop producing Z protein, which will help the lung and the liver, have it be under normal regulation so that the gene, which wants to really dynamically turn on and off when you're getting sick, and that's when all the damage to your lungs is done because you have all these elastases surge into your body. So you need a lot of alpha one to surge as well.
You know, we would be under that normal regulation as well, and all with a one-time therapy, right? So, so basically, no one else in the field has that set of attributes. You have certainly RNAi is logical to knock down the liver. It is most likely gonna make the lung marginally worse over time. But if you have an acute liver patient, which is a small minority of the patients, but it's nonetheless a meaningful population that could help. In our case, we would help the liver, but simultaneously protect the lung. Vertex, you know, we have a lot of respect for them. I think it's a it's just a hard challenge. You have a lot of alpha one protein, and they have to basically go one molecule of drug per molecule of protein. So you think about the stoichiometry of that, right?
So the dose levels they will need to really make a difference is very high. And it's still a mutant protein, and you have to kind of chaperone it out of the liver and have it still be functional. So it's a complicated situation. RNA editing, I think, is elegant. It's, you know, we've looked at it ourselves. Obviously, for every RNA transcript that gets edited, that's a job well done. That will now create a normal protein. It will not create Z. But the question is, how many RNA transcripts did you edit? You know, and we'll see. And then what is the dose response there? And how does that preclinical data translate in the clinic? I think that's a pretty unknown thing. We'll see. And of course, ultimately, even at best, it's a chronic therapy as well.
So you'd have to take it for life. And I think we would bring along a one-time cure. Finally, you have Intellia, which is doing a kind of knock-in of the wild type gene, leaving alone the Z mutation gene. And because the efficiencies are relatively low, they're gonna knock it into a different locus, the albumin locus. So the regulation would be different on that gene. And, you know, we'll see what levels they get to. And in that case, you need both an LNP and an AAV. So I think from our perspective, I think we've got a pretty clear path here, to a best-in-class profile without really any competition for that profile. And we're not far off either, right? I mean, we're gonna dose patients very soon. We'll, you know, this year, we'll be moving through a number of patients.
This is, you know, data that will be relatively available, pharmacodynamic, blood-based data. And so I've been saying, you know, it's certainly a it's 2025 data event, most likely. But if you compare, you know, to other liver programs in the editing field, you know, it wouldn't be crazy to think of this more on the earlier side of 2025, kind of the beginning of the year to the middle of the year, for, you know, 2-3 cohorts of data.
That's helpful. Maybe last question. We're running out of time here on IA. Maybe just can you remind us the rationale behind going after this indication? And also, is there any risk of bystander editing there? If I recall it correctly, you have an A that is in kind of close proximity to the A that you were trying to target. And again, I know a lot into one question. But, can you talk about differentiations versus Ultragenyx, given that their data is actually coming any day?
Sure. All right. I'll do this fast. So right. So bystander editing. So, you know, occasionally you have that with base editing, like an alpha one. We have a bystander in some of the allele outcomes. But it's a fully normal protein. So it works fine. And so it is not gonna have a biological impact, which is great. In the case of GSD, there actually was a bystander that would have been a problem. Not a problem. It just wouldn't have fixed the gene if you had it. So in that case, we engineered the editor to move away from the bystander, and we actually dialed it out. So we only make the wild type correction in the GSD gene. And that gives us, you know, full, you know, restorative credit, I guess, for all the editing that we make.
So that was the case there. So, the differentiation there, you know, I think, you know, Ultragenyx, the data looks okay. It could, you know, I think patients have some improvement. It's an AAV. So you have a question of how long will it last? This is not a disease where you would want your effect to wear off. You also can't treat young kids because as their liver grows, it will dilute the effect of the AAV. We have none of those problems. So we would just do a single cure, and that would be quite effective. You know, it's a rare population for us, obviously. It's about 300 patients in the U.S. You know, we used to think it was a little bit more.
But when you actually look, you know, a lot of the older patients who should be there by epidemiology are dead. And some of the younger patients maybe have been, you know, screening, prenatal screening, maybe lowering that a bit. But there's a very clear cohort about 300 patients who really really desperately need therapy. This is the most severe population in this disease. And I should also note it's the one where I think the Ultragenyx program works the least well. So, you know, we think there's a real opportunity for 301 to help these patients. And then, of course, alpha one, you know, 100,000 patients in the U.S. with the CZ allele, you know, sort of very large commercial opportunity as well. So and those are just the beginning.
We're gonna have lots more liver programs coming, both with our partners, Pfizer and Apellis, and then internal Beam programs to follow.
Super, John. Lots more questions, but no more time. Appreciate you joining us. And best of luck for the rest of your conference. And thanks, everyone, for dialing in. So thanks again.
Thank you very much.
Appreciate it. Thank you, John.