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

Good afternoon, everyone, and welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I cover U.S. [ Snicket Biotech ]. It is my great pleasure to introduce our next presenting company, Beam Therapeutics. With us today, we have Pino Ciaramella, President. Okay. So maybe Pino, before I ask specific questions, do you want to give a brief overview.

Yes, absolutely. So first of all, thank you for having us. So my name is Pino Ciaramella, I'm President of Beam Therapeutics. And I've been with the company pretty much since the beginning, just over 6 years ago. Beam Therapeutics is a company that has been formed around the next generation of gene-editing technology called base editing. It's a technology originally developed in Professor David Liu's lab at Harvard now at the Broad, which uses Cas9 protein as part of the editing machinery but has modified the Cas9 in 2 important ways. The first one is eliminated the possibility of this Cas9 protein to make double-stranded break, which we believe is quite a situation in -- which could cause some unwanted consequences in the cell. And then also modified it so that attached to this protein, there is an additional human enzyme called the amylase, they can actually directly convert a nucleotide to another. We have a CD amylase that converts a C to a T. And an A, the amylase can convert an A to a G. And of course, if you go on the top strand or the bottom strand you can actually convert 4 basis to with 2 editors. The Cas9 protein obviously provides us still the opportunity to use exactly the same guide RNA strategy to be able to deliver the protein in different parts of the genome, depending on the guide that you use. So we can build a lot on actually what has been learned by the -- sort of initial first-generation nuclease-based editing technologies.

Great. So you do have programs already in clinical development. So maybe like talk a little bit about sickle cell, and we just had a discussion with Editas. So maybe like your approach and then the differentiating part you're looking for?

Yes. So with the base editing technology, we are essentially focusing on our portfolio on 2 important franchises. One is on hematology franchise, focusing in initially on sickle cell disease, but potentially expanded even from that, and we can talk a little bit about that as well as well as in vivo delivery through LNP technology for essentially genetic diseases starting in the liver, but potentially going even beyond that. Sickle cell disease, as we mentioned, is obviously a program for which we are in the clinic. The ability of base editing to make a single nucleotide change and the ability to do that without making double-stranded break, it's something that we're exploiting in sickle cell disease by essentially doing an edit in the promoter of the 2 genes that make hemoglobin F, the fetal form of hemoglobin. These are called the gamma 1 and gamma 2 in the promoter region. So that now the single nucleotide prevents the repressor protein from binding there. And not only does it prevents from binding there, it actually makes the promoter even stronger. And as a consequence of that, we are able to make the edits on both genes. And we are seeing in preclinical study, the highest level of pre-regulation of act that anybody has actually been demonstrating. Vertex CRISPR region, it was in the 30%, 35%. Editas preclinically was it about 50%, although in the clinic, they are both running at about 40% to 45% hemoglobin F. And the reason why the higher level of F is important, not only because F obviously is a protein in itself, they contribute to anti-sickling. But perhaps more importantly, it's because when you get to the high level of F, you are now starting to switch off the production of hemoglobin X. And we are now the only company that has been shown, at least preclinically, that ratio of 60% good hemoglobin, 40% bad hemoglobin, which is typically seen in sickle trade individuals. These are heterozygous individuals that actually do not suffer from the consequence of sickle cell disease. And we believe that, that is really a recipe, if you will, to ensure that we see a deeper resolution of all of the conditions that cause sickle cell disease. And for example, the opportunity to differentiate, as you mentioned, is about deeper resolution of hemolysis. For instance, if you look at the Vertex data, I mean, it's great that these programs are providing such important opportunities for patients. And they've made a lot of improvements, but there's still a little bit of headroom to be able to get to the place where we want to be. So hemolysis resolution is important. The Vertex data shows that they've not yet normalized that. The hemoglobin levels, particularly in male is not yet in the normal range. VOCs obviously seems to be something that you can fix relatively easy, I would say. But even there with the latest data, it seems that the number of VOCs is creeping before they were in the mid-90s. Now it's in about mid-80s, but I've looked at the data recently. So again, there is an opportunity to optimize. And the other opportunity is also around, frankly, the manufacturing process. And in particular, the ability to generate a good number of cells, healthy cells that could minimize actually the production of the input I would say, the number of mobilizations. They're actually very -- really time-consuming and cost-consuming and really impactful on the quality of their patient journey. As you know, each mobilization is about a week hospitalization at Vertex. And so in Vertex label, there is essentially a comment that up to 6 mobilization may be necessarily including the fact that about 10% of patients are expecting not to have enough cells at the end of their production process to receive the transplant. Obviously, we're at the beginning of our journey, we will meet many more. But what we've seen so far is that we are tending to be around the 2 mobilization per cycle as opposed to the 6. In fact, I would say Bluebird is more similar to us in that setting. So they are more in the 2 range rather than the 6 range. So overall, I think it gives us the opportunity to provide some differentiation in what we call the Wave 1 of treatment, which is still reliant on the busulfan conditioning in which, as you know, is -- obviously works. But because of the infertility issue essentially allows only about 10% of the patients to want to undergo this particular treatment. In that case, it's still, we believe, a very meaningful market given the price point that can be justified in the setting. Obviously, Vertex is $2.2 million. Bluebird is in -- about $3 million. So we estimate about 1,000 patients per year, and that essentially is a $2 billion to $3 billion market, of which a best-in-class profile is the one that we plan to demonstrate hopefully allows us to be an important player in that market. But perhaps even more importantly, the way we are looking at hemo -- sickle cell disease is a longer-term franchise -- and importantly, what we are developing is also an opportunity to do away with busulfan by using the strategy that we call ESCAPE, which is based on the ability of base editing to make single amino acid change as well as the ability to multiplex editing without having double-stranded breaks and therefore, without the risk of chromosomal rearrangement. And in this case, what we do is to make a single amino acid change on a receptor known as c-KIT. This is a receptor that all stem cells need in order to access to both factors to actually survive. And in this case, the amino acid ensures that the edit itself do not bind to the antibody that we have developed. And instead, the antibody is still capable of binding to an edit itself and actually starve them of the growth factor that they need to survive. And so you selectively kill essentially the unedited cells and giving a survival advantage to the edited cells without toxins associated with that.

So this is very comprehensive. So maybe the 4 -- same for the first gen product, are you looking for 4 different differentiating of -- yes.

Parameters. Yes. Those are...

So then the key part is, we wanted to reach 60% physical open level.

Yes. I think the 60 to 40 ratio will be important. I think in looking at more deeper resolution of hemolysis would be important. The overall blood quality, by looking at viscosity for instance, is also an important factor. Looking at -- they may -- obviously, 80% VOCs is still a very good resolution of that, whether we can improve upon them remains to be seen, but that's also something that we look at. And importantly, we want to look at the entire patient journey. And if we can keep the mobilization rounds on the lower side of the numbers that we also feel will be an important aspect.

So should that be the bar we are looking for when you share [indiscernible] data?

Yes, we certainly -- we're going to aim essentially for being a best-in-class profile. And that's fundamentally what we are aiming for.

So maybe like outlined the data time line?

Yes. So the data, what we have disclosed is that we plan to essentially show data on multiple patients by the end of this year. We announced last year that the first patient actually was not only dosed, but also engrafted. And so you can imagine, depending on where the data cut is going to come, there will be a listed one patient with several months of follow-up. We've also guided that we are essentially on track to complete the sentinel dose in cohort as well as initiated in the expansion cohort, hopefully in the middle of this year. And so by -- towards the end of the year, we should have these multiple patients data. And we're starting to already collect data of the types of analysis and biomarkers that I've mentioned, including hemolysis. Importantly, that hemoglobin F on a per cell basis, looking at that 60-40 ratio, we're going to be looking at hemoglobin level, of course, VOCs will dependent -- will take a little bit more time to demonstrate, of course, but that's definitely something that we will continue to monitor.

Okay. And I think at the earnings press release, you said third patients to be treated. So has that patient already dosed yet?

Yes. We don't comment on individual patients conduct, but what we do would, we'll reiterate the fact that we are very confident about completing the sentinel cohort and initiating the expansion and also the ability to give you the multiple patients. So you can obviously make your own assessment of the fact that in order to do that, those things will have to be completed as well for that. But obviously, if we want to sort of manage the -- on a patient basis, clinical comeback, that's not what we plan to disclose.

Yes. And so when you share the data by the end of this year and first, I assume that likely will be at the ASH.

Again, we haven't said it, but you can -- we tend to want to go to clinically relevant conferences, right? And so there's a couple coming between now and the end of the year. Certainly, ASH is a very important one. And -- it's probably -- you could assume that, that could be certainly one of the venues that we are considering very stronger.

Okay. And then year-end data, do you have a cutoff of minimal follow-up for each patient for them to share the data?

It will just be basically the cut off when it generates enough data to -- in time for that presentation to be for whatever conference that we choose. And whenever we make the cut off, obviously, the first patient will have longer follow up. Second patient will have more. There will be multiple and depending on when they've been dosed, they will have some time follow up. The good news is you know that when we do the expansion cohort is actually -- several patients could actually be now dosed in parallel. Now they'll roughly be closer to each other at that point. And so would be shorter time line to follow up. But certainly the patient -- first patient will definitely have several months for follow-up.

Yes. So like, say, for the last patient, a minimum you wanted to see engraftment and you should collecting the, say, the initial assessment plan to...

I think time to engraftment is definitely something that we'll monitor very closely and will be part of data cutoff and disclosure as we need to do.

Okay. Very good. So maybe regarding our -- switch gear to the in vivo program AATD. That's also very exciting. And so maybe any time line regarding the CTA or R&D submission and then the data package?

Sure. So we announced that we filed a CTA in the U.K. at the beginning of this year, with the MHRA and the MHRA takes 90 days basically to provide feedback on that. So we are expecting imminently feedback from them. One of the reasons we're going to the U.K. initially is in -- actually we've also filed CTAs in other locations in Europe, and we plan also to file for Australia and New Zealand. And the reason for going ex U.S. at least initially is that protein replacement therapy is actually either not approved or not reimbursed in Europe and Australia and New Zealand. So it gives us a much cleaner readout. So whatever Alpha-1 antitrypsin up regulation that you can see will be as a consequence of the edit that we make rather than then have to distinguish between protein replacement versus others. We plan to come back to U.S. obviously, as soon as we have the data to justify basically patients pausing their augmentation therapy so that they can come onto the trial. So yes, in terms of time lines, the one other point and guidance that we provided is that we feel that we are on track, basically for dosing the first patient by the end of the first half of this year. So end of June, at the latest as part of that. So obviously, on track on that. And obviously, pending positive approval from the MHRA but we are pretty optimistic that we -- which we see there.

Will you announce it when it's [indiscernible]?

We haven't guided yet, but I think obviously the guidance is that we are waiting for the CTA. So it's likely that you will -- we will let you know on that whether it's been approved or not.

So maybe walk us through, say, if CTA got accepted and how quick you can run the study and -- like that, you need different process there?

Yes. I would say...

And then also initial dose?

Yes. So as I mentioned, our guidance by being the fact that we can dose first patient by the end of the first half would mean that -- we expect that between the end of March when we expect the feedback to the end of June will be -- to the 3 months that will be needed in order for us to activate [indiscernible] sites that we need to do. We cannot activate the sites or IRB review of the protocol until we actually have that okay from the MHRA. But on top of that, one of the things that we are doing, we're actually going to initiate a natural history study in some of the sites in the U.K. that gives us at least the opportunity to identify some of the patients, screen them, put them on the natural history study and then eventually to pivot them into the actual Alpha-1 treatment study. And so that might be a strategy for us to accelerate a little bit the recruitment of some of the patients. And so all of that is giving us the confidence to guide on the first dose in the -- by the end of the first half.

Okay. So when we look at the preclinical data, you do have a little bit -- I think that you do have a bystander in factor with 5G+7G.

7G.

Yes. And for CTA, maybe a little bit more straightforward for the U.S. R&D in the future. Do you think that, that will introduce extra say, scrutiny from FDA regarding the assessment of 5G+7G modification and then the safety? And I know you did show the efficacy part, right?

Obviously, we will not know for sure until we have the conversation with the FDA, which we have not yet had. Also, I wouldn't say that there is the possibility that the FDA will be more scrutinizing of the CTA if there was what I would call a true biological concern of that. The reality is that we have a very extensive package of data and information we generated and shared. That shows that really the presence of that additional amino acid change, which is a D to G position 435, is really -- does not impact the biology of that protein in any way, shape or form that we could test. So we have isolated basically that dual change protein compared it to the wild type, both in terms of structure, both in terms of activity against the last days, both in terms of security propensity from the cells, and it's basically identical, right? So we just don't see any biological way in which the 2 proteins are different from each other. And in fact, the biology would suggest that it's really the 342 amino acid that is really what is causing this protein to misfault. There is also 2 individuals that have there are heterozygotes that for that particular mutation, it's a naturally occurring [ SNP ] in human databases. So again, that's also evidence that occurs in human relatively frequently, but it does occur, and it doesn't seem to be causing any issue. So obviously, we'll see what happens with the FDA, but I would expect then at that point, the concern would need to be articulated into a biological potential consequence. In that moment, I don't see any rationale for that.

So you are also preparing 301 in GSD1a R&D package in the U.S.

That's right.

Yes. So you submit a CTA for the AATD. Any differences regarding the data preparation, the package when you prepare these 2?

No, they're essentially identical. In fact, if anything, the CTA data package will probably be helpful to file the IND when we come to U.S. for 302. There is really no difference in our experience. It really is about usual components, pharmacology, CMC, essentially safety, right? And that's the package that we are putting together. And for GSD1a, for the 301 program, we have guided and we remain on track for filing the IND by the end of the first half of this year.

Will you announced it when the R&D cleared or submitted?

Possibly, we haven't decided yet. So we'll obviously see -- I can't remember what we did last time, to be honest, but maybe [ Holly ] will help. We'll try and be consistent in the way we handle it.

Okay. Okay. That's fair. And maybe also the initial dose and...

Yes. So the dosing strategy are going to be relatively similar basically for both in vivo programs, which are pretty similar to what you've seen with Intellia, Verve or others where -- it's essentially a single ascending dose strategy, where there will be 3 or 4 different doses that we will look at in both cases because there are genetic diseases, it's actually both unethical and not sort of advice through the regulatory authority, the first dose needs to have at least the possibility of a clinical benefit. It might not be the optimal dose, of course, because of safety considerations. But you should expect to start to see some -- at least some hints of activity, Obviously, if our preclinical model is translated to the extent that we want. In terms of time lines to data, particularly coming back to 302, but 301 is obviously a more rare disease than compared to 302. So there is an element of recruitment of those patients. But for 302, I think if you look at Intellia as a comparator and Verve is a competitor, Intellia disclosed data after 12 months on 2 cohorts of patients. Verve disclosed data after 18 months on 3 cohorts, we're probably going to be somewhere in that range. And so you could expect the 302 to see some data as a 2025 event. If we're likely, probably earlier, maybe a little bit later on in '25, if we're not.

Okay. That's very helpful. I think the last maybe minute or 2, ask about your manufacturing.

Yes. So we have a manufacturing facility in North Carolina. The site is a 100,000 square feet facility. That is now GMP operational, it's a site that can manufacture both the autologous cells for sickle cell disease. And, in fact, has capability to be optimized for supporting also the commercial release as well as the pivotal part of the trial. As well as manufacturing LNP, and we've also manufactured several GMP lots already in for both. We eventually also are going to bring the ability to manufacture messenger RNA, which at the moment is relying on a CMO. So we think actually that there is a very strategic investment that we have done so from the get-go and we believe that given the complexity, unfortunately, these drug products, it's important to have the degree of control, both from a quality point of view, but also, frankly, from -- to respond to be more agile to the different changes that might come from time to time. The good news about the autologous process that we have been optimizing for is that it's highly automated. And what that allows us to do is essentially pretty much all way already commercial-ready. I would say, with the exception of optimization of some of the potency assays that will be needed when we launched, so that we can actually stick with the same process all the way. And that's really important that doesn't hopefully cause any delays during the course of the program, which unfortunately was something that you saw between CRISPR and Vertex when Vertex took over the program, there was about 9 months delay in the optimization of that process. So that would hopefully provide that robustness. That is also an important part of the release of that product.

Okay. Well, thank you very much, Pino.

My pleasure. Thank you, Gena.

Thank you, everyone.