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

All right. So I'm Eric Joseph, senior biotech analyst with JPMorgan. Our next presenting company is Beam Therapeutics. And presenting on behalf of the company is Chief Scientific Officer, Pino Ciaramella. We'll be doing Q&A in the room after the presentation. There should be mic runners around for those who want to ask a question from the floor. And if you don't, you can also submit a question via the digital conference book, and I'll work them in where appropriate. So with that, Pino. Thank you.

Thank you very much, Eric. And thank you very much for giving me the opportunity to give you an update on behalf of Beam Therapeutics, a precision genetic medicine company that utilizes next-generation gene-editing technology known as base editing. Usual cautionary notes. So our vision is really to provide life-long cures for patients suffering from serious diseases. With our technology, we have the potential for generating onetime curative therapies that we plan to deploy not only on rare diseases where the field and assets are starting, but also increasingly so on more common diseases as the safety of our products is demonstrated. And importantly, the platform that we are developing has the ability to rapidly develop program #2, 3 and 4, once program 1 has been optimized and derisked. And base editing really exploits the -- and builds on the success that has been made using the programmability of CRISPR, whereby a simple change of a small guide, RNA, a sequence of about 100 nucleotides, allows that protein to actually land on a different spot on the genome, actually with the incredible precision, but actually modify that technology such that we no longer make a double-stranded break, which we believe brings some unwanted consequences to that. In addition, the base editor is actually a fusion protein that incorporates directly an enzyme that directly catalyzes the chemical conversion of one nucleobase to another. And as a consequence of that enzymatic activity, the editor is actually very efficient and does not need to rely on the dividing or nondividing state of the cell. Therefore, it can be deployed actually in a variety of different cells and can be very versatile in the way in which it can be used, not only to make the change that corrects a point mutation but also to do other things like introducing stop codons as well as up-regulating promoter regions, for instance, like we do in our BEAM-101 program. Importantly though, in addition to the editor and the cargo, which obviously base editing is the one that is developing the most because it's so efficient and effective. However, Beam has developed arguably one of the more deeper toolbox of gene editing technology available, which we have our own proprietary nuclease. For instance, we also have access to RNA editing as well as exclusive access to prime editing for some fields. But importantly, where a lot of the innovation has been applied, particularly most recently in the company, is really in the ability to deliver this technology in a variety of different ways. We can obviously do autologous cells as well as some allogeneic cells. But importantly, we can manufacture mRNA and deliver in vivo with LNP technology that we have been developing and optimizing, thanks to the acquisition of a company called Guide Therapeutics a couple of years ago as well as developing some novel viral vectors. And importantly, the third part of the strategic deployment and investment that the company is making is really building our own capabilities for manufacturing. We believe that this is a very strategic asset for any gene editing technology, but in particular, complex products like ours because it gives us the control of the quality as well as the timeliness of that. And we have a facility being built in North Carolina, which is 100,000 square feet of utilizable space and potential for going even beyond that and should become operational later on this year. So having developed that platform, it allows us the opportunity really to deploy this base editing to a very extensive portfolio of opportunity. The span not only ex vivo approaches in the hematology but also in immunology and oncology, but also in vivo delivery to deliver initially and also other tissue as the delivery technology mature. We have really focused our portfolio on 3 main franchises. There is a hematology franchise, an immunology oncology franchise and genetic diseases in general, which leverage the starting block. In each one of these franchises, we have a series of programs. The lead programs at the moment are such -- they've developed and picked such that the probability of technical success is highest within that. But we have a series of additional programs that are coming behind the first lead program that as the technology and the particular franchise is optimized and derisked that we can deploy very rapidly to really expand the patient population that we will be able to tackle to. And we have finished the last year, 2022 with very significant momentum across each one of those franchises. In hematology, we have enrolled the first subject for the BEAM-101 trial. This is for the treatment of sickle cell disease. And we have made significant progress in what we call the ESCAPE technology. This is an improved conditioning regimen that overcomes hopefully the toxicity that busulfan currently leads and refocus the additional programs in the hematology pipeline, so that they can exploit their particular technology for the future expansion of sickle cell disease treatment and other hematological disorder. In immunology and oncology, we have cleared successfully the first IND for the BEAM-201 program by the end of the year, following a relatively brief clinical hold. And this is a treatment for CD7-positive T-ALL and potentially AML for the future. A set of patients that have left behind somewhat given some of the challenges of targeting antigens that are exposed on T cells. And the BEAM-201 is able to overcome that by delivering essentially 4 simultaneous edits, which is, to our knowledge, the first in the field. We also believe that there needs to be an investment at the research level to generate really truly allogeneic approaches, which we believe that, so far, it has been a challenge in the field to be able to do that. What we do know is that what you need to do in order to accomplish that, even though the biology can be challenging, is for sure the ability to edit several genes at the same time. And the base editing and the ability of base editing not to make double-stranded break is ideally suited to generate highly engineered cells of that type. And we're making very good progress in the preclinical phase. For the genetic diseases, we have initiated IND-enabling studies for BEAM-301. This is our product that aims to cure GSD1a, particularly the R83C mutation that causes the most -- is the most prevalent and also the most severe form of the disease. And actually, we nominated BEAM-302 as a development candidate. This is a program that aims to correct for the first time to our knowledge the mutation that causes alpha-1 antitrypsin deficiency. This is a single mutation that causes this protein basically accumulate in the liver causing liver toxicity as well as lung disease. And finally, we have expanded our strategic partnerships with a deal with Pfizer as well as a deal with a new company that has been formed called Orbital Therapeutics that aims to generate the next generation of RNA-based therapies. For 2023, we are excited to -- aim to complete the sentinel cohort -- the enrollment of the sentinel cohort and also to initiate the expansion in our BEACON trial. This is the trial basically to develop BEAM-101. And we have made some changes, so that we believe that this program can actually be accelerated such that we will be positioned in 2024 to present some clinical data on multiple patient as opposed to a single one. We plan to dose the first patient in the BEAM-201 trial. We believe mid-'23 is a realistic opportunity there. And for the genetic diseases, we aim to submit the regulatory filing for BEAM-301 by late 2023, beginning of '24, and by the beginning of '24 for BEAM-302, the alpha-1 program. Let me just give you some snippets of data on some of the key programs that we're moving forward, starting with BEAM-101. In this case, we are making -- we're using the precision of base editing to make single point mutations in the promoter regions of the Gamma 1, Gamma 2 genes that prevent the repressor protein from binding. And as a consequence of that, we can up-regulate hemoglobin F to a very significant level. In fact, if we are able to produce the preclinical data in human, we would have a best-in-class profile, where we have the highest level of hemoglobin F in excess of 60% and the concomitant lowest level of hemoglobin S because there is a regulatory control that the higher the F you generate, the less the hemoglobin S. And the reduction of hemoglobin S in itself has the ability to be clinically relevant. The BEAM-101 trial is to acknowledge the first clinical base editing program in the U.S. And thanks to the optimization of the protocol, we aim to accelerate this program significantly such that, as I mentioned, in '23, we can not only enroll the sentinel cohort, but also to initiate the expansion phase. In this case, it's a trial aimed at enrolling 18 to 35 years old with severe vaso-occlusive disease. And importantly, in addition to look at some critical safety profiles like engraftment time and potential, we are going to explore many biomarkers of disease in addition to vaso-occlusive crises. Obviously, vaso-occlusive crises are very important for the life of the patient and contribute clearly to the disease, but they're not the only thing that contributes to the diseases. And we plan to look at this very intensely with a variety of different biomarkers, including the quality of the blood, the hemolysis and many other parameters that are signs of progressive organ damage, which ultimately is what kills prematurely the patients. The way we see the sickle cell franchise is obviously the busulfan conditioning. We believe that, that is a commercial valuable opportunity where our preclinic profile, as I mentioned, if confirmed in the clinic, has the ability to be best-in-class. But where we see the opportunity for significant expansion is in what we call wave 2 and wave 3 of the programs. Wave 2 is where we would deploy an improved conditioning over busulfan that does not carry the toxicology -- the safety and consequence of that, like, for instance, stability, which really prevents many patients from actually accessing this particular transplant. And we have this opportunity that I will show in a moment that we call ESCAPE. And we're also developing the LNP technology that can actually overcome altogether the need for transplant and potentially deliver the editor directly to the stem cells in the bone marrow following an IV administration. And we've shown some data -- positive data in nonhuman primate, targeting the same cells last year to a range of about 20%. The improved condition that we're looking at uses this technology that we've named ESCAPE. And again, it uses the ability of base editing not to make a double-stranded break that enables our ability to do multiplex editing, whereby the same editor is used to not only make the disease correcting mutation, in this case the BEAM-101 correction, but also thanks to an additional guide, can make a single amino acid change in an epitope that is recognized by an antibody that we have specifically developed. This is an antibody that targets CD117. And it's an antagonistic antibody that prevents the binding of the ligand that activates basically the stem cells in the bone marrow. Because of the editor that we make in our cells, the edited cells are essentially stealthy to this antibody. So even if the antibody is present in the body, it does not bind the edited cells. And as a consequence of that, it creates a survival advantage towards the edited cells such that you are able to populate very effectively the bone marrow. The graph on the right-hand side shows some data that we have generated in mouse, where essentially proves exactly that. That as you increase the dose of the antibody, you can see increased chimerism of the edited cells versus the unedited cells in these animals. Moving on to the genetic disease franchise. BEAM-301 is a liver targeting, base editing technology, aimed at correcting the single point mutation across the GSD1a. This is R83C and, as I mentioned earlier, is the most prevalent most prevalent mutation that causes disease. This is a very high unmet medical need disease with -- basically, the mutation causes the glucose-6-phosphatase enzyme to essentially be unable to manage glucose homeostasis. And as a consequence of that, unless you are fed on a very regular basis, every 3 hours or so, you risk basically lethal hypoglycemic attack. And so as you can imagine is very impactful to the quality of life, not only of the patient but also their family. We have generated transgenic mice that in the homozygous setting are actually lethal within a few days of being born even when you give them -- you feed them glucose. And we've shown basically that we have a long-term preservation of vitality basically in these animals when we treat them with base editing. In case of BEAM-302, this is the additional liver targeting base editing program that we have generated, where we are aiming to correct the single point mutation that causes essentially alpha-1 antitrypsin deficiency. This is called the E342K mutation. And all of the patients carry this very same mutation. Typically, between 60,000 and 100,000 patients are estimated to be in the U.S. alone. And because of the fact that this protein is naturally produced in the liver, we are able in the liver to correct it to its wild-type state and as a consequence of that restore the ability of this protein to be correctively folded and released by the liver into circulation where it goes to the lung and does its job of protecting the lung from the attacks of elastase and other proteases. And therefore, in this way, restoring the normal functioning system for alpha-1 antitrypsin and, in particular, correcting both the liver and the lung disease. And the lung disease arguably is the one that it affects the most patients in this particular setting. We have achieved editing rates that if reproduced in human would be in excess of 11 micromolar. In fact, probably will be close to about 20 micromolar restoration of levels of alpha-1 antitrypsin and 20 to 50 micromolar are levels associated with normality. Finally, the BEAM-201 program, this is the multiplex edited CD7-targeting CAR-T program. As you can see, we are essentially making 4 simultaneous edits. They not only eliminate CD7 from the surface of the cells, essentially preventing the ability of the cells from killing each other. But also we eliminate CD52, which allows us the ability to use [ compass ] potentially as a lymphodepletion agent, and therefore, achieving allogeneic in this particular setting. We also eliminate the TRAC, the endogenous TRAC. This basically eliminates the endogenous TCR, which prevents the graft-versus-host disease and basically also eliminated PD-1 receptor to prevent premature exhaustion. You can see the efficiency of the base editing allows us to have in excess of 90% of the cells carrying all 4 mutations. So the clinical trial, which we are calling BTX-ALO-001, basically is targeting a population of 18 to 50 years old, where there will be a dose expansion phase. And once the dose has been selected, there will be further expansion to different cohorts, including hopefully, a pediatric population of 1 year and older following review with the FDA of the data. And here, basically, we're looking at complete remission as a prelude to essentially enabling transplant, which is the standard of care in this setting. And finally, we've continued to expand our strategic partnership not only obviously with Pfizer, which I mentioned earlier, we have an ongoing collaboration with Apellis for 6 programs looking at the complement pathway. We had a deal with Sana where we outlicensed our Cas12b nuclease. Obviously, we have opt-in rights to the 3 programs that Verve is prosecuting, 2 of which are disclosed, third is not. And opt-in rights after the Phase I data has been generated. We have exclusive access to prime editing for certain fields, which include basically the transition mutation as well as sickle cell disease. And then this new partnership with Orbital Therapeutics that is a next-generation RNA and delivery company utilizing amongst other technology, circular RNA and viral like proteins. And last but not least, we are extremely proud of our team that has come together as a real -- with real comradery and with a lot of experience, frankly, in developing and launching programs and project in a variety of different fields, but importantly also, in new technology as part of now. And so I'll leave it at that and happy to take any questions.

So while I guess mics get positioned and so forth, I can start out. And I think I'll start with BEAM-101 in sickle cell disease and really just kind of -- well, recently, we saw a clinical setback with another cell therapy-based competitor in this space. So I guess it would be helpful to sort of have you distinguish the approach that you're taking with 101 relative to perhaps that program and just sort of how -- I guess, how you would give investors comfort that you're going into clinic with a favorable tolerability profile from the get-go?

Maybe I'll jump in here. So I'm John Evans, CEO. I think that we often get the comment that the sickle gene editing space is very crowded. There obviously are a lot of entrants. I think though, if you step back and look at the data that's starting to roll in from the various players, we can actually start to differentiate what we're seeing and I think identify those companies that are going to hopefully rise to the top and then some that are obviously struggling a little more. Obviously, the graph idea was very disappointing. I'm sure they are all over that. We obviously think about the health of the patient as much as possible. That's a challenging approach, obviously, trying to make HDR work in long-term engrafting hematopoietic stem cells. That's been a challenge. It looks like it still is one. I think at the end of the day, we look at the field as Bluebird will get there. Clearly, Vertex and CRISPR are going to file soon and we'll -- and we expect them to reach market as well. You have another set of nuclease companies that are coming, and then there's us. We're really coming along with what we view as next generation editing technology. It's nonviral. It's non-cutting, so we're not using a nuclease. We make very precise changes in the case of 101 to turn on directly the fetal hemoglobin genes and deliver that very high level of editing and of F that Pino described. And we think that will be very competitive.

Maybe the only other thing to add is that really what is important to understand is that even though the CD34 is a starting patient population, actually the only proportion of targeted cells that are ultimately going to engraft for the long term is a very small proportion of that. It's usually about 1% or so. And really, the ones that you are aiming for is the long-term stem cell progenitor cells. Those cells are importantly in the context of HDR are typically very poorly replicated. They don't replicate very well. And therefore, HDR is a disfavored pathway in those cells. So fundamentally, what you're doing with HDR, you are selecting editing in the target -- in the population that is not your target population. And in fact, what my interpretation, what they've seen, is actually a secondary engraftment that they've seen. This likely stems from the fact that you can get engraftment thanks to the short-term stem cells. But actually, if you don't manage to engraft a significant number of long-term stem cells, essentially what you see, you will see secondary engraftment failure. And that -- it's my interpretation. I haven't seen the data, of course. There may be other factors that is part of that. But certainly, it's something that we would have predicted could be likely to happen in the clinic.

It won't be until next year where we might see initial data from the BEACON study. I guess that being said, how should we be thinking about updates from the study, particularly as it relates to certain safety checkpoints in the trial, yes, just the nature of updates from enrollment progress over the course of the year?

Yes, you will see signs of progress. I mean, I think the most significant -- so we did guide that we expect to have data in 24 on multiple patients. We wanted to have a really robust data set because this is about communicating the depth of our science in that program with the sickle community and getting them excited. So we want to make sure we do this in the right way at our scientific meeting. That said, this year, it's going to be a pretty active year. So what we've guided is that we will -- we basically accelerated the first part of the trial, as we talked about last fall, so that we can, as Pino said, complete the enrollment of the sentinel cohort this year and initiate expansion this year. So I think you'll have a sense as all that is happening, that things are hopefully on track and they're moving quickly even if we haven't shown you the data yet.

And the other thing that we are investing significantly on, as I mentioned earlier, Eric, is on the manufacturing capabilities there. Because, as you know, obviously, the editing is important, but the entire process of manufacturing is also of strategic importance in this particular process. And we're optimizing process that right now is already pretty much closed, which means it's really automated and very close to be essentially the commercially viable program that we want to be. So you will see also, hopefully, some updates in that commercial -- in the manufacturing component of that.

The -- I guess a couple of questions related to wave 2. It's a really elegant approach that you're taking with ESCAPE. Still would be interested to get a sense of what makes CD117 sort of an attractive target for myelosuppression depletion and sort of how your approach might differ from -- I guess, we've seen other anti-CD117 approaches, some of which have also had sort of clinical [ subtracts ]. I guess how is yours perhaps differentiated from them?

Yes. Perhaps I can give a couple of important consideration there. First of all, the CD117 and in particular, the binding of the ligand, which is called the stem cell factor to that receptor is essential for the expansion of the stem cells. And so it's a critical part of the biology that enables the central engraftment. And the antibody that are being developed are antagonistic. So basically you can no longer bind to that to some extent. The issue with the other approaches though is that they need to ensure that the antibody is out of the body by the time the edited cells comes in. And because otherwise, you will kill the edited cells as well as the unedited cell. So they have a relatively narrow window of opportunity as well as a PK profile that is limited in dosing because obviously, the higher you dose, the longer the antibody is going to stay in the body. By creating edited cells, which are stealthy to this particular antibody, we have the ability to allow the antibody to be present even in the presence of the edited cells, and therefore, creating really this competition opportunity that favors the edited cells above the others. And this actually happens in a preclinical animal model, which is the NBSGW mouse, where there is a hyperactivity of CD117, thanks to an amino acid change. And you can see that there, we can achieve very high level of engraftment with human cells. So we already have a system in a preclinical setting that shows that, that competition with a less than active CD117 can lead to successful engraftment. The important thing now and part of the pharmacology studies that we will be doing during the course of next year is to demonstrate that we can achieve the conditions essentially that we see in the preclinical model in also higher animals like nonhuman primates.

It's essentially like a -- it's kind of 2 products in one here, right? So how does the pre-IND enabling process work? How far -- I guess, how far advanced in -- sorry, how far advanced in non -- sorry, development with nonclinical models with 117 do you have to go? And then let me also ask sort of how close you are towards DC, development candidate selection for, let's say, ESCAPE 1?

Yes. We haven't provided any guidance in terms of time lines, but it's a very high priority program, so it's heavily funded, as you can imagine. But importantly, we will be doing some pharmacology studies in nonhuman primates, which we think are really important to understand really what is the clinical profile that we can aspire to have. Once we have that, then I think we will be much, much closer to a development candidate and moving forward because it gives us the idea around the dosing regimen, the frequency, the levels of engraftment that we can expect to see in what is essentially a kinetic sort of, in a way, fight between the edited and unedited cells in the bone marrow.

And maybe if I could riff a bit on your point about multiple programs here because I think it's an important point. As Pino mentioned, we had these pillars in the hematology -- and each one has sort of near-term assets in these long-term expansion opportunities. So in hematology, it really is all about ESCAPE and then in vivo delivery as a payer of ways to change the calculus for patients, right? So right now a busulfan transplant is a good option for severe sickle cell disease, but not a great option for moderate sickle cell disease or other hematologic conditions. And so if we can bring ESCAPE forward, now you make the transplant much more tolerable. And now many more diseases are potentially targets for gene editing, and we can move there then quickly. So I think it is a critical piece that opens the door to both, a lot more success within hemoglobinopathies but a lot of diseases to follow beyond that.

Can you take any plans to take ESCAPE beyond sickle cell? Because extensively, you could...

Yes. So you could do ESCAPE with other therapeutic edits for other diseases. You could also do ESCAPE on its own, right? Just to bring the benefits of autologous transplant to patients who would benefit from resetting their blood system at certain points. So the ESCAPE betted on its own could be a product on its own. So lots of opportunity if this pans out.