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

Ladies and gentlemen, the program is about to begin. Reminder that you can submit questions at any time via the ask questions tab on the webcast page. At this time, it is my pleasure to turn the program over to your host, Greg Harrison.

Hi, and welcome to the Bank of America SMID Biotech Virtual Conference. I'm Greg Harrison, one of the biotech analyst here at BofA. And today, I'm happy to introduce Beam Therapeutics, represented by John Evans, CEO; and Giuseppe Ciaramella, President and Chief Scientific Officer. Thanks for joining us, everyone. And for those of you out there watching, if you want to send any questions, I'm happy to ask them on your behalf. John, if you'd like to start off with some opening remarks, that would be great, and then we can jump into Q&A.

Sounds good. It's great to be here, Greg, and thanks for having us. So Beam, as people may be familiar, is a next-generation gene editing technology company. We are pursuing technological base editing, which is a newer version of CRISPR. We can use the same targeting power of CRISPR, we make much more precise single-based changes in the genome as onetime treatment, so we don't need to go through a double-stranded breaks to do that. So we don't ever have some of the consequences of cutting the DNA in the process. So it's a very versatile system, and it gives us a lot of different advantages, both near-term and long-term that we're exploiting in a very broad pipeline. Our strategy has been to pursue all of the different kinds of delivery in parallel. That has generated a lot of product opportunity. And we've shaped that into really 3 different, we call pillars within the portfolio. Hematology, where we're editing blood cells. That leads us to, in the near-term, sickle cell disease, where BEAM-101 is moving forward really quickly now in the clinic towards treating patients, which we think can be really competitive on a potential best-in-class product. Longer-term, we're using base editing to go further than that and even potentially change the conditioning that we use to get transplants done in patients and make this a lower genotoxic procedure, which could then, of course, rapidly expand the patient population. In immunology, our second pillar, lead program is BEAM-201, that's a quad-edited product, taking advantage of the fact that this base edits don't cut, we can make as many edits as we want in T cells and stack them on top of each other for more engineering and more function. So that is now off clinical hold moving into Phase I. Longer-term, our ambition here is to use that ability to make many edits to create cells that are truly allogeneic. This is more like 4, 5, 6 edits each cell. So that's a research work that's ongoing now and it could lead to a really significant franchise opportunity in allogeneic cell therapy. Finally, the third pillar in vivo, which liver is the lead. And here, we have BEAM-301 for collective storage disease now in IND-enabling studies, and now recently nominated BEAM-302, our first development candidate for Alpha-1 antitrypsin deficiency, both correcting the causative point mutation in those 2 diseases back to normal, in both now we report quickly. And then longer-term, very excited, of course, we have many different targets in the liver and the ability to potentially expand delivery using lipid nanoparticles, for instance, non-viral delivery to other tissues across the body. So a very broad set of opportunities, very diversified portfolio with a lot of different profiles in terms of how we use the editors, how we deliver them and what kinds of really significant franchise opportunities that can potentially create over the long-term.

Great. That's a great overview and tons of exciting stuffs that you're working on. Maybe if we could just start with an overview of how your base editing works to make these edits and how that's different from other strategies like traditional and CRISPR editing?

Yes. So CRISPR uses a guide RNA to target the DNA. And what's beautiful about that is, if you change the guide RNA, you have a new medicine. You can just retarget it to a different part of the genome, and that's why CRISPR has been so successful. So base editing builds directly on that, we use the exact same targeting approaches as CRISPR. We think that's -- really its best feature. What's different is, when the CRISPR gets there, it makes a double-stranded break, and that has a lot of consequences. It's a genotoxic event of the cell, you get cell damage responses come up, the cell can put the pieces back again in the wrong order, if you have multiple breaks, that can create chromosome rearrangements. You can also get large unintended deletions and changes at the on-target site. And finally, just remember that when you say we have 80% indels, which is often what people talk about with nuclease as well, that's actually a constellation of a variety of different random changes, right? It's all the different insertions and deletions, you're getting 100s of different alleles at the target site. You really can't control the sequence you get. And so, some of those alleles may be more or less productive, they're certainly uncharacterized. So with base editing, we really address all of those latter issues. So we have the ability to basically land and open the DNA, we don't make the double-stranded break. So you don't have any of those chromosomal problems or genotoxic stress problems. And instead, we're making a single base change using a deaminase, which is a chemical enzyme that we've tethered to the CRISPR that is tuned to just make one kind of change at that target site. And that change is permanent, it's efficient, it's biochemistry basically on the genome. And so we're intending at very high efficiency levels, and we don't care about the cell state dividing, non-dividing, we generally just will work the same in any kind of cell. And so, it's really the high efficiency, the specificity with which we can make the edit, the lack of double-strained breaks and the effects on the cell. And then the control to many of the sequence of results where we know exactly what allele will solve, we can fully characterize that allele, let us predict its function and really, I think, be now editing with a lot more rational intent.

Great. And so your lead program, as you mentioned is BEAM-101 in sickle cell. Maybe you could just give us an overview of where you are at with that, you'll, I think be treating the first patient soon. And so the time line, what we can expect in terms of the data readout?

Yes. So first patient is enrolled as it was our goal for this year, so that we've now started back in November, so that's very exciting. As we've said, it's about a 6 month process to get the first patient's dose. That's the extent of time for a transplant. You're going through confusions, several rounds, mobilization several rounds, manufacturing, conditioning and then transplant. So that could be Q2 kind of mid-year event for next year. We're making sure -- what we're working on now is making sure that subsequent patients can be as compressed as possible. So it is a [indiscernible] we have to do one patient at a time, but there may be ways and we're working on doing this to do some amount of that work in parallel, where you're going to [Technical Difficulty] the ability to go from patient one, patient 2, patient 3, and then on into expansion, which is the first and real -- the real ultimate goal. So that is ongoing. Ultimately, over the next year, I think we'd like to really make decent progress through those sorts of enrollment challenges and goals and with an eye towards the time of BLA filing, which is really our goal here, particularly as Vertex looks like they're validating a filing pathway for a single trial, which we'll know more about next year as they bring that in for filing. In terms of data, I think that we'll obviously be looking to probably target a medical meeting that tend to be our pattern. We haven't made a decision yet in terms of exactly how many patients we want to publish on. But we do want to make sure we bring forward a reasonably robust set of information that helps you understand the drug and it gets the community excited about it. And yes, so I think we see a clear path for 101, and we think that the market for a busulfan based regimen like this is actually meaningful, notwithstanding the factor that we will agree that if we can then fix the busulfan part and get rid of that impediment, more patients will definitely choose this and the market would be even larger, but we're quite motivated to get 101 as the best-in-class agent even for this initial wave of the sickle market.

Great. And you mentioned CRISPR and Vertex and your goal to be best-in-class. How do we tell, I think earlier stages when you have your data mid next year. So what should we be looking for that would indicate whether your product really is differentiated, just given that the bar is pretty high here in this indication?

Yes. Maybe I'll let Pino answer that. But I mean, just to lay out the time on, I think if we're dosing middle of next year, I don't think we have data middle of next year. You got it. We could follow that patient, obviously, again, it comes back, it will be published on just one patient and wait for several. And I think we may do the latter. We'll see how it goes. But at some point, yes, we will have a data set that should be pretty instructive. So Pino, if you want to talk a little bit maybe about the differentiating points of the product and what we'll be looking for in the clinic.

Yes, absolutely. And so obviously, VOCs, as you know, is something that is very impactful to the quality of life of the patient. These are excruciating pain crisis that they undergo. And it seems both from the Bluebird data from Vertex data and even from the one patient from Editas, that this is actually a relatively easy thing to fix when you get a certain level of editing efficiency. But the reality is that the disease of sickle cell disease is much more complex than VOCs alone. And in fact, really what kills the patients ultimately is the progressive organ damage, which is not just caused by VOCs, but it's caused by many other factors that are -- contributing factor of sickle cell disease, in particular, the very short half-life of the cells causes the cells to live all the time. So you have a frequency polices, you have a release of cytokine and chemokines that contribute to inflammation. You have a very -- the viscosity of the blood is thicker. So there are many parameters that actually are not necessarily fixed just by fixing the VOC. And what you -- what we have seen preclinically is that we are -- by achieving the highest level of a F upregulation that anybody has reported, we get in excess of 60%. Importantly, what we also see is the concomitant decline of hemoglobin S to levels of 40% or less, which are actually similar to ones that you see in sickle trait individuals. These are individuals who are heterozygous and do not typically have symptoms. When you look at the data from Vertex, but even this one patient from Editas now, we still have levels of hemoglobin S at about 55%, which is not quite where the sickle trait is. And so, it remains to be seen how deeply they actually resolve the progressive organ damage, which I think is ultimately what a curative approach needs to do. And so, we will clearly monitor, of course, the organ damage aspects, and we will focus on kidney, on the brain, as well as the lung. But there are many of these parameters that are actually early signs of efficacy, if you will, that you can monitor. So we will monitor, first of all, of course, the editing efficiency, the higher upregulation of F and the decline of Fs, will all these things that we've wanted to have. But also the quality of the rheology of the blood, the viscosity, the improvement of the half-life of the B cells, we will look at the inflammatory milieu that these patients have, the oxygen binding capabilities. So all of those parameters are able to provide a clinical, essentially a picture that could show how much more deeply we have resolved basically the sickle cell complications.

Great. Yes. That's helpful. So your next program within sickle cell is 102, where you're actually changing to a variant and fixing the gene directly. Where do you see this as fitting in down the road? It definitely seems like a more elegant approach than what people have been doing in the past. So where does this program stand? I know you've made some changes to the prioritization recently? And where do you see the potential here?

Yes. I think, I mean it is a very elegant approach, which we've always liked. But I think the key point is -- the reason for the prioritization change is, it was -- it's not totally clear how it will beat 101, right? I think for all the reasons Pino said, we're pretty sure that 101 is going to fully do the job. And so rather than create another busulfan-based regimen, which is what 102 really represented and wait for that to get into the clinic, then compare them and then think about what we go forward. We made a decision that, at least in Wave 1 for the busulfan market speed matters. And so 101 is there, so let's go, let's put all the patients there, minimize that time to BLA filing and compete with whoever is there, maybe it's Vertex, maybe it's others by then. And in the meantime, we think that the next best use of our energy and resources is really to climb this ladder away from busulfan towards a non-genotoxic conditioning regimen and/or in vivo delivery, those are our Waves 2 and Waves 3. And there, the delta for value is much greater for patients and obviously, from a commercial perspective. So that's the priority. And so we made that pivot, the Makassar edit is still with us, obviously, so we'll actually be publishing at ASH abstracts on what we call the ESCAPE technology, where we're doing this extra edit, so we can make a selective conditioning, where we can condition old disease cells but leave alone your new and grafting cells and do that alongside each other, which is something that no one else would have the potential to do. And we showed data on both ESCAPE-1 and ESCAPE-2. So ESCAPE-1 is what references that conditioning trick alongside the F upregulation edit. ESCAPE-2 is that condition took alongside the Makassar edit. So both are available to us for these future waves and definitely remain excited about it. But the key point is, we see more banks in the buck in terms of fixing the regimen with the ESCAPE technology as our next play.

Got it. Now this is something a lot of people are working on, right, trying to get rid of the busulfan. Do you -- I guess, do you have your own approach, what do you think wins in the end? Is there a common approach that could be shared? Or do you think it's going to come down to who comes up with the best proprietary approach to use with their product?

I think ultimately, it's going to I mean, the more efforts the better, because we think is a priority for patients. And of course, if anybody starts to fix this, it will be a huge rise and tied for the entire field, and we'd be very excited about it. So it doesn't have to be a proprietary approach, and we're actually partnered with Magenta. They're making good progress. We're hopeful for that program to make it. There are others out there. The trick is none of those programs have the advantage that our ESCAPE technology would give us, right? So what they all have to do is, fundamental question with the initiates, you have to go deep enough initially to get -- to create a niche and space for engraftment that is as good as a normal transplant, right, as good as busulfan. But then you've got to get out of the body in time so that you don't kill the graft, okay? And that is a tight rope to walk. And so I think the key point is that as far as we know that our technology is the only one that has the potential to really change the odds of that working, right? Because now we can have the conditioning agent alongside the grafts, high dose, re-dose, continue to titrate, continue to shift timers over time in favor of our graft. And I think that is a pretty powerful idea. So that would be, of course, a proprietary technology, it would support our programs, it would have to be customized with our program, so it wouldn't be used a little by others. And I should note that actually that principle could be then extended if it works to many other sets. We view for that technology sickle as the entry point, but we could then think about many other transplant settings, making the transplant better and that would be an interesting business opportunity and then revolutionary for patients as well as tip the balance on many other types of diseases in hematology and beyond that could be treatable with transplant that isn't currently -- doesn't make sense from a risk benefit perspective through the busulfan transplant. So sort of a beachhead to a potentially large franchise opportunity in hematology if it works.

Okay. Yes. Very exciting opportunity there. Now BEAM-201, you had your hold listed recently. Maybe you could give an update on where does that program stands? What does it look like as far as getting that in the clinic? And what do you see as the potential for this program?

Pino, do you want to cover that?

Yes. So we're obviously now in the process of opening several sites in U.S. to start with and with a view, hopefully, to start dosing in the next year. And the program basically is targeting CD7-positive TLL. It's the first quadruple at cell -- CAR T cell that anybody has produced. And we're excited about targeting a patient population that, frankly, has been underserved in the past because of this phenomenon of fratricide, the antigen that is on the malignant cells is also expressed on the T cells. And unless you remove it, you end up T cells killing each other. And the need for removing that increases the number of edits that you need to make. And that's why in the past, basically, it's been a challenge for developing CAR-T programs of this kind. We have taken the opportunity with base editing to do the multiplex setting. And so we remove CD7, we remove obviously the endogenous TCR, but we also remove PD1. And in this particular approach, our allogeneic strategy is similar to the allogeneic strategy where we're removing CD52 and then we can use this antibody known as COMPASS to actually create the lymphodepletion. And in addition to TLL, we also to do an expansion eventually to CD7-positive AML, which represents about 10% to 15% of the AML patient population.

Got it. And then how do you think about this indication with and you mentioned an expansion there into AML? But how do you think about moving into some of the larger CAR-T indications and balancing looking for areas of unmet need and where you can be differentiated versus larger markets, which may be more crowded right now?

Yes. I think for additional indication, frankly, for the bigger indication, our belief is that you really do need a better allogeneic strategy than the field has managed to produce so far. Unfortunately, as you can see, the persistence of all of the allogeneic strategies that are in the clinic right now, it seems not to be to the level that is needed to achieve the equivalent efficacy that autologous CAR-T approaches are actually having. And we think that basically, it's because the edits that are being made in those approaches are not yet sufficient to evade the immune system in a manner that gives you the adequate persistence. And so what we have decided to do is to -- before we actually go into an additional CAR-T approach, is to actually deploy some of our research strategies and ideas in order to generate a much more allogeneic, a much more stealthy T cell to the immune system. We're really not convinced that the current strategy, which is a better to non-cut or even the HLA-E overexpression are sufficient to adequately, I guess, clock the T cells from the -- both the T cells and the NK cell compartment. And we have some ideas that we're deploying. The key point here is that, there will be several edits that are needed. And so that's why we think that base editing is extremely well placed to actually do that. There will be 4 to 6 edits probably will be required in order to have the bile regime modulation as part of that. Of course, within research, we can't guarantee that, that is going to be successful, but we think that it's better to take that approach. And if we can do that, then frankly, would open huge opportunities for that. And if we can't, then we'll pivot away from these as one of the pivots.

It makes sense. What is the registrational path for 201, given that it's a smaller patient population? How quickly do you think you could get to the finish line here?

Probably similar to what we've seen with the other CAR-Ts. I mean, remember, one of the nice things about this from a development perspective is, you have the B cell ALL field, right? And that was where all the CAR-Ts went initially. And this is just the T cell component to that, right? It's a very similar disease and we would expect similar kinds of strategies could be used to get to an approval. Obviously, it is smaller. So I think it is a more niche population than the B cell population, but still a meaningful one to pursue and a very high unmet need, right? B cell ALL has been transformed by CAR-T and other therapies and really this T cell population has been left behind. And of course, the reason they have been is, because if you have a T cell CAR targeting a T cell, you have a problem for [indiscernible] cyto-killing, which is your T cells kill each other before they get to the tumor. And so that's one of those 4 edits that Pino mentioned was required. So I'd say increasingly, looking at a couple of autologous, a couple of academic programs that are out there on CD7. We think CD7 is a validated target biologically, which is attractive and rare in this field. And so it's actually reasonably open, I think, and we can hopefully get there first. And again, we're looking for high CR rates, deep CRs patients getting to transplant. These are patients who don't have a lot of other options in front of them if they hit the refractory stage of this disease. So we're quite hopeful to make an impact on their lives.

Great. And then the other area where you're in is liver in 301 has been progressing. What does it look like in terms of the time to the clinic there? And how are you thinking about that as an indication?

Yes. So I mean, you're basically looking to -- I mean, we're in IND-enabling studies now, which is exciting, it's a biologic. So from developing candidates, you have to do a lot of manufacturing, then you can get start the IND-enabling, once you've done that, you obviously write-in file your regulatory filings. So we see a good path forward for 301 now. I haven't guided on exact timing. It's generally a sort of 12 to 18 months process to get to the finish line here. And -- but a very compelling program, we think a low bar for editing, liver target, these are patients who cannot handle fasting and they really desperately need better options. And this should be a onetime in vivo correction of a mutation, which I think is the first in the industry for something like that. And we're obviously very excited about it. Again, smaller population, but something like 900 patients in the U.S., that's still a meaningful opportunity and a lot of good that we can do, and then really would set the foundation for many others to follow Alpha-1 and many others.

Okay. I guess one broader question. How do you think patients think about something like a base editor or gene editing even at this point? And what types of scale to where maybe some of the fear goes away and they become more broadly accepted over time?

That's a good question. Pino, do you want to take back of that?

Yes, of course. It's about generating good efficacy data without safety complication. I mean, there is no substitution to -- for that. But I would say that we talk a lot directly with patients. We have a lot of patients outreach, particularly even for the GSDIa. We recently had several of those patients actually coming to visit us and talk to that. There are some that are really looking for the opportunity to finally have a life that is independent of having to carry this complex starch. They have a safety kit there, everything that they do, they need to be -- every 3 hours, they need to basically use these things. So it really is so impactful in their lives that it creates really the opportunity for them wanting to export this as a solution. And we will do a lot of work on educating essentially the patient population of why we think that actually -- the risk is a appropriate here, particularly in some of the integration. It will take some time undoubtedly. But I think the outreach to the patient will certainly help understanding and putting it in the right context to risk the technology cares.

On that, just to say, I think we haven't talked as much about this, we're not at commercial phase yet. But I really think there are going to be tailwinds for this eventually, right? I mean, so there's that comfort building, the data generation Pino mentioned. And then ultimately, this is a onetime therapy that patients can kind of focus on and get done and then hopefully have a lifetime of benefit if we're able to deliver on the promise. And you're really creating value, I think, for the healthcare system. Obviously, the pricing will need to be high, there's a lots to work through there as a challenge, but you're displacing a lifetime of medical care to follow and risk. You're treating patients in the prime of their lives who have productive years ahead or kids. So the pharmacoeconomics, I think, can be positive, and then you're often displacing expensive chronic pharmaceutical or biotech products, right, which is another cost to the system. So I really believe there's a strong value story here if we can deliver on the potential of this product profile.

Yes. That makes sense. One minute left. I'm going to ask you a question that you could probably talk for hours about, but we got to keep it tight. But where do you go next with this platform? And how do you even narrow down all the opportunities to the areas that you decided to invest in?

Yes. It is a constant debate Pino and his whole team talk about this constantly, [ Brett versus ] focus, right? Obviously, our strategy is reflective of the fact that we are on a offense. We think we have something really compelling here that has a tremendous amount of applicability. I think we've designed a portfolio that has deliberately not just shots on goal, which people think about, but really are asking different questions of the technology in different ways. So that when we get those answers, not only we de-risk the product to move forward to patients, but we also have information that tells us, okay, this is working, we can do more of this, right? And we're going to sort of tune our portfolio over time based on that. And then I think I'd go back to where I opened, the sort of the pillars of conversation and already reflects some of that, where we sort of shaped it now to say, okay, there's a big hematology story, there's an immunologist story, there's an in vivo, let's say, liver story and beyond. And in each case, we've got these lead assets, which are very exciting and could create revenue and make an impact on patients. But at the same time, they open doors to these very big sustainable opportunities. And so, at least so far, changing transplant, changing the way that we do hematologic treatment, allogeneic therapy, cell therapy broadly with high levels of base editing, in vivo delivery, plug-and-play to liver and to other organs. I mean these are gigantic opportunities for us. There are other ways to even use base editing as well. And so we continue to have other opportunities that are always on the horizon, and we have a lot of discomforts on going to that could generate future seeds for growth even beyond that. So it's a -- I agree with you, it's a lot of opportunity. We're approximating as -- smartly as we can even while we focus on executing at the front of the pipeline.

Great. Yes, super exciting, and I can't wait to see where you guys go with it. So with that, we're out of time here. So I'd like to thank the team for joining us today and everyone out there for watching, and take care everyone.

Thank you very much.

Thank you.