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

Okay. Great. Thank you. All right. Well, good morning. I'm Eric Joseph, Senior Biotech Analyst with JPMorgan and our next presenting company is Beam Therapeutics. Presenting on behalf of the company, it's my pleasure to welcome CEO, John Evans. There's going to be a Q&A session after the presentation. If you want to ask a question, just raise your hand, we'll get a mic over to you for folks joining via webcast, you can also submit questions by just hitting the ask-a-question icon. So with that, John?

Thank you, Eric. Okay. So welcome, everybody. My name is John Evans. I'm very excited to be here to tell you a little bit about Beam Therapeutics and our effort to create new precision genetic medicines in the field of base editing. As a reminder, I will be making forward-looking statements today. So at Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. We see real potential for onetime curative therapies, which could be truly disruptive in medicine. We believe gene editing is going to be a treatment for both rare but ultimately also more common diseases. And we believe that because these technologies are programmable, they can be true platforms, not just creating one program, but creating multiple medicines rapidly over time. So to give you a quick tutorial on gene editing. So the state-of-the-art to date in gene editing have been what we call nucleases. Most famously, CRISPR. So what these tools have done is solve one very important problem, which is how do you target within the genome precisely. There are 3 billion letters in all of your genomes, AGC&T. We want to find 1 address for editing. And they do it very well. The challenge is once they get there, there's only one thing that they can do, and that's the cut. It's like having the scissors for the genome. And when you make that cut, it's a genotoxic event for the cell. But more importantly, you can't control what happens next. The cell puts the pieces back together again, but with damage. You have literally random insertions and deletions at the target site. So this means that you basically lack control over what's going to happen to the gene sequence. So base editing was designed to fix that problem. So with base editing, we keep that same precision targeting that you get with CRISPR. But now we're going to do an enzymatic-based conversion when we get to that target site, simple chemical change, turning one letter from another letter, A to G or C to T. This is very efficient, but more importantly, it's predictable. So now we know exactly what sequence will result when we've made the edit. That really opens the aperture for thinking therapeutically about reprogramming genes to a wide variety of different things. So this is what the gene editor looks like when you're doing base editing. So we use the CRISPR protein. It's targeted with a guide RNA, just like normal CRISPR. But now we have a deaminase attached to it, which does the chemical modification. And on the right-hand side, you see all the different kinds of edits that we can make here with this controlled and precise system. So now we can think about correcting mutations, literally taking something that is spelled wrong in the gene and turning it back to normal for the first time. We can, of course, think about silencing proteins, activating proteins modifying proteins, literally changing a protein's function by changing a single amino acid in the protein. And actually, we can also do multiplex editing because we don't cut. We can actually stack edits on top of each other as much as we want without creating chromosomal damage. And that allows us to target multiple pathways at the same time, letting us intervene in more complex biology. There are actually examples of all of these types of editing already in Beam's pipeline and with our partners. And in many ways, I think that we are in the very early innings of what is possible in this field. So we've been building a truly comprehensive and integrated platform of technologies to make these medicines a reality. Of course, it starts with base editing, the A and the C-based editors I described, world-class guide RNA and messenger RNA capabilities. For delivery, we use cell therapy, ex vivo editing of blood stem cells or T cells or lipid nanoparticles going in vivo to the liver or potentially other tissues as well over time. Finally, we enable all of this with GMP manufacturing. These are very complex medicines to make. We have established our own in-house GMP manufacturing facility in North Carolina. I believe it is the biggest in the gene editing industry, and that is already now doing runs as we speak. Importantly, this is a modular platform, okay? What that means is that we're already applying it to our current pipeline products. But as we get new ideas, we can pull all of the tools we need right out of this platform and quickly move new programs forward for patients. So here's the pipeline. So as you can see, a wide variety of different kinds of delivery, different kinds of editing being exploited here. Leading the way is BEAM-101 for sickle cell disease, followed by the ESCAPE version, which is a next-generation version for sickle, which I'll describe soon. In the liver, we're doing in vivo editing, BEAM-302 for Alpha-1 antitrypsin deficiency, BEAM-301 for glycogen storage disease 1a. We have BEAM-201, our quad-edited CAR T cell for T-cell leukemias and lymphomas. And then our major alliances with Pfizer and Apellis, starting to bear fruit with lead programs targeting the liver now moving forward into lead optimization. We're actually doing many more things as well than just this at BEAM, but these are the programs getting the most activity right now. So I wanted to double-click on a couple of areas here and give you a sense of why we're so excited about these 2 big drivers, I think, of value creation and patient impact for BEAM over the near term. So first with sickle cell disease in hematology. So we really believe in the best-in-class potential of BEAM-101 for sickle cell, and I'll show you some of that data in a moment. Importantly, we're operating with what we believe is now an increased probability of success for any ex vivo gene editing blood cells as well as for up-regulating fetal hemoglobin and sickle cell disease based on what we've seen in the field. We now have a validated FDA regulatory pathway to approval for this kind of agent. And our next-generation version, ESCAPE has the potential to eliminate chemotherapy altogether from the equation, which could dramatically expand the reach of base editing to many more patients. Ultimately, if these technologies work, this is a true platform in hematology, where the kinds of things we're doing here to help patients with sickle cell disease can help patients with a wide variety of other disorders. The same basic logic is true in Alpha-1 as well. So with Alpha-1, we have best-in-class potential clearly with BEAM-302. We have, again, an increased probability of technical success based on the success of in vivo LNP-based gene editing in the liver. We have potential for rapid clinical proof of concept, raising Alpha-1 levels, lowering Z protein levels. This will be the first and only clinical stage program with Alpha-1 with the potential to be a onetime treatment that benefits both lung and liver disease and is under normal regulation. And again, if we're successful here, this is a platform for creating a large number of liver-targeted base editing programs over the long term. So these 2 franchises, I think, are going to be very important to BEAM over the coming years. So 2023 was a truly transformative year for CRISPR gene editing, for base editing and for beam. Hopefully, you've been following some of the exciting news. In the gene editing field, we had the first in vivo INDs cleared by the FDA. We had the first in vivo liver base editing data published and we had the first CRISPR-based product approved in sickle cell disease. So tremendous wins at our back in gene editing. So at BEAM our job is to take that next generation of this technology forward. So we achieved the first patients dosed with a base editor therapy in the United States. We did that initially with BEAM-201 dosed in Q3. And then today, we're very excited to announce that we did, in fact, dose a patient with BEAM-101 in sickle cell disease, and they were successfully engrafted all in Q4. We had a very strategic deal, which Lilly acquired, BEAM's rights in the Verve programs. That provided a lot of capital for us. We prioritized our portfolio really highlighting into those couple of value-driving areas in sickle cell and Alpha-1 that I mentioned. And those decisions have put us in a position to announce again today with a revision that we do expect our cash balance to last us into 2027. So that's a great place to be, given all of the things that I think this pipeline can accomplish over the next 3 years. So 2024 is the beginning of that journey. And this is going to be a very dense year of catalysts for the company, very action-packed. So walking you through some of these things. So BEAM-101, coming off of our first patient dose, we do anticipate being able to complete the sentinel dosing and initiate expansion dosing in the first half of this year. That puts us in a great position to present clinical data on multiple patients in the second half of '24. ESCAPE, this very exciting next-generation program that we're working on has been making great progress. We're in late lead optimization and again, excited to announce today that we anticipate being able to initiate Phase I enabling preclinical studies in 2024, putting us on a definitive path towards the clinic. In vivo with BEAM-302, we had a goal of filing for Phase 1 in the first quarter of this year. And I'm thrilled again to announce today that we've actually already done that. So that is complete. BEAM-302 CTA has been filed in the U.K. We have different countries to be filed shortly. All of that puts us in a position to initiate a clinical trial for BEAM-302 in the first half of the year. BEAM-301 will follow shortly thereafter. This is for glycogen storage disease 1a, again, looking to file U.S. IND this time on the later parts of the first half. And finally, BEAM-201, our quad-edited T cell program going to be a lower priority for the company going forward based on the prioritization decisions that we've made. But nonetheless, ongoing trial, we do anticipate being able to present clinical data in the second half of the year. All right. So let me now walk through a couple of stories just to give you a little more detail on some of these areas that I wanted to highlight. And the first one I will do is sickle cell disease. So it's been obviously an incredibly exciting period for sickle cell patients with the approvals of the first gene therapies, onetime therapies. We've had truly transformative effects for these patients. But I pose the question, what if we can do better? Can we create even better onetime cures for these patients? Or are we really going to stop here? I think clearly, our team feels strongly that the answer is, yes, we can do better. And the technologies that BEAM has assembled are going to unlock that vision. So the path really looks like this. So this is a multi-wave strategy. It begins with the most severe patients. So this is going to start with BEAM-101, where we're doing precise upregulation of fetal hemoglobin, potentially best-in-class profile, non-cutting, nonviral. Following that will be Wave 2 with ESCAPE. So this is to add an extra edit that will allow us to pursue nongenotoxic conditioning, getting rid of chemotherapy that would allow a much broader range of disease severity and ages to be treated and expands the market dramatically. Finally, of course, our long-term vision is to do all of this in vivo to deliver these editing tools with lipid nanoparticles directly to the stem cells, avoiding the need for transplant altogether. At that point, really every patient is eligible for this kind of therapy, and we could even go global, if you think about the incredible global burden of disease that this disease represents. So a quick primer on sickle cell disease and what BEAM-101 can do. So as you know, this is caused by a mutation in the adult hemoglobin gene that has caused the expression of the sickle form of hemoglobin. And what that does is under low oxygen conditions, it can polymerize and cause rods that deform the shape of the sickle of the red blood cell, causing the sickling shape, which then clogs in your capillaries and causes vaso-occlusive pain crisis, organ damage and ultimately significantly shorter survival for these patients. So what we want to do is we want to go in and turn on the genes for fetal hemoglobin that are off after birth. We can do this more directly than anyone else because we don't cut and we can install single-letter changes in the on-off switches for those genes that will turn them on really robustly. Once you have that extra level of F, you then will protect the cells from the sickle protein and they will function normally. So BEAM-101 has the potential to be a more efficient editor, leading to greater and more uniform induction of F, more reduction of the sickle protein and more normalization of hemoglobin. We're also investing in wholly owned manufacturing and process development and the overall patient experience, making sure that we can deliver the best possible regimen for these patients. So this is the data that backs up my claim about best-in-class. This is the same animal model that has been used by others in the field. You can compare them directly. On the left-hand side, you see that very high efficiency that we're getting from base editors, up over 90% editing. But importantly, in the middle, because of the high number of cells edited but also that uniform production of the same edit in every cell, and we've literally chosen the edit that gives us the highest dynamic response from the gene. We get the highest level of F of anyone in the industry, up over 60%. And compare that to, say, the Vertex product where the preclinical data was in the mid-30% range, Okay? So that strong upregulation of F also leads to a lowering of S more than others. And so we're seeing S levels at 40% or less. As a reminder, these are human cells. So this is practically the clinical product. We're just putting it into a mouse rather than a human. And so that is -- gives us a lot of confidence in the potential translation of this profile. So the translation is going to happen in this trial. This is the BEACON trial. This has been designed explicitly to be a potential registration-enabling trial. We really believe that should be possible. And the FDA's decisions late last year give us increasing confidence that, that is indeed going to happen. As you know, a transplant is a long and complicated process. So patients must go through transfusion, mobilization, manufacturing, all before you can condition, which is where you get rid of the old cells, dose in the new edited cells and then engraft. So we're moving in parallel on the first part of this with many patients now on trial moving through the preparatory steps of this process. And now we have indeed successfully dosed our first patient with 101. We're moving on to patient 2 now. And once we finish all 3 sentinel patients, we can then dose as many patients as already in the expansion phase of the cohort. We've actually completed manufacturing for multiple additional patients beyond patient 1 already. So great momentum in this trial. And we do anticipate, again, dosing some expansion patients all in the first half of this year, putting us on track to present data in the second half of this year on multiple patients with long-term follow-up. So a lot of momentum here for BEAM-101, I can't wait to show you what it can do. So let me just highlight this next-generation version called ESCAPE. So with ESCAPE, what we can do is we can take that same potentially transformative edit, I talked about with BEAM-101, that will take care of the sickle cell disease. And we can add a second edit. And that second edit is going to be on a receptor on the surface of the blood stem cell. And this is something that only base editing can do because if you use a nuclease, you would just knock out the receptor, you would scramble the gene. But the base editor can make a single base change, changing a single amino acid on that receptor where you're only altering the epitope of binding for an antibody, all right? What that allows us to do is, for the first time, use antibody-based conditioning rather than chemotherapy to get rid of the old disease cells. And in such a way that it will bind to old cells and kill them off, but it will now not bind the edited escape cells and leave them alone, and they will grow, okay? So this, for the first time, lets us have in the body at the same time, the graft and the conditioning agent, okay? That is a huge breakthrough in the pursuit of this field to change transplant and conditioning. So on the right-hand side, you see that in action. You see a mixed population of cells, both edited and unedited. And as we add antibody, we dramatically shift the population towards edited cells and wipe out the rest of the unedited colonies. So very, very excited about what this potential breakthrough can do for patients with sickle cell disease. We now are on track to initiate Phase I enabling studies in 2024, which would put us on a definitive path to the clinic. Finally, Wave 3, of course, is the goal to go in vivo. We'd love to deliver lipid nanoparticles with base editors to blood stem cells. We've shown before messenger RNA payload delivery in primates at clinically relevant doses of 1 mg per kg or less. The research now is to adapt that to a base editing payload, which is much larger and more complex, that work is ongoing. And the ultimate goal here is to, again, remove the transplant altogether. This, of course, will be a truly scalable single-shot kind of cure that could potentially go global. So hopefully, you have a sense from this story about why I'm so excited about this wave of innovation coming from BEAM, what we can do for patients with sickle cell disease as well as what it would mean for other hematology conditions if these technologies work. There's a very broad aperture of medical impact that we can potentially make if this really happens. All right. So now I'm going to tell you the second story, which I'm so excited about with BEAM. We're doing a lot of exciting things in gene editing. We're knocking proteins out. We're activating them. But I would ask the question of, what if you could go back to that original dream of gene editing, which is to fix what's broken? And that's exactly what we're going to try to do with the next 2 programs I described. This will be the first time in the industry that we're going to try to correct disease cause mutations in the body. So this starts with BEAM-302. So this is treating Alpha-1 antitrypsin deficiency. This is a disease where you have a single letter misspelling in a gene. It's called the Z mutation. Patients who have the ZZ genotype, have the severe form of this disease. There's probably 100,000 patients with the ZZ genotype in the U.S., largely under-diagnosed. That's an upward revision from previous estimates from us. And the problem is the Z protein is building up in your liver causing liver failure as well as not secreting to the bloodstream, where it's supposed to be protecting your lungs from degradation by proteases when you have inflammatory or infection events. So BEAM-302 is designed to go directly to the cause of the disease, turning that 1 letter A, back to G back to normal as a onetime event. That would both stop production of protein in the liver that is being toxic, it would start secreting normal protein to protect the lung, and it would be under normal regulation, okay? This is a gene that wants to surge in response to infection. And by fixing the gene where it normally lives in the genome, we enable that to continue happening. And that's not true of all other therapies in this field. So really BEAM-302 is doing all the things that we would like it to do to be a really transformative therapy for this patient population. So late last fall, we published some data showing this in action. So you can see here on the left, really robust editing at achievable clinical doses and then on the right-hand side, you see the effect is exactly what you'd want to see. We're literally converting allele by allele from a mutant gene copy to a normal gene copy. So now you're increasingly secreting normal corrected Alpha-1, and you are eliminating or driving away the Z-form of the protein. And again, these dose levels, we believe, are quite achievable in humans. That's really important in the LNP field to always be thinking about that dose translation. So this is the trial that will show what it can do in people. So this is BEAM-302's Phase I/II trial that we're now starting up. It will have a standard dose exploration, up over 4 dose cohorts. We're going to initially start in lung patients. And then in Part B, we'll be looking at mixed lung liver patients who have more of a mixed phenotype to make sure we understand the profile of the drug in the full spectrum of the disease. All of this is to identify the optimal dose for the pivotal study. So as a reminder, this is an opportunity for the first time to demonstrate proof of concept of in the body correcting a disease causal mutation. So as I said, we've been accelerating this program continuously for the last year. The CTA has already been submitted in the U.K. We have additional country filings to follow, all putting us in a position to start this trial in the first half of this year. The second story I want to tell you in the liver is for BEAM-301. So this is targeting a disease called glycogen storage disease Ia. Here, patients can't convert stored energy, which is in the form of glycogen in their liver, back to glucose to maintain blood sugar. And patients with the R83C mutation have the most severe form of this disease. And so what they have to do is literally take cornstarch supplementation every few hours, where they can die of hypoglycemia. And that includes overnight. And if you were to miss one of those feedings, you could potentially pass away. So we estimate about 300 patients with this mutation in the U.S. That's also a revised estimate based on some updated epidemiology, but very severe patient population, of course, more patients ex U.S. gene therapy as well. So BEAM-301 is designed to go again, directly to the cause of the disease, turn that one letter back to normal, restoring enzyme activity, restoring glucose metabolism. We think there is a very low bar for success here. About 10% editing is probably sufficient to restore normal metabolism. And success looks like this. So this is a preclinical model of that mutation. We showed that untreated mice with this mutation are dead in a couple of weeks, whereas with 1 dose of BEAM-301, you see a very significant improvement over the long-term survival of these mice. So this is a rare disease. We know where these patients are in the U.S. will be beginning the clinical trials in the U.S. that will be a U.S. IND filing in the latter part of the first half of this year. So let me finally just say a little bit about our business development strategy. So we've had a very creative pipeline and platform strategy, having accumulated so much technology under one roof. We really want to make sure we get the most advantage of that. We've done strategic deals now totaling about $675 million of capital that we've been able to invest, obviously, in our own capabilities, but also to put great programs in the hands of our partners. The Pfizer deal, a landmark deal, that was a couple of years ago. That collaboration is going very strong. And then this last fall, the Lilly deal where they acquired our rights in the Verve programs for a significant amount of capital upfront, and a significant amount of still earnable capital as Verve continues to execute, then the Apellis and Sana deals as well. As a reminder, in Pfizer and Apellis, we continue to have opt-in rights to any one product out of those collaborations, creating additional strategic value for the company, and you saw that on the pipeline chart starting to come into focus. We've also done the innovator deals, as I call them, where we're trying to really gain rights to complementary technologies and continue to expand that tool kit. So we did a deal with Prime medicine, where we have exclusive access to prime editing for any AG or CT change as well as for sickle cell disease, basically, any place that base editors also work. And then Orbital, a newer company, where we have a significant equity stake, and we have access to IP coming out of their investment in the next generation of RNA as well as delivery technology. And certainly, as we seek to expand the application of base editors to more and more diseases, we think that could be a very helpful collaboration as well. So in closing, I'll just leave you again with this vision of what 2024 is going to be for BEAM. This is a true inflection point year for the company. Leading the way, BEAM-101 with now a really a lot of momentum and a very clear path both to data and ultimately potentially to approval, followed by Escape, this game-changing technology that could finally unlock the potential of transplant with non-gene toxic conditioning in sickle cell disease and beyond. Then in vivo, starting to finally talk about fixing mutations, starting with BEAM-302 for this huge patient population that desperately needs new options with Alpha-1 trypsin deficiency, followed by BEAM-301 for GSDIa. And of course, BEAM-201 as well, the first quad editing cell therapy in cancer, hoping to show what multiplex editing can do for cell therapies presenting data later this year as well. And behind all of this, now having built that full engine of capabilities altogether, we see a really clear sustainable innovation engine that can drive value creation for the company going forward and hopefully maximize our impact for patients with so many different diseases who desperately need new options. So with that, I will thank you very much for the time and very happy to take questions.

All right. Well, thanks, John. And just as a reminder, for those with questions, we have mics that we'll circulate. I'll start things off on BEAM-101 in the sickle cell program. And John, really just kind of to ask you to unpack what a higher-quality cure looks like or feels like from a patient's perspective when you talk about that potential being on the table for -- with 101? And maybe just given that the trial is now underway, whether there are sort of early term clinical endpoints that might predict for a higher quality outcome long term?

Yes. I mean, so we -- higher quality, obviously, deeper -- I mean I think it's quite clear that we have higher levels of editing that we're getting more F, we're having less S. So I think that biochemical profile is already clearly superior. I think from there, we'd like to see improvement. Obviously, vaso-occlusive crises, we want to eliminate those. They're not completely eliminated from, for instance, the Vertex product. So we'd like to go further there. Hemoglobin function hemolysis, again, not fully resolved. We'd like to see some improvements there, time to engraftment, even the process. We've worked really hard in the process to be as efficient as possible. So I think there's a lot of ways that this could show up, all visible in the short to medium term. Of course, long term, we're focused on things like organ damage and mortality. We want to deliver patients as full a correction as possible, that will take a little longer to mature.

And in terms of that process, I presume you're talking about manufacturing, I guess, are there ways in which -- I guess, material ways in which your manufacturing process with 101 differs from that of Vertex's [Indiscernible]. I'm thinking about sort of the amount of starting CD34-positive material and the like.

I'll let [indiscernible] maybe if you can describe yourself and then go.

Yes. My name is [indiscernible], and I'm the President, at BEAM, also responsible for manufacturing and other functions. In general, I would say the process that we deploy is not dissimilar from the process that others have used. But what we have done is to optimize the process very much with the high degree of automation as part of the entire manufacturing process. And what that buys us is a couple of different things. One is obviously the reliability, which, frankly, in this kind of setting, it's very important for the patient experience and potentially also buys us a greater yield overall of high-quality cells, they might be able to minimize the number of mobilizations that we actually need to do. And so even though the manufacturing process per se is similar, but automated to the full extent that we possibly can. The overall patient experience might hopefully be better because there may be a faster way to actually been dosed. And obviously, as more and more patients will come through the trial, we'll be able to reassure ourselves if that's the case.

Having now completed manufacturing product for a number of patients so far, I guess a lot of questions. I guess one is just sort of the manufacturing success rate that you're encountering that you're achieving? And then as -- maybe as a follow-on to that, I guess, how should we be thinking about sort of any gating steps to treating subsequent patients now having treated one and seen engraftment?

Yes. So I think we're going to generally not be in the business of giving patient-by-patient updates or lot-by-lot updates. I think suffice it to say, as Peter said, we have a lot of confidence in the process. I think it's performing well as well as both in our manufacturing partners externally and now becoming internal at North Carolina. So I think we -- again, I think that clinical map we showed, I think we're in a great position to execute on that this year to deliver what should be a really meaningful clinical update on the second half of the year. We really wanted to bring forward data when there's a real story to tell, and we can show the full picture of what the drug can do even as it accelerates through into the latter parts of the trial.

Yes. In terms of the manufacturing so far, I would say that we are really very pleased with the consistency that we see from the products actually that we're generating on several patients already. Of course, we need to do many more in order to confirm and continue to do that. But so far, we are very, very pleased.

I mean it's early days right now since the first movers have been approved here, but I guess, is there any material headwind you think from being able to enroll the expansion portion of BEACON with the 2 commercial products in the market?

Yes. I think we haven't anticipated that. We don't see anything yet. I think actually, if anything, the enthusiasm for the BEACON trial seems to be high and growing. So I think we feel a lot of confidence there. There are a lot of patients with sickle cell disease who desperately need therapy. Clinical trials are actually fairly easy to get going as opposed to a commercial pay reimbursement, and there's a lot of infrastructure that's going to get set up there. And again, we're only looking for 45 patients here. So I think we have a lot of confidence being able to enroll the trial.

Okay. On BEAM-302 in AATD. I think it was pretty well laid out in the presentation. But like I think it might be still useful to kind of make the contrast with 302 and sort of the other -- some of the other therapeutic strategies had -- that have either been -- they're either available, right, in the case of enzyme replacement therapy or that have been in development. I guess, how does your approach sort of address the full nature of the disease, perhaps relative to some other interventions?

Yes. I think -- I mean, because it's such an unmet need, and it's such a big population, it is desperately native therapy. There's a lot of people who are trying but it is also a big challenge to really get something to work. And so there's a variety of different approaches. Some of them are focused only in the liver, say, the RNAi knockdown. Of course, that's not going to help with the lung. You have RNA editing, where it's trying to do both. The question there, of course, is still a chronic therapy and what the efficacy will be. You have some other gene editing approaches, maybe knocking in the gene elsewhere in the genome, but of course, that won't be under normal regulation and more of an unprecedented approach. There's -- so -- but despite all of the different players out there, there isn't anyone that can do the set of things I described for 302. I think that's why we're so excited about the differentiation of the program because we're the ones going directly to the broken gene and with a onetime therapy trying to fix it.