All right, well, thank you. Good morning, everyone, and thank you for joining us on this next session. I'm Michael Yee, the Managing Director, Senior Biotech Analyst at Jefferies. And up here on the stage, we have the pleasure of introducing John Evans, who's the CEO of Beam Therapeutics. Beam has been on an exciting journey. Of course, most important as a milestone, I would say, is the announcement of some of the first clinical data for your platform, which is important, and obviously an upcoming potential presentation at ASH, which is exciting. So maybe, John, you could give some brief comments about that recent milestone and about how the company is doing, and obviously a brief summary of what that data showed for sickle cell in that abstract and what we've learned from that.
All right, well, thank you, Mike. And it's great to be here. So yes, it's a very exciting time for Beam, obviously been working on this next-generation platform in CRISPR gene editing using something called base editing, where we don't make the double-stranded breaks, we instead make single base changes, and we get a more precise, controllable but also efficient edit that's going to open up a lot of possibilities in therapy that haven't been possible before. So we have a number of catalysts sort of coming up in this next phase as we reach clinical development, start to reveal that data. The first one has begun, which is sharing the data with BEAM-101 in sickle cell disease. So we had abstracts come out in early November that'll lead up to an ASH presentation in early December.
But the headlines are already in view, and we talked them through a couple of weeks ago. And so basically what we're seeing with BEAM-101 is what we believe is a potentially best-in-class profile for BEAM-101 to treat patients with severe sickle cell disease using gene editing. So what we showed, we're upregulating fetal hemoglobin. That's the genetic target. We showed about 20 points higher levels of F than you see with Vertex. So we're up in the mid-60s across the patients that we showed. That also means that we've turned down the sickle protein by about 20 points, so down in the mid-30s instead of maybe in the mid-50s for Vertex. So a deeper reversal of the disease phenotype. And these thresholds are important because we're now getting to the levels that you see with patients who don't have disease.
So like a carrier of the sickle gene, a trait patient does not have symptoms, and they are in that 60-40 range, and that's where we're at. So that was very exciting. And of course, what we intended to show. We also showed resolution of anemia, stronger than what we've seen, for instance, from the Vertex product. Other areas of differentiation have also started to emerge, which is exciting. We're seeing faster time to engraftment. This is really important. So when you are getting a transplant, you literally have no immune system for several weeks to a month. That leaves you in the hospital vulnerable to infection. So we saw about a 10-day faster time to neutrophil engraftment than you saw with Vertex. That means patients protected from infection, going home sooner, less hospital utilization, all really important factors. That may be because we're using this non-cutting form of CRISPR.
So the cells may be more robust and more viable. We also saw fewer cycles of mobilization. So that means faster to get to the dose, very advanced manufacturing process. So across a range of different features, we see this sort of differentiated clinical profile for BEAM-101, all enabled by the base editing.
So if I could take a step back, in the first handful of patients that you had presented, one would believe that this essentially validated the technology clinically, first time in humans for the base editing technology. I know there's some competitors coming by, but this was the first human data for base editing. And you would believe that this affirms greater editing efficiency, right, based on the results, which gave you higher hemoglobin F results than Vertex CRISPR. What are the clinical ramifications of that? Just because you have higher editing and higher hemoglobin F, is that going to be clinically a better drug? Is it clinical results for the patient? Is it a convenience thing also because of the engraftment and some of those issues? How important is that?
Yeah, great question. So the advantages of base editing are quite diverse. And people often say, oh, is it just safer than cutting CRISPR? And there may be some truth to that, but often the differentiation is even at a deeper level than that. So in this case, it's the high efficiency, right? So we get higher levels of editing. So our input editing is over 90% of cells edited, as opposed to Vertex, what we think is around 80%. But it's also the fact that because we're doing single base changes and we know what change will result, we can literally screen to the point where we know the exact single base that if you change that one base, you get the highest biological response. So that's the optimization we can do because we control the editing. We also get a much more uniform editing product, right?
Every cell will get the same kinds of edits, whereas with a nuclease, when you cut, you kind of scramble the genome. You're going to get some edits that are very productive and some that aren't, whereas we're going to get the same uniform high level of editing across all of those edits of cells. It just gives you a more uniform product. To point to one sort of biomarker that we looked at, tracking the first two patients here, we see after several months, 99.9% of detectable cells in the periphery have F expressing, and only 0.1% of cells were detectable that had only the sickle protein left. If you think clinically, those are the cells that are going to get you in trouble, right? Those are the cells that will sickle in the periphery under low oxygen conditions and cause trouble.
So we've almost eliminated that. So I think the depth of the editing, the uniformity of the edit, all make a big difference. And then yes, the non-cutting makes a big difference, maybe not just for safety, but in this case, we're seeing that in terms of cell viability and health. And I would say timing of engraftment, I think, is much more than a convenience factor. I think it is a safety factor for patients. I think this is the tough phase of the transplant, right? It's chemo. You have a lot of symptoms you're going to go through. If you tell patients that's going to be 10 days faster, I think they'll be pretty motivated. And then, of course, for hospitals, right, they have to think about what's the throughput, how many beds am I taking up, what's the cost of this whole transplant procedure.
I think it is a very big deal. We also saw faster engraftment for platelets, whereas both Vertex and Bluebird have a warning on the label for slow platelet engraftment. We're not seeing that. I think all of that adds up to, I think, a potentially superior product.
Okay. There was also updates on, so on efficacy, significantly higher hemoglobin F that should lead to minimal or potentially none, but I won't set that bar for vaso-occlusive events. But again, you're getting people to carry your levels. So biologically, they may not ever have these types of events. That's important. Vertex actually has had one or two, I think, in some of the data. And then in addition to potentially significant efficacy, also a faster time to engraftment and mobilization. So totally where we're talking about 20, 30 days or more or less time overall in the hospital, which would be a convenience factor.
You mentioned vaso-occlusive events, I just mentioned it. So we didn't have any VOCs, of course. I think it's just early days to speculate on that. So we'll obviously follow that over time. Nonetheless, you are seeing breakthrough VOCs with the Vertex product. Their kind of best top-line number they can hit at this point in their trial is about 89% reduction, which is a very good number. But clearly, there's still some room to improve. I think with the depth of correction we're seeing here, I would certainly be optimistic that we may at least match them if not have something better over the long run.
Yeah, clinically, the level that you're getting to, sort of like hemophilia and 13% factor allowed, should imply that you have a much better chance. But overall, the point is five years from now, when all of these drugs are on the market, physician has a choice, patient has a choice, you believe if this data holds up, there would be a compelling choice, obviously, for the Beam program. Now, in addition, of course, safety. I'm going to talk about safety on two fronts. One is, of course, give us a summary of that, and there was a serious adverse event. But secondly, perhaps that would lead to why getting rid of the conditioning regimen would be important. And you also have an abstract on that at ASH. Talk about the safety, what your opinion is of that. Stock went down initially on this data, then it's gone back up.
And then how do you think to solve that?
Yeah, great question. So the safety of the BEAM-101 product was actually sort of, as we would have expected, no major serious adverse events to the product itself, and really, the profile is consistent with getting a transplant, so that was as expected. Now, the issue is transplants are risky, and so we did have a patient who died of basically a pulmonary toxicity that's sort of slow progressing, and that's typical and known to happen with busulfan. So this is the chemotherapy patients have to go through to get these kinds of cures, and so the main point from that is this is exactly why we've always said we think these kind of initial products are a good fit for the about 10% of patients who have severe disease and cannot wait, so they're having a conversation with a hematologist about risks, benefits of transplant.
And they've concluded, yes, I need a transplant. I know there's some risks, but I have to go for a cure because I'm frankly dying of my disease, just like in a cancer situation. So for those patients, we want to give them a better cell product. And we think that BEAM-101 will be that. The transplanter will work with the hematologist to make that choice. They clearly can have multiple available. And we think BEAM-101 will be the best option for those patients. Now, it gets even more exciting, of course, if we can get rid of the chemotherapy. And so I think when we got into this field, we were just thinking about the edit initially. But the more we looked at it, the more we felt that there was a big opportunity to address that part of the problem too.
That is our next generation version. So we call it ESCAPE. That's a technology that we basically will create almost exactly the same product as BEAM-101. So everything we are de-risking and building with BEAM-101 will apply. We literally add just one extra edit. And that one extra edit creates a single change on a receptor on the surface of your stem cells. Doesn't change the biology of those cells. But now we can use an antibody to condition the patient, get rid of their stem cells, make room for the graft. But that antibody will no longer bind our edited cells. So it will bind old disease cells, get rid of them. It will leave alone our graft. And you can literally have the antibody alongside the graft in the body at the same time, which is an amazing breakthrough.
To where is that added?
And so that data we showed in primates. So we literally did a monkey clinical trial where you have primates, you mobilize the cells, you take them out of the monkey, you edit them outside of the body. We condition now with the antibody instead of with chemotherapy, put the cells back in, and they did indeed engraft. And in fact, we kept dosing the antibody alongside and didn't hurt the graft. So beautiful proof of principle. And basically, we achieved gene therapy-like efficacy in that monkey, but now without chemotherapy. And so that would be a revolutionary product profile, of course. In our view and research, that takes us from maybe 10% of patients to up to 40% of patients would be a really good fit for that.
So you're dramatically expanding the addressable patient population and eliminating what I think is still the most burdensome part of this therapy for patients.
And so when would that construct go into the clinic?
Yeah, so that's now moving towards the clinic. So we've declared the development candidates. So the antibody is going to be known as BEAM-103, and then the cell product that pairs with that antibody is BEAM-104. So we will be in effectively IND-enabling studies by the end of the year, GLP tox. We're already manufacturing. So that leads you to some sort of regulatory filing back half of next year. We're likely to start with a normal healthy volunteer study to quickly get the PKPD and safety of the antibody sort of confirmed, and then roll that right into a patient study where we're doing transplants to try to give therapy.
And conceptually, is that you would expect the same amount of efficacy because of the same construct, but on the other hand, you obviously have to block rejection. So how would that work?
Yeah, I think the cell product itself will have certainly the same level of editing that we would get with BEAM-101. That's all the same. The difference here now is we're going to be creating the space with the antibody rather than the chemotherapy. So I think TBD in terms of comparative chimerism levels that we reach and things like that. But basically, I think we now are convinced, based on this monkey data, that we can create a deep enough opening in the marrow.
Does that require a longer time to engraft? Because rather than completely knocking out with chemo and then putting in the cells, you're doing that at the same time.
Yeah, it's an interesting.
Does it take more time?
It's a great question. So the kinetics here are different. So we're using the antibody, and it's a gentler process, right? We're not just blasting with chemotherapy. So you're going to pretreat with the antibody, and then there will be some amount of treatment post-cell dose to kind of maintain that suppression of the old clone and let the new cells grow.
Before you put in the new cells, they have the old cells in. You give the antibody. I think it's starving the cells to kill them. And then you're going to put in the new edited cells. And then I don't know what amount of the cells have been replaced or they're gone before you put in the new.
Yep, exactly. And then gradually over time, we'll continue to suppress old cells and let the new cells grow and replace.
So at what point does they kind of hit the same?
But the point about time to engraftment is really interesting because actually, remember, these patients are now not myeloablated.
Right.
So there really isn't the same concept of, okay, you have to wait until it's there. We're actually, in a way, just titrating old cells for new cells. And in fact, based on what we see so far, this could even be an outpatient procedure. So we would mobilize the cells, take them, edit them, we're ready with the cell product. You would visit the hospital for your infusion of the antibody. And then at one point, you visit the hospital and you get the infusion of the cell dose. But you still have your immune system. The rest of your hematopoietic system is still intact. And so then we're just waiting that time for the kind of new cells to start producing hemoglobin that is corrected. And then, of course, the disease protection would be there.
Okay. So at ASH, coming up, I guess in a few weeks, what update will we get? How much more patients? Is this sort of incremental? What's at ASH?
Yep. So ASH will be, obviously, the updated Beam-101 data will be showing data on seven patients total for both safety and efficacy. The trial is moving very quickly now. We've actually got, we announced 35 patients enrolled, many more in screening. I think that is really moving quickly. As a reminder, that's a potential registration-enabling trial itself. We will also, of course, give more depth on the ESCAPE data in primates. That'll be there. There's also a biomarker poster, some really deep profiling of the blood of these patients on the clinical study for Beam-101. We really want to bring a lot of science. We believe in the depth of our correction, and we think that will show in some of the blood parameters that we see normalizing. Finally, we do have BEAM-201, a CAR-T product.
It won't be a core priority for us just given we're not moving into CAR-T, but that also looks active. We had multiple complete responses for the first few patients there. There will be an update on four patients at ASH.
Right. Where are you in terms of enrollment progress on the amount of patients needed for a potential filing?
Yep. The BEACON trial is designed. This is BEAM-101 for sickle, designed to enroll 45 patients total. As I said, 35 are already on. We're certainly well on our way to fully enrolling the trial. In fact, if you think about the timeline to filing, we believe that the efficacy data set the FDA will need is really that probably about 30 patients. Already patients on study, dosed, and followed for, call it 15 months, which is enough time to get that VOC 12 time. You basically have to find a 12-month period where there's no VOCs and see if you hit that target.
So, is that possible to have that data at ASH next year? Or that's more of an early 2026 time?
For the full follow-up on the 30 patients, you would be into 26. So we'll be dosing these patients through 25.
Cut and clean the data in early 2026, and it'd be a filing in 2026.
So no guidance for sure. But I think that if you think about six to eight months to treat patients, if the 30 patients are already on study, then we would anticipate by mid next year, you've probably treated all those patients.
Okay, got it. Add to the.
15 months later. So we're probably in the early 2026 on that timeline. But I think, yes, those kinds of timelines are possible.
So, again, important was that you have put up the first clinical data in small number of patients so far, knock on wood. The data has obviously played out, I'd say to the high end of your expectations. I think the safety event we can reasonably attribute obviously to the conditioning regimen, not the product. And you're executing on the pivotal program. You're looking to finish that, and eventually you're going to have data. And that's great. In addition, you are obviously preparing to file an IND on a much better second-generation version. And let's see how that plays out. Now, obviously, Wall Street is excited because the technology is working. And now this could be applied to other programs, in vivo programs like AAT.
Tell us about where you are in your phase 1 in vivo gene editing for AAT and compare and contrast what you think you could show versus Wave, which just put up some data, and compare and contrast the programs.
Great. Yeah. So in vivo is our second main pillar. Here we're using lipid nanoparticles to deliver the base editor to the liver. This is a validated approach by others in the field, so we know it's achievable. But unlike what others are doing, we're doing what I believe is the first effort to use, again, you need base editing to do this, to actually correct a mutation in the body rather than knock something out or turn something on. So here we're literally taking a single letter misspelling in the gene for SERPINA1, which is for the alpha-1 antitrypsin protein, and turning it back to normal. The Z protein is the mutant protein. We're turning it to the M version, which is normal. And so this is an A base edit. So very, very excited about this product.
Of course, 100,000 patients in the U.S. have the ZZ genotype, which gives them the classic alpha-1. They all have that same misspelling. And the BEAM-302 product would be a fit for all of them. So this is a single product for the whole population. So what our ideal, I mean, I think the ideal target product profile for these patients would be a one-time therapy that fixes the disease at its root cause, which means the gene and the DNA, where for every gene I fix, I'm going to start producing normal protein. So I want to normalize the alpha-1 levels in the blood. I also want to lower Z protein because I'm literally converting Z genes into M genes. And I want to be under normal regulation. So the on-off switch of that gene will be normal because I'm fixing it in its normal location.
That's important because alpha-1 is an acute phase protein. It goes up and down as your body needs more protection. So one-time therapy, raising normal, lowering Z, normal regulation. So we are in the clinic. We're very excited about that. So we've just disclosed we've completed the first cohort of dosing. Enrollment's going well. Obviously, we're now into the second.
I think it's in the United Kingdom.
This is a dose escalation. That's right, nearby. So yes, we're in the U.K. We're actually opening now in New Zealand. I think that's disclosed. There'll be other countries coming. So it's a dose escalation. The first dose has to be a biologically active dose, but certainly not optimal. We're then dose escalating to get into that optimal biological range. Pre-clinical data suggests that anywhere between 0.25 and 0.75 mg/kg, we should be able to get into those normal ranges of alpha-1 protein. And we are excited to see what can happen in the clinic.
So your first cohort has been dosed. They've been infused with the drug. And analysts' math or view disclosed at least a few patients of the first cohort. Have you disclosed that you've been able to dose the second cohort, which is a higher dose?
So we haven't disclosed, but I think it would be a higher dose. Yes. So it's a dose escalation. And so I think the beauty of alpha-1 is it will be relatively clear early in development what we have. So I think this is an early proof of concept kind of situation, like many of the precision medicines that we work on, where our first data disclosure would be looking for higher levels of normal alpha-1 protein, lower levels of Z protein. Those should be visible in about a month for patients. And then obviously safety. This is still a dose escalation. We want to see the tolerability of the drug. You had asked about competitors in the field, Wave and others. So I think it's an exciting time for alpha-1. It's a patient population that desperately needs new options and new therapies.
A lot of other players are going more indirectly because they haven't been able to do what we're going to do, which is to go directly at the gene. I think RNA editing is one of the interesting areas that are active. In that case, they are going to edit a single base, but now on the RNA rather than the DNA. And so in some ways, it's nice proof of principle for what we're going to try to do. We're going to try to make that same edit and turn a Z protein into an M protein. And it does appear that it works to a degree. Obviously, there though, because the RNA is transient, you have to keep editing. And so with RNA editing, you'll have a chronic therapy sort of redosing with some frequency for the lifetime of the patient.
A lot of sort of data still needed, I think, to draw many conclusions. They clearly got some level of protein up. How long does it last? What will that frequency of dosing be? What will happen when they dose escalate? I think TBD. I think for us, we feel.
Point being that they are editing the RNA. It will have to be a chronically dosed drug.
That's right.
You are obviously fixing the underlying DNA such that it's a one-time thing and will forever be producing the corrected M protein.
That's right.
They did get proof of principle. They did show increases to 10 or 11 micromolar, depending on how you look at them. I'm a little confused by the data, but they are getting to increase levels that do show, would predict some benefit at 11, and we need to see more, so therefore, if you have proven that you can edit the DNA ex vivo, if that can happen in vivo, and that's a reasonable leap of faith, then you should be able to get much higher levels than 11, which is what Wave is showing, but do it in one time.
Correct. I think with Wave, you're going to want to ultimately understand the trough level, right? Because it's a chronic therapy, so we need the multidosing data. And you want to know not the peak of the effect, but where does it live long-term. But yes, I think basically clinical benefit begins at 11. Higher is better. So we're certainly going to look to raise those levels into that normal range. And then also.
So carrier levels of which you think you could get to based on like 25% editing.
Yeah. So we think the 20%-25% editing probably gets us into that 11 or above. That's the threshold for clinical benefit. Because remember, ZZ patients basically live in the single digits. They're sort of four to six. So once you're in the teens, you're into a different regime in terms of basically out of that disease mode. Carriers are generally in the mid to high teens.
Normals are like 30, 40.
Normals are 20, 20.
20, okay, so if that's possible and you would agree, you said that you should get pretty clear proof of concept at a first cohort because it is a predicted therapeutic dose level, then Wall Street would say, "Well, come on, John, clinically meaningful data, certainly material for your company, a smaller company, should be disclosed," and you're going to be sitting on the data. How can you sit on the data for a year and know this? It's open label, so how can you sit on that and know the data and not put it out? I mean, we would have data by early 2026, 2025, 2025.
We appreciate the enthusiasm. The first cohort is designed to be active, but not likely optimal biological dose. You have to start low and then go higher over time. I think we have said that we're not going to complete the entire dose escalation before getting data out. I think that what we have said though is I would like to see multiple cohorts. Two to three cohorts. It's a dose escalation. We want to give some science that both the investor community, but also the patient and physician community can dig into. You'd like to see what happens.
You'd like to know after two patients. Two cohorts. How much is a higher dose? How much more does that get you?
That's right. That's right. And we want to be able to also do the science on this, show not just levels, but functional levels. Remember, that's what really matters here. Z protein, safety, tolerability.
We will talk with you in a few months because you will know the data and then be dosing the second cohort.
Thank you, Mike. We're excited about what's coming. That's for sure.
Very good. Thank you guys very much.
All right. Thank you.