Let's do it.
All right. Well, everyone, thank you for being here this morning. It's my pleasure to introduce John Evans, CEO of Beam Therapeutics. John, thank you for being here.
It's great to be here. Thanks for having me.
Excellent. So, maybe we could just start with some opening remarks, yeah, two to three minutes of overview of Beam for those that are maybe less familiar.
Sure. So Beam is a next generation gene editing company. We were founded around a technology called base editing. So base editing is a new form of CRISPR. So we're using CRISPR for the same ability to target the genome selectively, using programmable guide RNA-driven targeting, which we think is an incredible breakthrough in the field, but we're not using it to do the edit. We don't have the double-stranded break, which the normal CRISPR applications use, which creates some real challenges to control the editing outcome. Instead, we use a form of CRISPR that has that turned off, and instead, we've added a deaminase, a chemical modifying enzyme that can take a single base, change it to another without modifying the gene sequence.
And so this gives us a very high efficiency, high precision, editing tool that does not need double-stranded breaks and has full control of the editing outcome. We've been working on this for the last five or six years, developing a very broad platform, which can bring this technology forward in all the different areas where genetic medicines are possible. So hematology with sickle cell disease and other blood disorders, oncology, editing T-cells, for multiplex edited CAR-Ts, and then in vivo editing using primarily lipid nanoparticles, looking at the liver. And so all of these are now set up and running, and we're going to have a very rich pipeline coming forward across all three of those areas, moving into the clinic, and then lots of next-generation technologies coming behind.
Excellent. I wanted to maybe just start with your in vivo pipeline, specifically, BEAM-302, which is your asset targeting Alpha-1 Antitrypsin disease. You recently prioritized regulatory submission for a trial clearance for this program over your other in vivo program, BEAM-301. So could you just, you know, give us an overview of BEAM-302, you know, what disease is it targeting, and how does BEAM-302 actually address that?
Yeah, great question. So Alpha-1 Antitrypsin Deficiency is a huge disease. There's at least 60,000 patients in the U.S. who have this disease. It is almost completely defined by this one mutation. It's called a Z mutation, and that's a single letter misspelling in the gene, and the patients who have the severe form of this disease have a ZZ. They have both copies are broken in that same way. It turns out this exact mutation is editable with a base editor. Just an A to G change will turn it back to normal, and that will do two important things. So one is it will stop producing the mutant Z protein. So Z protein is a bad actor. It causes polymers, it builds up in the liver, causes liver toxicity, so we can potentially help the liver pathology.
At the same time, the mutant form of the protein is not secreting effectively into the bloodstream, where it's supposed to be there to protect your lungs and other parts of your body from degradation during infection by your, by your endogenous proteases. And so you have low levels of circulating normal protein. And so if we can fix the gene, we also will start secreting normal protein that can then protect the lungs and stop from this emphysema sort of insult. So these, these patients are very sick. They end up sometimes needing double lung transplants, you can need liver, you know, liver failure, so it's a real problem. And it's really a perfect fit for base editing, right? So every time we make an edit, we're going to simultaneously stop producing Z and start producing normal secreted protein to protect the lungs.
There's lots of other people in the field, of course, going after this, but, but if you think about it, it's a, it's a really perfect fit for, for what we're doing. So Beam- 302 is our, is our asset here. It's obviously the second liver program that we created. We had to take a little more time to make sure the potency was there, as we were engineering it. It's always been a target we've been very passionate about. But last year, we published research that showed that we had done it. We had actually improved potency significantly, to the point where we think we can achieve a single dose to potentially normalize patients, with, with a potentially curative therapy. And so, that was obviously very exciting.
We then declared BEAM-302, and we've been accelerating it ever since. In August, we announced that we'd gotten to the point where BEAM-302 was basically on top of BEAM-301 from a timeline perspective, and we needed to choose which one the team would file first, and so we prioritised BEAM-302, just given the magnitude of the unmet need and the excitement around the program. So that'll be our first liver filing in first quarter 2024, and then as soon as that's in, we will turn to filing 301 shortly after, hopefully, and that'll be in the first half of 2024.
Perfect. And you touched on this a bit about why base editing is perfect for this disease. Can you just contrast it with some of the other mechanisms that are out there, and why is your approach potentially more efficient?
Yeah. So, you know, there's the alpha-1 community that really needs a therapy. I mean, they are very eager. It's an incredible foundation that drives this. There's so much unmet need, but it really has resisted breakthroughs in terms of meaningful therapy. So there's a bunch of different approaches. You can think about, well, first, protein replacement. So people take a recombinant form of the alpha-1 protein and just put it into the body. You need a lot of protein, and so it's really difficult to get enough in and keep it in for long enough. And so it's... And also, the levels of the protein are not going to respond in your body when you get infected, for instance. The body wants to surge your levels of alpha-1 protein.
If you're on protein replacement, that's not going to happen, okay? So that is, you know, one aspect. You also to try to help the lung. For the liver, people are doing knockdowns. So you use RNAi to try to knock down production in the liver. This will, of course, help relieve the pressure on the liver, and I think I'm excited about that for patients. At the same time, it's probably going to, if anything, exacerbate the problems for the lung because now you're blocking production of this critical protein, and what little secreted protein is getting out there is going to get impacted. So we don't think that's a full solution either. In the editing front, you've got people thinking about RNA editing.
That's really preclinical and would have to be a chronic therapy. You have gene editing. You know, gene therapy has not worked here because you need so much protein produced, and the liver is very stressed, so AAV therapies have not worked, and that, of course, would also not address the liver pathology. You know, Intellia is trying to do a cut and insert of a normal gene and then also a knockout of the mutant gene, sort of an indirect one-two sort of approach. You know, ultimately, you really just need to go and correct the allele. It's a very simple approach that we're taking, and importantly, the correction that we make will be under normal regulation, so it will respond when the body needs it to respond. It's native within the chromosomes.
It also, as the liver divides, it will pass on those edits to daughter cells, which means that we can treat patients as early in life as we want, because as the liver grows, it won't dilute out your signal. Okay, so that's really critical. And so I think for all of those reasons, we think, you know, the elegant thing to do here is to fix the one letter that's wrong, and that's what base editing can do. So we feel very confident about the differentiation of our product versus others. You know, all options are good for patients, but we're certainly, you know, pushing ours fast because we think it could be a best-in-class approach.
Got it. So when you talk about the potency that you work to achieve, and you talk about. How do you think about editing efficiency in humans? What is the bar there, and what would be, like, a meaningful concentration of protein secretion that you think would be beneficial?
Yeah, it's a great question. You know, when we're doing in vivo, you're talking about LNPs. LNPs are now a validated approach to deliver to the liver. Of course, you had Alnylam with Onpattro, delivering RNAi for ten years now, which is a major breakthrough. Delivering larger payloads like mRNAs is a significantly more complicated challenge, but we're building on that same foundation. That's now validated with Moderna delivering to the liver and then in editing with Intellia. You know, we know this is possible, but we also know LNPs well enough to know that they don't have an infinite therapeutic index. You can't dose up forever. You're putting a lot of lipid and things into the body.
Of course, it's a one-time therapy, so we have a fair amount of tolerance for that one-time therapy. But I think it's really important to make sure you're potent enough so that your activity is gonna fall, you know, into that safe range where you're still able to give the LNP. And so, I think it was a real priority for us to make sure that we felt, with a single dose, that we could get a, you know, therapeutic, disease-modifying amount of upregulation to really provide that kind of one-time cure potential for patients. And so, so that's what we did. So I think in terms of what we're hoping to see, I think clearly, you know, there's a couple sort of benchmarks we can use. So there's a threshold of about 11 micromolar of alpha-1 protein.
That's chosen based on clinical genetics. So there are patients who are carriers of the Alpha-1 mutation, but don't have two copies of it, who have ranges of their circulating Alpha-1 levels down to about 11. And it's really the patients who then get those two copies that are broken, that fall below that level, who start to have the sort of expressed disease. So I think that's something that we use, and in fact, with protein replacement, they talk a lot about dosing up to that level. So clearly, we wanna clear that. The reality is we wanna go as far into the normal range as possible.
I mean, if you think about both to provide deeper protection for the lung, but also to try to get as much of the liver corrected as possible to relieve that liver toxicity, you know, we're gonna try to go as far as we possibly can. But I think the bar we've said in the past, we think, is somewhere around 20%-25% editing in the liver would be... you know, provide that clinical benefit, and then the more, the better. The reality is, you know, between, I think, the potency of the assets that we have, and then, of course, the potential to even redose them if we needed to, there's nothing that stops us from going, you know, completing the edit of the entire liver. So that certainly is a goal.
Got it. Okay. And so I'm sure it's in flux, and I'm sure you're still developing it, but how are you thinking about the first-in-human trial in terms of design? What would be the endpoints for particularly a base editing therapy versus, you know, some of the protein replacement therapies? How are you thinking about that?
Yeah, so the phase I is being designed, but it's getting finalized. It will be fairly predictable. I think, you know, we've seen this from others, Intellia and Verve, on the editing space. So it will be a dose escalation. You go in with a, you know, a dose that is plausibly beneficial, but low enough that you're gonna have some chance to really assess safety, and then you dose escalate. And so that's gonna be the design. So it'll be cohorts of patients that are sort of moving up on that dose level. That said, we would anticipate within the first, you know, two, three, four cohorts, we will be at an active range, well, maybe active right off the bat. So it won't take too long to generate that data set.
The other important thing about this disease, one of the reasons we like it for the in vivo approach early, is you get this great biomarker, right? So you're pretty much quickly going to see what you're doing in terms of upregulation of normal protein. So we're gonna look for patients to have sort of their background levels of Alpha-1, and then on drug, within a few weeks to a month, you're gonna look to see, has that changed? Are you now editing and then producing more of that normal protein in circulation? So that's, you know, that's really the goal. Of course, we'll also be looking at all sorts of other endpoints, but I think that, you know, the sort of the headline out of the trial is probably gonna be those Alpha-1 levels-
Mm-hmm
Which will be relatively quickly ascertained.
Got it. Okay. So, you know, how quickly do you think you could enroll this study? And when would we maybe see potential data once you get the study up and going?
Yeah, it's a great question. I think, you know, I think the Alpha-1 patients are out there. This is a big disease. They're, they're well followed. I think we know where they are. So one important point that we've said before, we are gonna take this ex-U.S. first, so this will be a CTA filing. The reason for that is really a technical reason. So we are in the U.S., patients are generally on protein replacement, okay? It's approved, and it's reimbursed, and that's, you know, good for them. But, but we, we would rather do our experiment on a background of patients who aren't on protein replacement, because you wanna know the patient's natural background of Alpha-1 levels, and then see that change under therapy.
So you could, of course, in the U.S., have a conversation about discontinuing patients on that, but for a novel therapy, that's you get into ethical questions of discontinuing an effective therapy. Ex-U.S., protein replacement is generally not used and not reimbursed, and so it's very easy to go ex-U.S., get patients who aren't on it, generate that data set, and then come back into the U.S. and say, "Look, we've got an active drug. Let's come off protein replacement and do this," and investigators will go with us on that. So that's basically the plan. So this will be an ex-U.S. CTA filing first, and probably towards the end of dose escalation, we'll be coming back to the U.S. So I think that's roughly the plan.
So then, in terms of enrollment, I think, you know, this is a normal-looking phase 1. I think that, you know, I won't set any expectations, but I think we should be able to enroll this fairly rapidly, you know, generating the right kinds of sites. Certainly, we're gonna have a multi-site network, and bring patients in. And then, you know, again, in terms of timing for data, again, wouldn't guide just yet. Let's get started first. But if we're able to file on the timeline I mentioned, you know, this, this could certainly be a data set that comes out in, you know, 2025, something like that. I mean, that's been. That would be consistent with what others have done in the field.
Got it. Okay. Yeah, you mentioned that you're going ex-US, and those CTAs have had a pretty decent success rate, I think, easier to get through than, say, with the FDA. You know, as you come back to the FDA, once you have some of that data in hand, what have you learned from, say, Verve's experience or Intellia's experience on how to approach the FDA to get that IND cleared?
Yeah. So this is obviously a hot topic for a lot of investors. You know, but I like to remind people, this is just the process of working our way through a novel kind of therapy, you know, with the FDA. The FDA is, in general, a little more conservative than other agencies. That's true for decades. You know, I think the RNAi field, you know, generally, a lot of companies did their first trials outside the U.S. Of course, now it's quite standard. In the editing field, of course, we've now worked our way through, so obviously, with sickle cell, we got our trial open with the FDA on the first try. In the case of BEAM-201, we got a clinical hold, which I think was quite, you know, minor, but we were able to quickly resolve that. We're open now.
And now the next one is in vivo, and so that's where we are now. So I think with in vivo, we have a better sense now of the FDA. They're asking for, you know, basically a long checklist. They wanna know not just off-target potential in hepatocytes, for instance, but they wanna understand your biodistribution in the body-
Mm-hmm.
And then have some sense of off-target characterization in each of the tissues where you're exposing. And, you know, it makes sense. I don't think we expect the off-target profile to vary much. It's the same chromosomes in all those cells, but, you know, I think it's a reasonable question to ask, so that's work that we now know we need to do. We have learned a lot from Intellia, from Verve. Obviously, we're collaborators with Verve, and then we have our own advice from the FDA as well. So we did a pre-IND meeting for BEAM-301. For GSD, we got all that same feedback, and so we've been working towards that package, and I think it is achievable. It's just more work. So I think this will all get cleared.
You know, Intellia has an open IND now. Obviously, they then went forward with a proposal for a later-stage trial. The FDA then said, "I'd like another reproductive study from you," and so they're not yet enrolling that. So that's been another sort of challenge they need to overcome, but the IND is still open, right? So clearly, you know, you can have an open gene-editing IND in the U.S.. So I think this is all gonna happen. It's just been slow.
And so I think we feel like we understand the bar, I think we're gonna go for it, and I think with GSD, so that'll be our first U.S. filing, at this stage. So that's gonna come after BEAM-302. So in that case, we need to go to the U.S.. You know, it's a rare disease, orphan population. We certainly know there are patients outside the U.S.. We'll probably file a CTA as well, but a lot of them are in the U.S..
They're followed here, we know the investigators, and their genotype. So our, you know, program there is a genotype-specific editor as well to correct the causative mutation in a number of these patients. And so they're all genotyped here as well. So we do plan to go to the U.S. We're not afraid of that, and I think that we'll, you know, we expect to get there. We expect Verve will get open as well. So I think this is, again, something that will get itself resolved over the next year or so, and, you know, and we'll have a path that is clear with the FDA.
Got it. Yeah. My next question was gonna be: Has the FDA figured out what their list is, or do we expect, as a field, there could be additional on top of what Intellia has just asked, other assays as they continue to get comfortable with this field? How do you think about that?
Yeah, it's a great question. I mean, I certainly won't speak for the FDA, and I've, I would've lost if I had gotten into the prognostication business on FDA decisions. But again, that's what I'm trying to illustrate the nuances here, that I think it's not clear to me that the list to get an IND open has changed at all in the last 12-18 months. I think that list has been static. It's a long list, but it's a doable list. The new wrinkle for Intellia, I think, is a new list. It is the, what do you need to do to open a phase II, III trial in the U.S. with gene editing? And, you know, the bar does go up.
So I think the study that Intellia has asked for, our team would say, is not a surprising study. It's a study we would've anticipated doing at some point. Maybe they're asking for it a little earlier than we might have normally guessed. Okay.
Yeah.
You know, so I think, you know, the next bar will be CRISPR and Vertex, right? In front of the FDA with an adcom for a gene editing approval in sickle cell disease, right? So we've never done that before, so, you know, we'll see how that goes. And then, you know, I'm pretty confident on that one. And then if Intellia comes with a filing in liver, that'll be yet another win. So every time you do a new gate, you know, for a certain kind of program, certain tissue, certain stage, I think you're gonna learn more about what the FDA is looking for. But if you step back, again, the field is advancing. I mean, all of these things are moving forward.
Yes, we need to lean on the ex-U.S. sometimes if the FDA is setting a higher bar, but we're getting there, and I think there will be a first editing approval in the U.S. shortly. Intellia is obviously going to be doing late-stage development here soon, and then Verve and us doing early-stage development with next-gen technology. So I think it's all, if you step back, I think the trend lines are actually quite positive.
Yeah. Got it. Okay. And so you, you've brought up 301, which is your, your asset for GSD Ia, very rare disease. It sounds like you have identified some patients or you, you've started some sort of patient-finding work in advance of a trial. You know, what would that trial design look like, and what would be the key endpoints that you would read out and that investors should be looking for?
Yeah. So, GSD Ia, BEAM-301, is our other liver program. You know, really high amenity population. So this is a rare disease where you have a mutation in the enzyme that converts glycogen, which is how your liver stores energy, back into glucose, which circulates in the body and gives all your cells the energy they need. And so the reason you need that is you need it to fast, right? So we're not always eating. You know, when we're not eating, we're actually relying on the glycogen in our livers to stay alive and to maintain that homeostasis of glucose levels. And so in these patients, they can't do that. And so basically, the glycogen just gets stuck in the liver, and you have to basically maintain continuously your blood levels of glucose.
Those are always crashing because you're using them, and so then you have to spike it back up by consuming something. Usually, it's a cornstarch. It's kind of a slow-digested thing, but that only buys you two to three hours, so then you have to do it again. And you're basically continuously spiking your glucose levels to try to stay up, and keep ahead of it. That includes overnight, so you can't sleep through the night. So literally, you have to wake yourself up every couple of hours, take this, and then go back to sleep, and set your alarm, and try to wake up again.
It's a terrifying disease because if you do all that perfectly, you can live a normal life, but you always are in fear that if you were to miss—sleep through your alarm or something like that, you can go into hypoglycemic shock, and it can be fatal. So you talk to parents, you know, of these kids who have, you know, themselves not slept through the night in 14 years. I mean, it's just unbelievable. So again, in this case, unlike Alpha-1, where effectively the entire population has the same mutation, in GSD, it's—there are multiple mutations, but our drug, BEAM-301, goes after the most common mutation and the most severe, so it's called R83C.
Once again, it is a single letter spelling in the gene that is correctable with a single letter change by the base editor. And so BEAM- 301 can do that. It's a, you know, very low bar for editing, even a little lower than Alpha-1, to correct this. We've shown that in mouse models. You know, in these mouse models, you have the mutant mouse, it gets born, it literally cannot survive multiple days without glucose supplementation and therapy, whereas with one treatment, with BEAM- 301, it has a normal lifespan, so normal glucose control, and normal metabolism. So we think this is, you know, also a very promising therapy.
So in this case, to your question about the phase I trial, again, we should get a pretty good read fairly quickly on this. Not so much the way Alpha-1 is with a blood-based biomarker, but in this case, you do a glucose challenge. So patients will be, you know, under close scrutiny in a hospital setting, and you basically will stop taking the cornstarch, you know, allow yourself to try to start to fast, and then see what happens. And if our editing has been successful, we should see, you know, normalization and improvement of the ability to fast and to have longer time without needing to intervene with a, you know, cornstarch sort of diet.
So, so that also will be something where in the phase I trial, we'll be dose escalating, to try to get to that safe and effective range of, of dose, and we will know at the end of that phase I trial, if we have something that looks like it's disease-modifying.
Great. I'm looking forward to both of those entering the clinic next year.
Me too.
So, we've talked a little bit about Verve. They have some data upcoming for their asset, VERVE- 101, in the fourth quarter. And you have the option, through your partnership with them, to opt in on that asset. I believe it's as the last patient is dosed in the phase I. If you're able to say, has that opt-in period been triggered? If-
Yep. Yeah, so Verve, our partners, and we've been partnered for many years now, you know, really, you know, visionary company, to go after cholesterol pathways-
Mm-hmm
And try to address cardiovascular disease, which is the biggest killer still, in the country, and in the world. So in that case, they're editing PCSK9 with their lead program, VERVE-101. There's another couple of targets in the cardiovascular space that they're working on with us. One is ANGPTL3, which is the second program, and then there's a third undisclosed target as well. In each case, we have an opt-in right at the end of Phase I to a share of U.S. costs and profits. You know, we had originally done this deal because although the editing strategy in these targets was fairly straightforward and obvious to try, the development pathway really required cardiovascular expertise.
You know, that wasn't something that we had or we felt that we would build, and Verve really was consolidating that with Sek and the entire team over there. So, that was sort of the genesis of the deal. So, the quick answer to your question is no, we are not at the opt-in point yet. So as you noted, it's really at the end of phase I. So although there's a first data set coming, you know, it's just the preliminary data set. There's, you know, dose sort of confirmation cohorts and things like that in the phase I that have to complete. So, you know, we really haven't thought too much about the opt-in decision because I think it's not here yet.
But we're certainly excited to see the data along with everyone else, and see how that looks. And then over time, you know, certainly not this year, maybe it's next year, we'll see about the timing exactly. We'll have a better insight into that data set, what the development pathway would look like, and then what that opt-in decision will look like for Beam.
Okay. What would you say the bar is for, for PCSK9 knockdown and, and for LDL-C reduction for base editing therapy? How should we be thinking about that compared to, say, a wouldn't inclisiran show?
Yeah, it's a great, it's a great question that I will not answer. So I think mostly I would defer to Verve. They know that space way better than we do. So I wouldn't speculate. Although I will note that, Amy Simon, our Chief Medical Officer, came from Alnylam for 10 years. She actually did the porphyria drug, Givlaari, from discovery all the way through approval. Before that, she actually ran the phase I for inclisiran at Alnylam. And so we actually know this space a little bit now, and we're, again, quite excited about it. So no, I would defer to Verve to sort of decide about how to answer that kind of a question.
What I would say is, I think we're quite convinced in the kind of the general thesis behind Verve's approach, which is, you know, the, these are situations where you're trying to prevent a very serious outcome at some point in the future for some number of patients, right? So it's really a prevention kind of intervention. And we're asking these patients right now to take chronic therapies for life just to prevent that, right? So you're taking a statin pill, many people are probably on that. Now, maybe you're going to take an RNAi every six months or 12 months. You're still taking something for your entire life to prevent something that may or may not happen, and you feel fine, right? So as we know, there's a huge challenge with adherence.
You know, patients, they don't feel like they need therapy, so why would they pay attention to these things? There's also a lot of patients who aren't controlled despite those therapies, right? They still have high cholesterol. And so for both of those reasons, I think there is real need for more therapy, actually. And in fact, a one-time therapy where, you know, you have to kind of pay attention, "Okay, doc, you know, I'm ready. Let's do it," and then you get the infusion, and then in theory, you will get a lifelong benefit and protection after that. I think that is a really important paradigm that could be game-changing in this space, and it actually applies to cardiovascular disease and beyond.
I think there are a lot of these sort of more general common diseases where we can think about a chronic therapy for life, but the bar there is high on safety, on adherence to have the effects you want. And a one-time therapy to modify a risk factor that is known in patients or in people to genetically protect them, you know, could be a, you know, a very powerful, different approach to treating some of these, you know, really serious common disorders. So, we're, you know, big believers in the, in the Verve thesis there, and in fact, there are other common diseases that we are looking at that I think, you know, the same paradigm could really apply.
Great. All right, well, we'll look forward to that data. Before I move on to your ex vivo pipeline, you know, what's the next steps for in vivo, for Beam? You know, how should we think about where you're going to go next? You have two liver assets. Should we start thinking about other tissues? Should we think about more liver assets? And we can talk about Beam ESCAPE in a little bit, but, for sickle cell disease specifically, but, yeah, outside of that as well.
Yeah, absolutely. So I think in vivo, you know, I believe our Beam will be an ex vivo and in vivo company for a long time. But there's no question that when possible, if you can do it in vivo, you'd like to, right? I mean, it is a lot easier. It's simpler to manufacture. The cost of goods is much lower. So we love in vivo. We've been building LNP and mRNA capabilities from the very beginning, and now, of course, we're there. And this really speaks to the beauty of what we're building. You know, this is a platform company, right? So we build these technologies, and as a reminder, you know, this is the elegance of CRISPR technology and base editing, of course, as well. Change the guide RNA only, and you have an entirely new medicine.
And yet the editor, the lipid nanoparticle, the regulatory package, the off-target package is identical. We may not even need to run acute tox again and again at some point because the FDA will say, "I've seen this before. It's the same thing every time." The fact that you've changed some letters on the guide RNA is not going to change the outcome there. So the leverage we get from the investment we've made so far is going to start to really pay off in this next phase. And so, you know, obviously, a lot of work to get to the first one and a lot of learning, and then you get to the second one. Numbers three, four, five, six become easier and easier and become really plug and play. And that is really exciting to me. I can't wait for that phase.
So we're really looking forward to that. So in liver, we're getting there now. And so I think we certainly have the ability now to print out a whole lot of different drug candidates. The next ones that you'll see, we actually have some partnered assets. So we've not yet partnered anything in our core pipeline. That's a real strength of the company. We retain all the value and control there. Of course, we may do so in the future, but that's been a deliberate strategy. Instead, we've done partnerships in what I call the white space, so targets we weren't working on. And so we did a big deal with Apellis-
Mm-hmm.
I n the complement pathway, you know, really taking advantage of their visionary approach to complement space. There are multiple organs in view there, but liver is one of them. So that's obviously low-hanging fruit, so there's programs moving forward there with them, which we're quite excited about. We then did a deal with Pfizer, so that was $300 million upfront, and then also multi-organ scope, but liver included. And again, that's a low-hanging fruit. So that liver program with Pfizer is also moving along nicely, and we're quite excited about it. So I think the next things probably that are in our liver pipeline would come from there, you know, some of the partnered assets in the liver, which will start to move forward.
When you'll hear about them and which targets they are, will obviously be somewhat up to the partner. But, but in each alliance, we have the ability to opt in again to a U.S. cost profit split, on any one asset. And so obviously, the liver programs being the low-hanging fruit, coming along more quickly, those, those would be, you know, likely opt-ins for us, potentially. After that, we have other programs. We have a really interesting program targeting hepatitis B, which takes, again, advantage of a base editing, where you have this, you know, chronic smoldering infection with the hepatitis B that can't be cured. And it's because of resident genetic elements that are stuck in the liver.
We can potentially silence those with base editing, and it is by definition a multiplex edit, 'cause these sequences are all over your genome, so you don't want to be cutting, but you'd rather use a base editor to silence. And we've shown some really nice data on that so far. So that's moving along. There are lots of other targets, both rare diseases and common diseases as I said, that we're interested about in the liver. And then finally, as you noted, I think that LNP technology can go beyond the liver as well, and we have a lot of work ongoing for that. We've shown some data already for LNPs targeting blood cells. That could be interesting in the sickle space, as well as other hematology disorders. So that's a very active area of research for us.
We have some evidence of delivering LNPs to T cells, which again, could be interesting for our immunology platform. You know, other organs are also of interest. So I think the LNP, mRNA field is definitely going to grow, and we're going to follow it and try to innovate there, not even just in the liver.
Great, looking forward to it. So let's move on to the ex vivo, and maybe let's start with your allogeneic CAR-T-
Mm-hmm.
Pipeline. You just dosed your first patient yesterday for 201. Can you just give us a background on the edits that are in 201, and, you know, I think it's a T-ALL that you're targeting there, yeah?
Yeah. So we're very excited. We actually dosed in August, but sort of announced it this week.
Mm-hmm.
So this is our first CAR-T product. And in cell therapy, we're really taking advantage of the fact that base editors can make really as many edits as you want simultaneously in a cell. And, you know, the editing field in CAR-Ts has started with sort of one edit at a time, maybe they're up to two edits now, and that's very exciting. But I think our view of the field is very clearly that you are going to need more and more edits to build higher and higher levels of engineering into your CAR-Ts. We'd like to make them allogeneic. We want to avoid the tumor microenvironment, we want to avoid exhaustion, we want to... all these treat solid tumors. There's so many different things we want to do, it's going to take a lot of edits.
The problem with nuclease is, again, the gen one technologies, is you make those double-stranded breaks at the same time in multiple locations, the cell doesn't know how to put the pieces back together again in the right order. And so you get these translocations, which are basically chromosomal rearrangements. You also start to get cell viability hits because the damage to the chromosomes is lighting up all these damage pathways, and the cell starts to arrest and even die. So one or two edits is probably fine, three edits start to be really tough, anything above that gets really difficult. So our differentiation in this space is primarily in the world of many edits. But the good news for us is I think that's where the field is going, okay? So BEAM-201 is our first version of this.
It is a quad-edited cell. To our knowledge, it is the first four-edited therapeutic in clinical development in the world. So this is taking four different edits. We edit CD52 to prevent graft-versus-host disease. We edit PD-1, which gives us more efficacy. We edit CD52, which allows us to do similar to allogeneic, and we use Campath to deplete the host immune system so that it won't reject our cells. That lets us use an allogeneic cell source, which is much more scalable than autologous. And finally, we edit CD7, which is the target of the CAR-T. And so we're kind of going after these T cell cancers, which have CD7 on them. The problem is our CAR-Ts are also T cells, so they also have CD7.
So if you don't knock that out, the T cells will attack each other before they get into the patient. So you have to, you have to knock that out so that you avoid what's called fratricidal killing.
Mm-hmm.
So these are all edits that people have done or thought about before, but no one's ever been able to put them all into one package at the same time, and that's what we can do with base editing. So that program is very exciting. This is a population of very severe unmet need. You know, the B-cell ALL has really been transformed by CAR-T therapy to CD19, but the T-cell population has been overlooked for some of the reasons I've mentioned. We just haven't had the technology to do it yet. We now do. So that's a very exciting program. The future of cell therapy for us, of course, you know, taking advantage of that is, is coming. Importantly, though, we, we think that we need to sort of solve some biology first. The, the editing is, is ready to go.
We can make as many edits as we want in T cells. But we really are committed to allogeneic in cancer. I think that's really critical. Autologous is just too, too difficult in this setting. And so we're doing the work actually to say: What are the edits you need to make? That Campath CD52 edit that Allogene uses and that we're using for BEAM-201, I think is great in that setting because we're going to go to transplant.
Mm-hmm.
You'll get a new immune system. We think it is not going to be scalable for the broader population. So that's work we're doing now to try to generate a next-gen allo platform, knowing which edits to make. Our guess is we're in the kind of four to six edit range to get to the kind of allo platform that we want to get to. That's work that's ongoing, and if we can get there, then we would come back and say, "Okay, we've got this now, new platform, potential for many cell therapies and allogeneic products in the future." That's work that's now ongoing.
This is work on the biology to, I guess, increase cell persistence, immune evasion, like those types of goals?
Exactly right.
Okay.
Exactly right.
And so I think you'd said we might get an update on where you stand there sometime this year. Is that still, your expectation?
Yeah, we will. I mean, I think just given the movement guidance, we will give an update on that, this year. I think it is going well. We're excited about the future of this. It's of course, a grand challenge in biology to create, you know, truly allogeneic cells. But at the same time, I feel confident, given the tools we have, that we will be able to create products that are more allogeneic than what anyone else is capable of doing, and that could be a real game changer for patients.
Yeah. Looking forward to hear more about that later this year. So okay, in our last 10 minutes or so, let's turn to your sickle cell disease program. So BEAM-101, you know, maybe a little bit delayed versus what you had hoped early in the year. Can you just give us an overview of where you are now, some of the protocol changes you've made to help accelerate the trial, and what can we expect throughout the rest of this year?
Yeah. Sickle is obviously a huge priority for us as well. BEAM-101 is our lead asset. In this case, we are using base editing to install a single point mutation change in the on/off switch of fetal hemoglobin. Others are doing fetal hemoglobin-raising strategies as well. The elegance of this is that it will both protect the cells from sickle cell disease because they no longer. The sickle protein will not polymerize, causing these crises and these deformed cell shapes, but also you can treat beta thalassemia by just raising hemoglobin levels in general. What's nice about our approach is because the base editing, because we don't cut, we can go straight to that gene. We don't need to worry about disrupting it.
We just install these sort of single letter changes that patients actually have, you know, in the world, right, that we know raises fetal hemoglobin. So that's a, you know, clinically, genetically validated approach. So BEAM-101 is using the same sort of standardized approach to transplant, where we take the cells out of the body, we edit them, we then give busulfan, which is a chemotherapeutic, to try to clear away the old cells, and then bring in the new edited cells in a transplant, let them grow out. This is a long process. It takes at least six months, sometimes more, to get all of this done. So we were due to get a patient dosed around the middle of this year, and obviously, we were very excited about that.
Unfortunately, we had a patient withdraw from the trial, and it was actually just due to totally personal reasons, so this was an unfortunate event. We still hope maybe we can treat that patient in the future. We'll see. It was not related to the drug, not related to their disease even, not related to seeking therapy. So that was unfortunate. You know, nothing to say about it other than that. So we are delayed as a result. But, you know, the good news, the team has really rallied, and the investigators have as well, 'cause there's so much enthusiasm for this, for this approach.
While we had already enrolled a couple more patients, right around the spring, which was always planned to be patients two and three, we've gone ahead and basically, you know, for the last year, we've been amending the protocol to make it more flexible.
Mm-hmm.
So at this point, what we have the ability to do is basically do as many patients as we want in parallel. So that long six-month process, we can now just start it in parallel on as many patients as we want, and that really opens up the critical path for the trial. And in fact, it's been so successful, we've now got, you know, a handful of patients already on trial, more than needed for the initial sentinel cohort-
Mm-hmm.
All moving through those first steps of the process, the screening, transfusions, mobilization, then manufacturing. So, that's great news. And so the reality is actually, when we look at the timelines, you know, the latter part of the trial isn't actually delayed relative to our previous estimates. It's more that the first dose milestone, obviously, is gonna come later. Timing for that, I mean, we'll see how it goes with these first patients, but if you think about having, you know, enrolled a couple of patients in kind of the May timeline, you know, add six months for the first patient. So it's around the end of the year would be a first patient, and then we still have to go... The first three transplants are in order, serially. That's the key for the FDA.
So that first patient, maybe it's around the end of the year, then you know, second patient, then third patient, probably into 2024. But the key point to our trial design now is we'll be working on patients four, five, six, seven already.
Mm-hmm.
And so all we have to do is wait through that sort of one, two, three transplant process, and then you can transplant as many patients as you want. So the reality is the dosing, although critical, of course, is not on the critical path for the trial. The critical path for the trial at this point is enrollment, and just moving all the patients through, preparing their doses, and getting ready. So I think 2024 is gonna be a pretty active year for that trial.
And so, yes, although the first patient is coming later than we had hoped, the overall momentum of the trial is really high, and I think 2024, you know, when we've guided, we will have a data update on multiple patients, should be a pretty rich update and put us in position with a lot of momentum to really get this to filing. Because ultimately, this BEACON has been designed as a registrational trial. We think that's possible still. We'll, of course, learn a lot from the CRISPR Vertex ad board, but we have a fair idea already about what the data set is that's required, and BEACON has been designed to produce that.
And so your critical path is basically enroll BEACON, treat all those patients, follow them for a certain amount of time, which we will know from the Vertex and CRISPR experience, and then file.
Oh, great. So, you brought up the Ad Com. I think yesterday it was announced that October 31st is the date. You know, what other than, you know, the obvious ones of what the requirements will be for you guys, you know, what topics are you interested in and paying attention to at the Ad Com?
Yeah, it's a great question. So we are pretty confident about this. I mean, you know, we'll see. The FDA can always surprise you, but I think, I expect this will be approved. Our base case has always been that this product would get approved. I think Bluebird will also get approved, for what it's worth. We think that, that has benefit for patients as well. So that's, that's sort of our expectation. I kind of am not surprised Bluebird didn't get an Ad Com. They've already been there for beta thal. I'm not surprised CRISPR did get an Ad Com. It's the first gene-editing product. I'm sure the FDA wants to sort of have an open discussion about it.
Mm-hmm.
It all kind of seems standard to me. We will be more focused on what's in the data set, okay? So obviously, they've shown a lot of great data on vaso-occlusive crisis reduction. That's, of course, the acute pain crises that sends the patients to the hospital. And we wanna take patients from having frequent vaso-occlusive crises down to zero, right? That's the goal. And Bluebird and CRISPR have both shown that's achievable. We certainly will expect to try to achieve the same. That said, you know, we wanna go deeper, right? So BEAM-101 has a higher level of editing than those other cell products, 90%-95%. A higher level of F upregulation because we control the genetic sequence outcome, right?
We know exactly what the allele is that we will create, and then we've been able to tune it so that allele is as productive as possible, and all the cells get the same allele. That's not the case with nuclease editing. With nuclease editing, you're effectively making a random allele change in every cell. So you can disrupt, you know, for instance, BCL11A binding to the on/off switch of fetal hemoglobin, but you're doing so with a random genetic change every time. Those changes are not always gonna be equally productive. So you're gonna get some cells that have really strong, you know, upregulation, but some cells that may not have any upregulation. So you get a wide variability. This has been shown in some recent research. With base editing, we get the same biological response in every cell. It's very consistent, very high.
So we're up around 60%-65% F, whereas the, you know, preclinical data for CRISPR Vertex was around 35% F, and that represents a lower number because they're getting this wider range of outcomes. So that's a really important point. So we have an expectation that that BEAM-101 may be a deeper cure, potentially, and so we're gonna look for that. So obviously, what happens to that vaso-occlusive crisis reduction rate? I think it actually eased off of a 100% reduction recently, maybe we're in the 94% range. You know, more data is still coming in, so does that continue to drop? Do we have a chance to show, you know, better protection there? That would be very interesting, but also all sorts of other endpoints. We're gonna look at hemolysis.
You know, have you really normalized the signs of that marrow hemolyzing, okay? Signs of inflammation, you know, pain beyond just vaso-occlusive crises. You know, those are just the pain that's sent to the hospital. There's actually chronic pain for these patients. And then, you know, you know, blood function. Longer term, of course, we're gonna look at things like organ damage, right? It actually isn't a vaso-occlusive crisis that kills you. It's organ damage. And so I think there's a lot of room here to go farther with a cure. We will be looking for evidence from the AdCom discussion of where we can show differentiation on some of those points, 'cause we do expect our cell product will have potential benefits for patients.
How do you see that playing out in a commercial setting? Let's say Exa-cel and Bluebird Bio, Lovo-cel, both get approved this year. We have Editas, who's running a trial as well, and then yourselves.
Yep.
That's potentially four on the market. How do you think about that?
Yeah, I mean, this is a great, you know, example of a drug category. I mean, these drugs are working, and they're gonna help patients, and there's never been a drug category I can remember that had only one entrant, and then it was over. You know, you get excited about the first, but then you end up with several people coming in, and may the best win, and that's good for patients, too. So, you know, we're gonna come in with what we hope is a best-in-class option. So our goal will be to generate a majority, you know, stake in that population. Obviously, the more differentiation we can show that's tangible, the better we can drive that share up. And we do think we stack up well against each of those competitors. We'll obviously come in later.
We'll have a, you know, 3+ year, you know, whatever it is, gap. But I think this market's gonna evolve a little slowly, too. It's gonna sort of have to establish a lot of operational infrastructure, reimbursement. I mean, this is not gonna be an S-curve launch, where it's everybody's cured overnight. It's gonna be more of a steady build. So I think we've got plenty of time to get in there. And, of course, we're also trying to set the stage, not just for BEAM-101, but for future versions. So you mentioned before ESCAPE technology. So this is our next-gen version for sickle, where we add an extra edit, we modify the c-Kit. This will allow us to get rid of the chemo in that product profile.
So now we can bring in an antibody, okay, which would be very benign, to clear space in the marrow, bring in our edited cells, and help them grow through in vivo selection over time in the body of the patient. So that could be a next-gen version, coming, which we call ESCAPE, which could be a total game changer then, you know, very compelling product profile. So we're certainly fighting for share in the first wave of this market with BEAM-101. We think we'll get there, and we can do that. At the same time, we're also really thinking about that next-gen version, which we think will have very significant, competitive advantage over the entire field. Base editing. If you were to use... need that control the base editing provides to make that specific change to enable something like that.
So it's a sort of mind-blowing idea, but one that, you know, I've been incredibly excited about since the team thought it up, several years ago, and we're driving that one really fast as well. So this is really part of a long-term life cycle strategy in sickle, where our goal is to best in class.
Yeah, looking forward to that next update on ESCAPE. We're nearing the end of our time, but maybe we could just end with, you know, could you recap your cash runway, how far that gets in, and what are the upcoming catalysts over the next 12 months that we can all look forward to?
Yeah, great. So, so we've got, I think it was Q1 updates. We're obviously very well-financed. And it's. We've said cash is, you know, at least into 2025. I can tell you that's somewhat conservative guidance. So we've got plenty of runway, and, and that's on an all success burn, where we're, we're doing everything we can possibly think of. So I think we've got plenty of runway here, and, and significantly, as we've talked about, that really carries us through all of, you know, the data points that are exciting that we've just talked about. So obviously, you know, BEAM-101 , you know, getting those patient doses, getting BEACON enrolled, and data next year on multiple patients, that should be very significant. BEAM-201, enrolling more patients here, start continuing on that trial.
You know, that could be data next year. We'll give more clarity on that at some point around the end of the year. And then the liver programs, getting those filed in, you know, Q1, first half of next year for 302 and 301, setting up that, you know, equally, hopefully fast generation of data over the course into 2025. So, in addition, preclinical updates, obviously, ESCAPE, you know, how that's moving forward, the Allo platform for CAR-T, next-gen liver products. So an awful lot is coming behind as well. But, of course, obviously, the momentum and execution on those four lead programs to generate data in 2024 and 2025 is probably the key theme.
Yeah, looking forward to it. Well, thank you so much. It's, it's been a pleasure, John.
Thank you very much.