Beam Therapeutics Inc. (BEAM) Earnings Call Transcript & Summary

Good afternoon. I'm Eric Joseph, senior biotech analyst with JPMorgan. Our next presenting company this afternoon is Beam Therapeutics, and it's my pleasure to introduce John Evans, CEO of the company, to take us through the story. There's a Q&A after the presentation. If you have a question, just raise your hand. We'll bring a mic over to you. And folks can submit questions as well via the online portal. So with that, John, thanks for joining us.

Thank you, Eric. So yes, so I'm John Evans, CEO of Beam, and very excited to be here today to tell you a little bit more about Beam Therapeutics and our vision for a new kind of precision genetic medicine using exciting technology called base editing. So as a reminder, I will be making forward-looking statements today. So Beam's vision is to provide lifelong cures for patients suffering from serious diseases. We see the real potential for onetime curative therapies in this industry. Of course, that uses gene editing. We'll begin targeting rare diseases. But over time, we see the ability to treat more common diseases as well. And importantly, this is a platform. So once we get it to start working for one disease, we can rapidly retarget the components to other genes, other diseases and help many more patients over time. And patients are very much on our mind. So patients like Branden -- and I want to tell his story quickly here. So Branden grew up with severe sickle cell disease. So in and out of the hospital continuously with pain crises. Had both of his hips replaced in 6th grade because of the damage caused by his sickle inflammation. By 17, he was having life-threatening acute chest syndrome attacks where the sickle cells are blocking blood flow to the lungs. And he missed his entire junior of high school because of that. So this is a good illustration of incredible burden of disease that patients with these kinds of conditions face. I'm happy to say that Branden was actually patient #1 on our BEACON trial for BEAM-101, treated by the team at Boston Children's Hospital. And he's had a very good response. He's a year out from therapy, and he is so far free from his sickle cell disease. He's got a job, and he's thinking about grad school. So a really profound illustration of what's possible with these kinds of tools, but also motivation that we need to go faster, we need to reach more patients who need help. So why are we so excited about base editing? So the gene editing field begins with nucleases. This is CRISPR and other tools. And what they -- what nucleases do is they solve one important problem, which is targeting specifically within the genome. But once you get there, there's only one kind of edit that they can make, and that is a double-stranded cut or break, which is a genotoxic event for the cell. The cell will then rush to put the pieces back together again, but it'll do so with mistakes. So you actually end up scrambling the gene sequence cell to cell at that target site. So this is a good way to knock things out, but maybe not such a good way if we want to repair them or reprogram them or do something more deliberate to their function. So base editing solves that problem. So we use the same CRISPR technique to target precisely in the genome. But once we get there, we're going to make a specific single letter change, an A to G change, in this case, and we will not disrupt the sequence around that letter. So we know exactly what sequence will result from our edit. This gives us a powerful tool with a lot more versatility than nucleases. So I want to talk a little bit about the different elements that we think are coming together right now with Beam to put us in a strong leadership position within the gene editing field. So this starts with our -- the strength of our base editing platform with now clinical validation; then the high-value franchises that we're deploying it towards with assets that we think have clear best-in-class potential; third, real evidence of rapid execution across our portfolio; and finally, setting up for multiple catalysts this year and beyond as these programs advance, all of which is built on really strong financial strength, $850 million in the bank. That's cash into 2027. That's actually inclusive now. This is an update to our guidance of any commercial readiness activities towards a BEAM-101 launch. So let me take these each in turn. So first, the platform that we have. So base editing, powerful next-gen technology. We have the dominant position in this field. We have the IP. We have the capabilities. And of course, now we also have clinical proof of concept for this working. From a delivery perspective, we can deliver this ex vivo, outside of the body. We've shown that now in CD34 cells and T cells, again, generating clinical proof of concept. We also have world-class lipid nanoparticle capabilities or LNPs for in vivo delivery to the liver, potentially other places as well. Data on those due this year. But beyond that, you really have to build the rest of your development infrastructure. So we've made great progress in establishing GMP manufacturing at our North Carolina facility shown here at the bottom of the slide. And at this point, we've actually done over 100 batches or isolations already at GMP grade out of that facility. Regulatory is going very well. We have 7 approvals across 5 countries, across all of our products. Our clinical footprint is now global. We have over 30 clinical sites and over 20 patients treated. So very gratifying, I think, to see this engine finally come into focus for us. But of course, none of that matters unless you point it in the right direction. So we're very excited about these 2 franchises in our portfolio that we think can drive significant value creation over the long term and help a lot of patients with significant impact. So first with hematology. Our lead program here is BEAM-101. So this is for severe sickle cell disease data that I will recap for you in a moment. And we have a very clear path, we think, to a BLA filing with the FDA. But beyond BEAM-101, we also have a life cycle strategy to potentially bring the benefits of base editing to many more patients to follow. And if that works, not only do we help more sickle cell patients, but actually, it sets up for a platform approach, helping many diseases across hematology and beyond using these same tools. The same is true of our liver portfolio. So we have a lead asset, BEAM-302, which has best-in-class potential for alpha-1 antitrypsin deficiency. This is a potentially exciting onetime treatment for both the lung and the liver manifestations of this disease, and it would be under normal regulation. The on-off switch would be as it is normally. So a very exciting program. But again, as with hematology, if this works, it gives us -- it derisks the delivery to the liver and sets us up to have many potential other liver programs that we can confidently put forward with base editing to help even more patients. So how are we doing? At this point, I'm happy to say that we're rapidly executing across all of our clinical programs. We have over 40 patients enrolled just in the last year with the BEACON trial. Over 20 doses are now manufactured for BEAM-101, and 13 of those have been delivered. We're also already open in our adolescent cohort. We've got the sign-off from the FDA to do that just late in the fall. On the liver side, our in vivo therapies, BEAM-302 is now open and cleared in 4 different markets. That's a new update as of this week. Enrollment very much on track for that program. BEAM-301 also, of course, now an open IND in the U.S. And the first site is now also activated in screening patients. Finally, ESCAPE, next-generation hematology. We named last year the first development candidates out of that program, 103 and 104, which I'll tell you about. And we did, in fact, achieve the beginning of Phase I enabling tox studies in December. So all of that sets up for a very exciting 2025. So with BEAM-101, we anticipate continuing to dose patients. We should get to the 30th patient sometime around middle of the year. That's an important milestone. It's about 2/3 of the way through the trial. But that probably sets the clock for a BLA filing. And so that's why we're going to monitor that event. We're also enrolling, of course, in dosing adolescent patients this year. And we do anticipate presenting updated data on the trial by mid of the year, most likely at EHA. For ESCAPE, the 103 conditioning antibody should be in its healthy volunteer study by the end of the year as well. In vivo, BEAM-302, this has narrowed guidance. So we used to say 2025. We're now confident we can deliver the first data for this program across multiple cohorts in the first half of this year. BEAM-301 right behind that, we anticipate dosing the first patient in that trial early in 2025. So I hope you can see why I'm excited about where Beam is at. This is the pipeline that results from all of that progress. I'd also like to just highlight our collaborator programs, collaborating with Apellis and Pfizer, among others. And actually, with Apellis, we just disclosed -- Apellis did, the identity of one of the lead programs that we're working on with them. And that is to modify the neonatal Fc receptor, FcRn. So this is an exciting target. It's validated now with a lot of activity for a variety of different autoimmune disorders. And so we're going to bring forward the first gene editing approach using base editing to modify this receptor. So a very exciting program that's in late preclinical studies. And obviously, Apellis will be leading further disclosures around that. All right. So now I'd like to walk through our 2 major franchises in order, first with hematology. And in hematology, we've been asking ourselves, can we do better? There's been a lot of exciting progress for patients with these diseases. But can we do more? And specifically, what can base editing bring to the conversation for these patients? And I think the answer is going to be a lot of exciting progress. So we see sickle cell disease breaking out into 3 waves of technology, okay? So wave 1 are the most severe patients, patients like Branden. We think there are about 10,000 of these people in the U.S. And they are having those progressive organ damage, constant sickle vaso-occlusive crises, risk of stroke, early death. So very, very urgent situation. And for these patients, they're going to talk to a hepatologist. And they're going to conclude that a transplant with chemotherapy makes sense for them, okay? So once they've done that, they're going to go to the transplant clinic, and they're going to have a choice of cell products to use in the context of that transplant. So with BEAM-101, we want to provide a better, potentially best-in-class, cell product for them to choose when they seek that treatment. But we're not done there. So then in wave 2, what we want to do is we want to do that same ex vivo manufactured cell product, but we want to get rid of the chemotherapy, okay? Chemo is the major risk factor when you think about a wave 1 therapy and the thing that holds more patients back from seeking it. If we can eliminate that, we think that as many as 30,000 to 40,000 patients in the U.S. could be a good fit for something like a wave 2 genetic cure from Beam. Finally, we are also active on in vivo delivery. So in vivo is, of course, to get rid of the transplant altogether and just infuse it directly. A lot of folks are working on this. We do believe, at some point, there will be a transition from ex vivo to in vivo in the market. And we're very -- I think we're leading the way actually here. We haven't given an update on it in a while, but it's not ready yet. So we're sort of in the late research stage here. So our guidance is we believe there will be a phase of the market that will really be ex vivo, beginning with wave 1 followed by Wave 2. Before at some point then, there is a transition to in vivo. Ultimately, team is prepared to lead the way on all 3 waves with leading technology in base editing. So I also want to double-click on wave 1. There's been a lot of discussion among investors of, well, how actually big is the wave 1 market. And I'm here to say that we continue to be confident that there is a real market here in wave 1. So if you look at only the existing level of allogeneic transplants -- so this is using someone else's cells, and you have to find a match in that case. But this has been going on for a decade. If you just look at that amount of treatment, it would imply a demand for autologous cell products in the $1.5 billion a year in the U.S., okay? In fact, when we do market research and we talk to doctors and patients, we even see a little bit of upside from there. And it could be that you reach a peak annual transplant level of more like 1,000 patients a year or 1,200 patients a year. Now we're clearly not there today, but this will grow over time. It's a complicated therapy, complicated operational footprint. The reimbursement dynamics are quite new, and we're really working them out. But over the next couple of years, we do think that this will start to appear, which is good timing for us as we think about entering the market with what we think is a differentiated product. And I'll leave you with just this quote from a high-volume U.S. transplanter that we heard at ASH. And he said to us, look, the demand for gene therapy in sickle cell disease will be dictated by the industry's ability to supply, not by the demand of transplanters and patients. So more to come here, obviously, but we remain convinced there's an exciting opportunity here. And that's exactly where we want to bring BEAM-101. So with BEAM-101, we're using base editing to turn on, to upregulate the protective form of fetal hemoglobin, called HbF. We want to do that more precisely and efficiently than others have done. We also want to turn down and -- at the same time the sickle globin and reach a ratio of F to S that is sufficient to protect the patients and protect the cells from sickling, right? It should prevent that sickling phenotype. And so we're going to test this in this trial. So this is the BEACON trial. It's a Phase I/II trial. As I already said, we have great operational momentum here, making a lot of progress. And specifically, this was designed to be potentially fileable. So we think that this trial can produce a data set that would potentially get us to the approval finish line with the FDA based on precedents that we've seen in the field. So now I'd like to walk you through a couple of highlights of the data we shared at ASH. First, focusing on the treatment journey and the early phases of treatment. So with BEAM-101, we're doing an ex vivo manufacturing. So we're going to take cells out of the body of the patient. We're going to manufacture them, put them back in. So the very first step is, how many cycles of collection does it take for us to get to the number of cells we need to do the manufacturing? And we want that number to be as low as possible. So what we saw in this first 7 patients is every patient used either 1 or 2 cycles to get to that cell dose. That is a good outcome. So we're excited by this. The fewer cycles we have here, it means fewer days in the hospital, faster time to dose. So then once we manufacture the drug, we're going to give the chemotherapy. The patients are now myeloablated, and then we give the cell dose. At this point, we're waiting for engraftment. So we're looking for those immune cells to turn on and start protecting the patient again from the new graft. We want that number to be as low as possible. And we want to minimize the number of neutropenic days. These are the days when you're truly bottomed out and most at risk of infection in the clinic. And that's exactly what we're seeing. So we're seeing rapid neutrophil engraftment, an average well under 20 days, which compares very favorably to what others have shown in the field. We're also seeing rapid platelet [indiscernible], which is more about bleeding risk. And here again, other products approved in the field actually have warnings for delayed platelet engraftment. We're not seeing that here. So overall, this looks very good. It's early days. We're going to follow this, of course, as we go. But we think there might be 2 drivers of this profile. One is manufacturing. So we have a generally next-generation manufacturing process. It's largely automated, largely closed. And of course, we control our own manufacturing facility, which means that we have a lot of flexibility in how we schedule the patients. Second, this is base editing. And we have preclinical data that suggests, it's a hypothesis, that the lack of double-stranded break and that genotoxic event on the cell means our cells may have a little bit of extra viability and are ready to turn on faster once they're in the patient. Again, we'll follow this over time and certainly report more as we go, continuing to follow these patients out. Of course, now a patient out over a year, and many more patients being dosed as we speak. So then how about the hematology parameters? So those also look just like what we wanted them to look like. So we're seeing strong induction of HbF. This is the fetal form of hemoglobin shown in the dark blue. And it's rapid. And then we also see the ratio of the blue, F, to the teal, S, here, is tracked at the bottom. And we're plateauing out in the mid-60% range. And that shows that we're reaching this 60-40 threshold of protective fetal hemoglobin to sickle globin, which we think will be protective. The reason we know that is because people who carry just one copy of the mutation for sickle cell disease, who don't have the disease, are generally at a 60-40 ratio. So this tells us that for the first time in the industry, we're actually getting people, patients into this nondisease range in terms of their blood profile. We're also very clearly resolving the anemia that, of course, is a big part of the sickle cell disease phenotype. So in summary for this data set, we're seeing efficient cell collection with few mobilization cycles. That could mean fewer days in the hospital. Safety profile consistent with busulfan and transplant with no SAEs related to BEAM-101, rapid neutrophil and platelet engraftment, again, creating for the potential for fewer hospital days, potent induction of F, reaching that 60-40 sickle cell trait profile. And in fact, when we look at the blood cells in exploratory assays, we see them performing in the same way as a normal or a trait blood sample as opposed to a sickle cell disease sample. So very exciting early results, but we'll be able to report more on this midyear and to follow. But we see clear signs from this data set of clinical differentiation, that base editing is bringing something new to the table for patients here, and of course, we hope in other conditions as well. Let me talk now about the ESCAPE technology. So this is the next-generation version within hematology. So here, we want to do almost the same thing I just described. But instead of using chemotherapy, we want to use something much gentler and more precise, okay? And that's an antibody conditioning agent. So we're going to call that BEAM-103. This targets CD117. And then for the cell product, which we're calling BEAM-104, we do that same fetal hemoglobin edit, but now we're going to add one extra edit with the base editor that will render the cell invisible to the antibody, okay? So now we're going to have the ability to use the antibody to suppress and eliminate old disease cells and allow our new grafted cells to grow up in its presence. So this is a very, very exciting concept. The synergy between BEAM-101 and ESCAPE is very high. Everything that we do with BEAM-101 will really set the groundwork for ESCAPE to be both derisked and accelerated. And even the commercial ramp, we think, would be faster. So we showed some exciting data at ASH in primates. This is 3 different monkeys that have been conditioned not with chemotherapy but rather with this antibody. And we are, sure enough, achieving our goal of a high number of cells expressing, fetal hemoglobin. And the percentage of globin that is the F, it's also called here gamma globin, which is the same thing, it's about 50%. So this will be a transformative outcome for patients if we could achieve it. And importantly, the monkeys were never given transfusions or antibiotics. They were never myeloablated because they never got chemotherapy. And so that shows you that different profile. In fact, in a real-world commercial setting, we imagine that it's possible that this regimen, the cell dose could be given as an outpatient procedure as opposed to having to be in the hospital because you're never fully ablating the marrow. So obviously, that would be a game changer, and that's why we're so excited about the program. So next steps here. That antibody, as I said, in preclinical studies. We anticipate being in a Phase I study of 103 to evaluate PK/PD and safety by the end of the year. And in parallel, we're doing more NHP studies really to optimize that antibody dose regimen, the dose response and chimerism. And those all should come together to set us up for an efficacy study of BEAM-103 with 104 in sickle cell disease as well as we're going to add in now beta-thalassemia patients. So hopefully clear why we are so excited about our hematology technologies and progress both for sickle cell disease and beyond. Let me now close by talking about what we're doing in the liver. And here, we're asking a slightly different question, which is, can we use base editing to literally correct misspellings in a gene from mutant back to normal? And I think the answer, hopefully, will be yes. The first disease we're doing this in is alpha-1 antitrypsin deficiency. This is a major disease where you have a single letter misspelling. Patients have an A where there should be a G. And when that happens, the protein that's produced actually is mutated. It builds up in the liver, causing toxicity. And it also isn't secreting to the blood stream, where it's supposed to be protecting your lung from degradation and lung failure. So this is called the Z protein of the Z mutation. So there are 100,000 patients in the U.S. who have the ZZ phenotype or genotype, and that's our target. With the base editor BEAM-302, we want to literally rewrite that A into a G while preserving the function of the gene. And if we do that, we'll start producing the normal type of proteins called the M protein. That should not build up in the liver. It should secrete normally and should protect the lung. So again, this would be a onetime therapy for both lung and liver and be under normal regulation. The goal here is to get to therapeutic levels of circulating M protein and reduce the Z protein in the liver and the blood. That's exactly what we've shown in preclinical studies. You see here, as we add editing, you have a significant rise in total alpha-1 protein and a reduction in Z protein at the same time. On the right-hand side, you're seeing conversion from that Z genotype over to the corrected form and all at doses that we think are achievable in humans. I should also note that the editing is expected to be durable. Of course, the entire gene editing field benefits from this. There's no reason gene editing will ever wear off. This is a true lifelong effect. In fact, in alpha 1, if anything, you may accumulate editing over time. And why would that be? It's because edited cells are no longer creating that toxic protein, whereas any unedited cells up behind are. And so we see this in preclinical studies that actually, there may be a competitive advantage for edited cells over unedited cells. So not a short-term effect but potentially a medium to long-term effect that we'll watch for. So we're studying this in this Phase I/II trial, BEAM-302 in initially primarily lung patients for alpha-1, where we're dose escalating across 4 dose cohorts and then expanding. We'll then go back and add patients who have heavy liver involvement. That's more of a minority, but we want to make sure we have a clean read on tolerability with and without a very diseased liver. Ultimately, the goal is to have a single dose and regimen for a pivotal study and beyond. And again, this is potentially the first time that we're testing in the world to actually correct a disease-causing mutation in the body. So as I said before, we're anticipating first clinical data across multiple cohorts of patients from this trial in the first half of this year. So then let me close on BEAM-301. So BEAM-301 is for glycogen storage disease 1a. Here, patients cannot take the glycogen, which is how you store energy in your liver and turn it back into glucose to maintain blood sugar levels. And so what that means is when they're not eating or when they're sleeping, they're actually plummeting, and they have potential for fetal hypoglycemia. So they have to continuously feed these sort of corn starch supplements, including overnight. And if you were to sleep through your alarm, it could be a potentially fatal mistake. So it's a terrifying situation. Our goal in targeting the most common point mutation in this disease called R83C is to take again that one letter misspelling in the gene in A, turn it into a G. That would fix the enzyme and restore normal metabolism. In animal studies, a relatively low level of editing was sufficient to restore that metabolic profile, and we've seen a single dose of BEAM-301 enough to rescue animals very quickly. So we're studying this in a Phase I/II trial. Again, a dose escalation. This is in the U.S. already open. The first clinical site is activated. And again, first patient dose is expected to commence in early '25. So as I wrap up, I'm going to come back to this slide, which is, again, the kind of the key attributes that we really feel are coming together in Beam right now that make this a very exciting time for the company. It's the next-generation base editing IP and capabilities that we've built now clinically validated and fully surrounded by manufacturing and development capabilities. It's the high-value franchises that we think are commercially meaningful and could drive significant patient impact with assets that have potential best-in-class profiles. It's the rapid execution that we're now achieving through clinical and regulatory milestones across all of our programs, setting up for a catalyst-rich period for the company in 2025 and beyond, again, across all of our programs, and all on a significant financial strength to give us the runway to really turn over all these cards and more. And so I'll wrap up where I started, which is with patients. Patients are truly at the heart of our vision at Beam, thinking about the burden they carry, the suffering they face, the uncertainty and the effect not only on their lives but on the lives of their families. So that is why we're so motivated to bring these technologies and these programs forward, because the people with these diseases desperately do need more options, and we really believe that's going to be possible. So with that, I'll say thank you very much, and we're very happy to take some questions.

Great. Right. And for those on the -- seated who want to ask a question, just raise your hand, and we'll bring a microphone around. But just to start things off, I want to pick up, John, on a statement you made around the sickle market opportunity where the feedback has been -- this market will be dictated by -- not by demand but one of supply, right? Obviously, there's -- the component that you can control there is manufacturing capacity and so forth. The other is I would think as part of that supply equation is really beds at transplant facilities. Can you just talk a little bit about sort of how you see the field maturing from where it is right now in order to support what could be a much greater supply of cell therapies for sickle cell disease?

Yes. It's a great question. So I think of the 2 factors you raised, I think supply -- manufacturing supply slots is the more important one. It's the most difficult to adapt. These take a while to turn on. The bed side may be an issue. And in fact, that's why we're so excited about the emerging profile for BEAM-101, because that rapid engraftment, the fewer cycles of mobilization, that could mean fewer days in the hospital that's good for patients, but it's also good for hospitals because there's fewer beds that are needed and you're going to have more patients going through every year. All that said, I think in general, although there's not a ton of beds lying around, what we've seen in the oncology CAR T field is as the therapies become available, the hospitals have been able to adapt. So I would expect hospitals to be able to add new beds once there's that much use of these technologies. I think the bigger limiting factor is the -- how much supply comes online from the manufacturers upfront.

For BEAM-301 in the animal studies, are you seeing a resolution of hepatomegaly? Or is that just not part of the treatment goals?

Yes, we are. And just to introduce myself, I'm Pino Ciaramella. I'm the President of Beam. Yes, the answer to your question is yes. We actually see a resolution of that. We also see resolution of dyslipidemia. So these patients actually have high triglyceride as well as high cholesterol. We actually see resolution of that. And by the way, we've kept these animals going all the way pretty much to the end of their life, and that benefit is persistent from birth all the way to death. Yes.

Just picking up on the ESCAPE platform and the data that you've shown so far, showing pretty compelling engraftment in NHP models. I guess if we're trying to put those data in the context of the level of engraftment you see with chemoablative preconditioning, I guess, maybe just make that contrast. And I wonder whether in the nonclinical to preclinical setting you've been able to kind of look at depth of -- the pace of engraftment and also relative tolerability in both chemoablated and nonablated animals.

Yes. I think that's partially what we're going to be continuing to study this year. I think I would agree with your statement. We're quite excited about the data that was shown at ASH. Very clearly, if we were to achieve those kinds of numbers, we would have a transformative effect for patients. I think there was a busulfan control-treated animal that was shared in that presentation that was maybe a little bit higher, but not by a lot. And so I think we're clearly in the zone here. In terms of tolerability, I think we'll see. I think at the end of the day, we know a lot about kit antibodies. They're being developed for other conditions already. And that's been well -- very well tolerated. So -- and of course, we already have a reasonably good feel for the cell product, which would be very similar to BEAM-101, also being well tolerated. So we don't anticipate a lot of uncertainty on the tolerability side as we move into this kind of regime. And that's, of course, why we think this whole vision is so attractive. You're really taking that consideration out of the equation for many more patients to then seek a therapy like this that would be potentially curative.

You talked about a future of in vivo gene editing delivery. And I saw that you use LNP as sort of the AAV code. And that's a big question mark because everyone know that it's kind of a challenge here, is what is the delivery mechanism that you can use to get to the cell and sort of integrated. And AAV has been the gold standard, but it has a lot of his limitation due to patient antibodies, et cetera. So how far are we in terms of successfully using LNP to deliver the editing materials in vivo? And what's the efficacy that you're seeing?

Yes. So we'll have Pino answer the question. So I mean, clearly, for the liver, LNP is ready now. And we're hoping to show that this year in our liver programs. But I think for your question to do sickle cell editing, you have to get to the marrow and get to the stem cell, which I think is an entirely different challenge. So we do favor LNP as a route for that.