Okay, can you hear me? All right. Welcome, everybody, and thank you. Great to be here today, and we're having a wonderful day here at the Cowen Conference. I'm excited to tell you a little bit about Beam Therapeutics and our efforts to create a new class of precision genetic medicines through an exciting technology called base editing. I'm going to walk through an abbreviated presentation just to give you a quick introduction to maybe the big picture of Beam. I know we'll do some Q&A to follow, and look forward to the discussion. As always, just a reminder that we will be making some forward-looking statements today. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases.
We think that this really builds around this incredible potential within gene editing for one-time, potentially curative therapies for a wide range of very serious diseases. This will begin targeting rare diseases, of course, with a strong genetic underpinning. Over time, we'll think about treating more common disorders as well as the technology is de-risked. Excitingly, this is a platform. This is a true platform technology. What that means is it's new, it's novel. As we reduce to practice each new element of the system, it should work predictably in the future for other applications. That means that once we've seen it work once in a given tissue, if we go to that tissue again with a new program, we have the reason to expect it will work again. What that gives you is leverage, right?
We invest a lot upfront to getting the technology reduced to practice, but then you can create many programs over and over again targeting different kinds of diseases with very minimal incremental investment. Boiling all that down, for me, that means can we treat many more patients, which goes back to our mission, okay? That is what we are going to try to do at Beam. One of the reasons we are so excited about what we are building at Beam is around the technology. Gene editing has really come into its own in the last few years. It begins with this first-generation set of technologies which are called nucleases, okay? What nucleases do, and CRISPR is, of course, the most famous one, but there are others as well, is they are able to precisely target one spot within the genome.
If you think about it, every one of your cells has 3 billion letters in its genetic code. Every one of those letters is an A, G, C, or a T. Somehow, we want to be able to find one location out of all of those letters. That is hard. It turns out that this first- generation of tools can do exactly that. They achieve what I think of as precise targeting within the genome. CRISPR is by far the easiest one to use and to reprogram and to use again and again, and that's why it has become the dominant approach. The challenge is once you get to that target site, there's only one kind of edit you can make, and that's a double-stranded break or a cut, okay?
What happens is when the cell puts that back together again, it does so, but it makes mistakes at random. You basically scramble the gene sequence at that target site, and that will basically destroy the function of the gene. You'll turn that gene off. It's a good way to turn genes off, not such a good way to repair or reprogram genes, okay? That was the foundation for the development of this next-generation technology that Beam uses called base editing. With base editing, we want to build on that same precision targeting that we get from the first- generation of tools, in this case, again, using CRISPR to find a single spot in your genome. Once we're there, we want to make a much more controlled change.
We want to make a single-letter change using chemistry, literally an enzyme that will modify one letter to another, in this case, showing an A to a G change, without losing control of the sequence. There is no randomization that happens. The chromosome stays intact. It certainly is going to be more precise, potentially safer, but also we have control and predictability of the editing outcome. I know exactly what will happen. Now we can use this tool for many more kinds of applications, not just knocking things out, but turning them on, repairing their function, reprogramming their activity, right? Once you can recode deliberately what those letters spell out, you can do a lot of therapeutic things to the genome. I am quite excited about where Beam stands today.
I want to make a case that Beam has an emerging leadership position in the field of gene editing, and it's built on these pillars, which have really come together in recent months and years. First, of course, is that base editing platform. It's a proprietary technology. Beam has the core licenses. We've done all the core work to develop this and reduce it to practice. Now, of course, we've moved it to the clinic, so it is clinically validated, and we've wrapped around it manufacturing capabilities, which, of course, in these complex medicines are so critical. I'll say more about this in a moment. Second, if you have that engine, where do you point it? Are we choosing the right diseases? Do we have real commercial value that you can look to potentially emerge from our pipeline? I believe we do.
We have two very important high-value franchises led by assets that we think have clear first-in-class potential. Third, how are we executing? Okay, this is novel territory. Are they moving through the regulatory agencies swiftly? Are we opening sites? Are we getting patients enrolled? I'm happy to say we see very clear signs of rapid execution. Finally, what's next? We have a lot of catalysts coming. We're in a catalyst-rich period for the company now. I'll talk you through what we can expect. Behind all of that, of course, is capitalization. We have $850 million as of the end of the year that's expected to fund operations into 2027 through all those catalysts and more. Let me double-click and just give you a little bit more information on each one of these areas.
First, in our platform, as I said, it starts with the base editing technology, comes out of the labs of David Liu at Harvard, specifically to develop the base editors that we use, again, clinically validated at this point. You have to deliver that to the body in certain ways, okay? One way we deliver that is by taking cells out of the body, editing them, and putting them back in. That's called ex vivo. We have shown that that works. We have clinical proof of concept for that as well. That was the sickle data that we shared in December. The other way to deliver it is to deliver it directly into the body. That's in vivo using a lipid nanoparticle, okay? Similar construct to your COVID vaccine, but this time we're going to infuse it to your bloodstream.
It'll go to the liver and edit the liver, okay? There may be other places that LNPs can go as well, and we're working on that. Obviously, we have not generated data yet ourselves. Others have. We expect that soon. Around that, we've put these capabilities to really develop these into medicines. That starts with manufacturing. Again, these are hard to make. GMP manufacturing is done at our own facility. This is in North Carolina. We've already done over 100 GMP batches and isolations at that facility. It continues to grow by leaps and bounds every year. It also is commercial grade. Today, we're doing clinical, but ultimately, it can transition to commercial. Regulatory, we have seven different approvals around the world in five different countries. We clearly are understanding what regulators are looking for. They're satisfied with the package we've put together.
That's continuing to be a success story. Clinically, we have a broad footprint at this point, over 30 clinical sites, over 20 patients treated, and more every day. Very, very excited about the development engine that we've been able to build here. These two franchises. We've done many different things at Beam since its inception. We have a lot of different programs that look quite promising, and we continue to look for homes for those programs if they didn't quite fit in our focus portfolio. The company that we're building for the long term, we believe, is going to be in these two areas, hematology and genetic diseases starting in the liver. With hematology, we're really focused initially on sickle cell disease. We showed data for our BEAM-101 program, our lead program, which we think has clear best-in-class potential.
We showed that data at ASH. I would say the level of differentiation that we saw relative to what had been reported previously by others in the field was on the high side of expectations for us. Very exciting evidence of advantages in the hematology profile, the blood profile we were creating, as a reminder, getting to that 60/40 ratio of good hemoglobin to bad hemoglobin, resolving anemia, but also few mobilization cycles to get the dose ready, rapid time to engraftment, which means fewer days in the hospital. Really exciting data set that continues to move forward quickly. There is a clear path to BLA filing with the FDA that has been a precedent set by others. We are not done there. We have a lifecycle strategy to bring forward new generation versions of this.
Most important is called Escape, where we would like to do all of that that I just described with BEAM-101, but take the chemotherapy out of the transplant process to get those new cells back in. That is something we're exploring. Ultimately, we'd also like to move the entire sickle editing process in vivo, where it's just an infusion. We can't do that yet, but it's an area of active research as well. Finally, if all that works, it's a real platform where, again, we can start to do many other things in the blood using those same components, but just reprogramming the base editor to go to a different site in the genome, you get different medicines. A really sustainable business there. Liver, same story. Lead program is BEAM-302 for alpha-1 antitrypsin deficiency, a huge disease.
100,000 patients in the U.S. have the ZZ genotype, this mutation that we literally will try to correct. We'll try to recode the one-letter misspelling in these patients back to normal. We think BEAM-302 has a clear best-in-class potential profile as a one-time therapy that can address both lung and liver manifestations of the disease in a single medicine. Where that editor would be under normal gene regulation, that's the on-off switch of the gene because we're fixing it in its normal location in the genome. We're returning it back to normal. Obviously, very excited about that program. Talk more about that catalyst, which is coming up for first-in-human data.
If that works, obviously, it'd be exciting for AATD, but also we hope can serve as a platform for future liver-directed programs because, again, the delivery to the liver, the payload, all of that would be identical. You just reprogram it to go after a different part of the genome. You have an entirely new medicine. This platform approach, that flywheel, is getting built and quite hopeful that we'll be applying it in blood and liver, at least, if not other places in coming years to great effect. All right, rapid execution. This is, again, really good evidence that we are rapidly executing. On BEAM-101, the update here as of our latest annual report filing, we have achieved our adult enrollment target a=t this point in the BEACON trial. That enrolled very quickly. I think kudos to our team.
Also, I think you see a lot of enthusiasm in that enrollment progress from both investigators and patients for the profile we're showing. We've already enrolled also our first adolescent patients as we look to expand the potential label down into younger patients. With BEAM-302, enrollment is on track with that program. We have sites now active in four different countries, again, through regulators there. As a reminder, we are not in the U.S. yet with that program. Our plan all along has been to generate some data ex U.S. where patients generally don't have augmentation therapy. And we want a patient without augmentation therapy to know their baseline and then dose the drug and see what happens.
Once we've generated some data, we will come to the U.S. during phase I , and that data will give the patients confidence to discontinue augmentation therapy and then obviously move on to our trial. That is all sort of moving per plan. Second, our next in vivo program is BEAM-301, which is for glycogen storage disease. That is in the U.S. We filed that IND last year, and that was cleared over the summer. First site is now open. We're screening, and I'll tell you a little bit more about timing for dose there as well. Finally, back to blood, our next-gen version in sickle is called Escape. The programs were named in the fall. We have declared development candidates here, and we did indeed start our phase one enabling tox studies in December.
That's now moving through those preclinical studies rapidly as we speak. Moving really fast, which is great. What's ahead? As we look at the catalysts that are anticipated in the coming year, we have a lot of exciting things going on. First, of course, again, with BEAM-101 in the BEACON trial, we were guiding to dosing the 30th patient by around the middle of the year, okay? I think we said in January we had dosed 13 patients. We're clearly steadily dosing more patients every month with a somewhat accelerating pace, which is exactly what you'd expect. Given that we've now substantially enrolled certainly all the adult patients, you can imagine by the end of the year there will be an even higher number dosed. The reason we call out 30 is for the following reason.
When we think about a path to BLA, Vertex and CRISPR, the CASGEVY drug, that was approved by the FDA based on an efficacy set of 30 patients followed for about 15 months, okay? Base case, it would be reasonable to think a comparable data set would be expected of us. If we can dose to that 30th patient, that may start the clock, if you will, towards the time to when we would have a data set ready to write up and file with the FDA. We will work with the FDA. Maybe it's less than that. Maybe it's more than that. There's always a dialogue there. At least as a reasonable base case, that's a milestone to watch in the execution.
As I said, we are enrolling and dosing adolescent patients this year and expect that to be a part of the package we want to pull together. Of course, we will have updated data as well. We are likely to be most likely at EHA in the middle of this year. Obviously, we will make a determination about ASH as well. There, in terms of what we would like to see, I think it is primarily just confirmatory picture across a larger number of patients. We were very pleased with the profile we saw at ASH. That was seven patients. We have already dosed, as I said, 13. You can expect the number in the teens, certainly, by EHA. Do we continue to see the same hematology profile, the same advantages in terms of cell collection, time to engraftment, etc.? That is BEAM-101.
Finishing up on hematology, then with Escape, the program there is moving through tox studies, as I said, and we are on track to initiate a phase I healthy volunteer study of the BEAM-103 conditioning antibody by year-end. That is a relatively efficient short trial. It is a single-dose trial. You are just getting a little bit of PK information on the antibody that you can then pair with your preclinical information to set up a patient experiment. Because with the patient experiment, we do not want to be searching around for the right dose. You want to go straight to that. Excited to see that move forward and, of course, continue to be very enthusiastic about a world where we can eliminate chemotherapy from transplant to deliver these kinds of genetic cures that would dramatically expand the addressable patient population within sickle cell disease and many other blood disorders.
On BEAM-302, on the liver side for alpha-1 antitrypsin deficiency, we are going to be presenting initial data across multiple cohorts in the first half of this year. Obviously, a highly anticipated data event for us. We are clearly in that first half now. What I have generally said to people is multiple cohorts means something like two to three, not through the whole dose escalation. It is an open-label trial. We think we expect that somewhere in the middle there, we will have a sense of how the drug is doing and that that will be a useful data set to share with, obviously, the investment community, but also with patients and physicians to help them understand what we are seeing, even though we will then, obviously, continue on with the trial. What will we be looking for, which I am sure will be a topic of conversation?
Certainly, safety and tolerability. It's a phase I study. These are LNPs, right? We are dose escalating. We would like to understand what is the tolerability of the LNP and then how that changes as we go up in dose. On the efficacy side, if you basically look at our preclinical data, you have a sense of the kinds of things we are hoping to see. Certainly, we would like to see total AAT go up. We think a lot about the thresholds that matter there, right? We have talked a lot about clinical genetics telling us that patients who have this disease are progressively losing lung function and liver function. They live in the 4-6 micromolar range for this important protein called alpha-1 antitrypsin deficiency or alpha-1 antitrypsin, excuse me.
If you do not have two copies of the mutation, you just have one, you are in that carrier state, right? You generally have AAT levels in the 10-20 range, okay? Clearly, if we can get patients from single digits into the double digits, then we have moved them out of that disease category where we would not expect them to have any more progressive disease. The threshold that I think the field generally aligns around is 11 micromolar. There is some regulatory precedent for that. There is nothing magical about the number 11, but I think it is illustrative of the kind of bar we would like to get to over time with this drug.
If we can do that, we, again, as I said before, have a drug that could be a one-time therapy that would permanently generate, hopefully, therapeutic levels of AAT and reduce the levels of the toxic protein that are building up in the body and causing a lot of chaos. That is because we are literally changing mutant genes into normal genes through gene editing. We really think that is an attractive target product profile, and we are excited, of course, to present that data and walk you through it at some point, hopefully soon. Finally, BEAM-301 for glycogen storage disease 1a. Here we are, as I said, open in screening. This is a rare population, so a little slower to enroll, certainly, than an alpha-1, but we know where the patients are. We are getting the right sites open.
We continue to be on track to dose the first patients in that trial early this year. All right, in summary, this is the pipeline that I have basically just described for you. You can see here the hematology franchise across three different waves that I sort of gestured to. BEAM-101, of course, well in the lead. The second-generation version, which does almost exactly the same things as BEAM-101, but hopefully without chemotherapy, instead using an antibody for the transplant, and ultimately a vision to move all of that in vivo as well. The liver, again, the two programs that I have mentioned, alpha-1 and then glycogen storage disease, both now in the clinic.
I would say a number of liver programs behind that that we're excited about and that if we can see positive data from one or both of these early programs, based on that platform flywheel, it sets us up to then move those forward with relatively high confidence. We also have a number of collaborations ongoing. I would defer to our partner organizations to tell you more about those programs, but remain excited about some of what's happening there with the Apellis we just disclosed recently with the lead target of that collaboration targeting the FCRN neonatal FC receptor for autoimmune disorders and other conditions. A really elegant approach requiring the precision of base editing to get to the right therapeutic effect.
A very busy time at Beam and obviously a growing platform with increasing amounts, I think, of clinical validation and science behind what we're doing and a lot of excitement about, I think, a leading position that we can really build here with Beam over the near and long term. I'll just close again with where I started, which is patients. These are truly the heart of our vision. The more you get to know people in these communities, the more you realize how devastating these illnesses are, both for the person themselves and for the families and communities that they live in and how desperately they are looking for better options, not just that are chronic medicines, but are truly one-time transformative therapies that can free them from a life of disease that they've lived to date.
That remains our mission, and we remain optimistic we can make a lot of difference for these kinds of patients.
Great. Thank you, John. I'm Senior Analyst Ritu Baral. I'm going to be doing the guided Q&A, which, as I mentioned before, is not monopolized Q&A. Please feel free to raise your hand and get your questions in. I'm going to start actually with Escape. John, can you walk us through the actual mechanism? You mentioned it's an antibody. What are the receptors involved in that depletion that should eliminate the need?
Yep. Yeah, great question. A little deeper here. When we do an ex vivo transplant, we take the cells out of the body, the blood stem cells, we edit them, we correct them for their sickle cell disease. Before we put them back in, we have to get rid of the rest of the old cells, okay? Otherwise, there will be no room for the new edited cells. We do that traditionally with chemotherapy. This is a 60-year-old technique that we are stuck with. It works. It will eliminate all of the cells in the body, and then our new cells will quickly refill the body. You'll have a new blood system, but it's very toxic. Tolerability is difficult. You become sterile for the most part. It has real issues and real risks for the patients, okay?
Because of that, only the most severe patients who are sickest from their disease are good candidates for that therapy because they're so sick that that is a good trade. We estimate that in sickle cell disease, that's about 10% of the patient population, right? Out of 100,000 patients, that's 10,000 people who are desperately waiting for BEAM-101 and other products like it. That's great.
They're also the most frail to be experiencing chemotherapy-like side effects.
That's true. That's right. It's no joke. They have had a lot of accumulated body damage and other things like that. That's absolutely.
You're whacking them with chemo.
That's absolutely right. That's true. There are actually a lot of patients who are actually in that sickest bucket, but they're actually so sick they're not eligible for the chemotherapy, right? They may have had a stroke. They may have some other issue with their body that means we just can't give the chemo. There's a lot of unmet need that we leave on the table if we're using chemo. That doesn't mean that there's not a great market for BEAM-101 and other products. Those patients need therapy. What Escape is designed to do is to expand that to more people. What we do here is we use an antibody. We would like to have something much more precise that targets just the blood stem cells and will deplete them, suppress them. We target a receptor called KIT with this antibody.
It's on all of your blood cells. It starves them of a growth factor, basically. They can't survive without that. They can't proliferate without that. If we do that, we ought to be able to selectively create space for our grafted new cells, but not have to get rid of all of your immune system and your platelets and everything else that's in your body at the same time. This works in animals. We've shown this working in mice and with monkey where we successfully edited cells, used only an antibody, not chemotherapy to create space, put the edited cells back in, and showed long-term engraftment where we saw a potentially transformative effect. We're trying to try to do that in people.
That begins with the antibody being developed with BEAM-103, but shortly thereafter, we'll be moving into patients as well. The way that it works, sorry to answer your final answer to your question, is we literally add a second edit. This is, again, using the power of base editing to make these very precise changes without making cuts where we add an edit that is literally on the receptor, the KIT receptor, such that the antibody can no longer bind the edited cells. If you think about what that means, it means that as we put the graft in, the antibody's suppressing and killing off old cells, but it will leave alone our graft. The graft will grow, and you're literally selecting for the graft at the expense of old disease cells.
That's only possible if you make such a subtle change that you're literally only changing one amino acid on the receptor of that protein, not knocking it out or changing its function in any way.
On your AAT program, for 302, have you started dosing patients?
Yes. AATD, first dose was last summer. We did announce that we'd completed our first cohort in an early November call, I believe. If you think about then the progress since then, where we came up with the guidance that we believe in the first half of this year we will be through that two to three cohorts' worth of patients where we can take a look at what's happening and then have a data set to share.
Is the target to present this at the Alpha-1 Foundation?
We have left open the door to exactly how we will do the disclosure. Certainly, we like medical meetings. Obviously, we did.
There's ATS too.
Yep. Yep. There are several options. I think the only caveat to that is this is an open-label data set. The biomarkers are going to be readily available. At some point, it may be a material amount of information. I think we have left the door open that we may just need to do a top-line kind of corporate update. If we do that, we certainly would then want to follow up at a medical meeting at some point. If the timing lines up, those medical meetings are available for us as well.
Based on your modeling, that first cohort, what levels of AAT or antitrypsin activity, which is a different question, right? Could you reach an important threshold with the low-dose cohort?
Yeah. What we're doing in this trial to start is there's going to be initially four dose cohorts between zero and 1 mg per kg is the range. That's comparable to what other LNP products have been exploring as well. There will be four cohorts basically selected across that range. The lowest and first cohort typically is going to be one where we do expect to see some biological activity, right? That's important ethically. You want to make sure there's some prospect of benefit for the patients. Usually, you're on the conservative and low end in terms of dose.
You know where you're at the threshold that allows.
Exactly. I think the goal would then usually be to go from there to higher dose levels, and hopefully, you're getting a dose response, and you're starting to see something converging towards that therapeutic threshold that we're aiming for. Our preclinical data, obviously, was designed so that we do expect to potentially be able to reach a therapeutic threshold within this dose range on a single dose, but that's, of course, what the human experiment has to show.
It depends on where these patients were at baseline. If they were at 5, 5 at baseline, and then they go to 11.
That is true. Yeah, patients generally, it's exactly right. Patients are generally in the four to six range, but there is variability, and also that range is already fairly wide. That is certainly something to take into consideration, yes.
Hypothetical question. If you're starting from like a 5 and you get patients to a halfway there, say to a 9, right? How long would you have to follow them before you would be able to start seeing actual clinical benefit, whether in lung function, on what measures, if these are patients with liver manifestations, what should we be looking for at what time point? Even if you're not reaching the 11.
No, no. It's a great question. I think that it almost perfectly illustrates why we ultimately do feel we need to get to those numbers. We could certainly show it. There are definitely patients who either maybe they're carriers, but they're on the low end. They're at that 9 level who don't have the disease, right? You can find that. To prove that, I think we would need to look at functional endpoints, right? You'd be looking in the lung for things like respiratory capacity or CT densitometry.
Is that an FVC issue?
Like that. You could also look at CT densitometry, which is how much lung destruction is happening, kind of like you do with osteoporosis. We think that's a good endpoint. In the liver, of course, you're looking for liver function over time. Those are longer endpoints, right? The beauty of the 11 threshold and kind of getting people into the double digits is now you can just rely on clinical genetics, right? We just rely on every we know fully that all the folks with progressive alpha-1 antitrypsin deficiency are in the single-digit mid-range because they have that ZZ genotype. The people who maybe carry one copy of the gene, they are in the 10-20 double digits range, and they don't have progressive disease. We know that already.
I think that that's almost a much faster and stronger argument, I think, for benefit is if we can just get you out of the disease category into something that looks much more like a normal person. That's where we'd like to get to. Obviously, within that range, the higher, the better. Pretty much once you're above that 11, you should have taken everyone out of the progressive disease state and should have had a transformative effect on their outcome.
Is that going to be a correlative analysis, or is it that's the threshold, I think, that augmentation therapy was approved on on an accelerated basis?
Yeah. That's where it comes from. That's exactly right.
Have you had FDA interactions where there's been clear buy-in to that approach?
It's too early to get the FDA lined on a registration pathway. I think the first step is hopefully generate an exciting data set and then bring that to them. I do think that this is a setting where that sort of conversation would make a lot of sense, right? The FDA likes it when you're on the fundamental mechanism of the disease and correcting it at that level. When you have lots of biomarkers, that should visibly point you towards the prospect of having really had a transformative outcome. I think that this disease, for both the lung and liver function, with the biomarkers that we would have access to, really lends itself to that.
Great. Question. Go ahead.
Redosing, any dose to effect? Is this something that's supported by your clinical data? We discussed this with the FDA.
For the webcast, the question was on redosing.
Great question. Can we redose to effect? The answer is likely yes. Certainly, our preclinical data shows that there has been at least one redosing experiment with Intellia in the clinic that did work. We will, at the very least, be redosing patients who got the very low doses so they can whatever the optimal biological dose, we would want to be able to give that to them. You are absolutely right. LNPs can be redosed. They can basically stack editing over time. As I said before, our preclinical data is designed so that we should have the ability, in theory, to get to that 11 therapeutic threshold with a single dose. There is no reason that multiple doses at some point could not be used if we needed to or if we wanted to go higher.
Yeah, we haven't disclosed the details of that, but I think that's safe to say we've done all the things and are doing all the things that would be needed to make sure that we have all the flexibility to develop the drug in the right ways, yes.
Great. John, thank you. Thanks, everyone, for joining.