Good afternoon, everyone, and welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I cover U.S. [biotech at Barclays]. 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?
Yeah, absolutely. So first of all, thank you for having us. So my name is Pino Ciaramella. I'm President at Beam Therapeutics, and I've been with the company pretty much since the beginning, just over six 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 Broad, which uses Cas9 protein as part of the editing machinery, but has modified the Cas9 in two important ways. The first one is eliminated 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 deaminase, that can actually directly convert a nucleotide to another. We have a C deaminase that converts a C to a T, and a A deaminase 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 four bases with two 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.
Okay, great. Thank you. So, you do have, you know, programs already in clinical development.
We do.
So maybe, like, you know, talk a little bit about sickle cell, and we just had a discussion with editors.
Sure.
So maybe like, you know, your approach and then the differentiating part you're looking for.
Yeah. So, with the base editing technology, we're essentially focusing on our portfolio on two important franchises. One is on hematology franchise, focusing initially on sickle cell disease, but potentially expanded even from that, and we can talk a little bit about that as well.
Mm-hmm.
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 diseases, 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, is something that we're exploiting in sickle cell disease by essentially doing an edit in the promoter of the two genes that make hemoglobin F, the fetal form of hemoglobin. These are called the gamma one and gamma two genes 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.
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 regulation of F that anybody has actually been demonstrating. Vertex, you know, CRISPR originally was in the 30%, 35%. Editas preclinically was in about 50%, although in the clinic, they are both running at about 40%-45% hemoglobin F. And the reason why the higher level of F is important, not only because F obviously is a protein in itself that contributes to anti-sickling, but perhaps more importantly, is because when you get to the high level of F, you are now starting to switch off the production of hemoglobin S.
We are now the only company that has been shown, at least preclinically, that ratio of 60% good hemoglobin to 40% bad hemoglobin, which is typically seen in sickle trait individuals. These are heterozygous individuals that actually do not suffer from the consequences of sickle cell disease. 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. For example, you know, 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 a 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. VOC is obviously seems to be something that you can fix relatively easy, I would say. But even there, with the latest data, 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, well, 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 various. And so, in Vertex label, there is essentially a comment that up to six mobilization may be necessary, 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 a journey, we'll need many more, but what we've seen so far is that we are tending to be around the two mobilization per cycle as opposed to the six. In fact, I would say, bluebird is more similar to us in that setting, so they're more in the two range rather than the six range.
So overall, I think it gives us the opportunity to provide some differentiation in what we call the wave one of treatment, which is still reliant on the busulfan conditioning, which, as you know, is obviously works, but it—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 this 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-$3 billion market, of which a best-in-class profile is the one that we plan to demonstrate, hopefully allows us to be a, an important player in that market. But perhaps even more importantly, the way we are looking at 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 the 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.
In this case, what we do is to make a single amino acid change on a receptor known as cKit. This is a receptor that all stem cells need in order to access to growth factors to actually survive. In this case, the amino acid ensures that the edited cells do not bind to the antibody that we have developed, and instead, the antibody is still capable of binding to an edited cell and actually starve them of the growth factor that they need to survive. So you selectively kill essentially the unedited cells and giving a survival advantage to the edited cells without toxicity associated with that.
Mm-hmm. So this is very comprehensive. So maybe, you know, the four, say, for the first gen, product you're looking for four different differentiating, yeah-
Parameters? Yeah.
Yes.
Those are,
The key part is we wanted to reach 60% fetal globin level, right?
Yeah. I think the 60/40 ratio would be important. I think in looking at more deeper resolution of hemolysis would be important. The overall blood quality, you know, by looking at viscosity, for instance is also an important factor. Looking at, you know, they may... You know, 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'll look at. 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.
Okay. So, you know, should that be the bar we are looking for when you, you know, share?
Yeah, we certainly, y ou know, we're gonna aim essentially for being a best-in-class profile. You know, t hat's fundamentally what we are aiming for.
Okay. So maybe, like, you know, outline the data timeline. Yeah.
Yeah. 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 gonna come, there will be at least the one patient with several months of follow-up. We've also guided that we are essentially on track to complete the sentinel dos ing cohort, as well as initiating the expansion cohort, hopefully in the middle of this year. And so, towards the end of the year, we should have this 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, you know, looking at that 60/40 ratio.
We're gonna be looking at, you know, hemoglobin level, of course. VOCs will depend on... You know, will take a little bit more time to demonstrate, of course, b ut that's definitely something that we will continue to monitor.
Okay. And I think that the earnings, you know, press release, you said, you know, third patient to be treated. So has that patient already dosed yet?
Yeah, we don't comment on individual patients' conduct, but what, you know, what we do, 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 i n order to do that, you know, those things will have to be completed as part of that. You know, obviously, we want to sort of manage the on a patient basis clinical conduct, you know, we-- that's not what we plan to disclose.
Yeah. And so when you share the data by the end of this year, and first, I assume that likely will be at the ASH?
We, again, we haven't said it. But, you know, we tend to want to go to clinically relevant conferences, right? There's a couple coming between now and the end of the year. Certainly, ASH is a very important one, and i t's probably, you could assume that that could be, again, certainly one of the venues that we, we are considering very, strongly.
Okay. And then year-end data, do you have a cutoff, minimum follow-up for each patient for them to share the data?
It will just be basically the cutoff when it generates enough data to … in time for that presentation to be for whatever conference that we choose. And wherever we make the cutoff, 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, you know, 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, right? Now, they'll roughly be closer to each other at that point, and so will be shorter timeline to follow up. But certainly the first patient will definitely have several months of follow-up.
Yeah. So, like, say for the last patient, the minimum you wanted to see engraftment, and you should collecting the, say t he initial assessment.
I think time to engraftment is definitely something that we'll monitor very closely and will be part of the data, cutoff and disclosure we need to do.
Okay. Very good. So maybe, you know, regarding now, switch gear to the in vivo program, the AATD. You know, that's also very exciting. And, so maybe, you know, any timeline regarding, you know, the CTA or IND, submission and then the data package.
Sure. We announced that we filed the 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. You know, we are expecting imminently feedback from them.
One of the reasons for going to the U.K. initially is, and actually, we've also filed CTAs in other locations in Europe, and we plan also to file for Australia and New Zealand. The reason for going ex-U.S. at least initially is that protein replacement therapy is actually either not life not you know 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 other. We plan to come back to the 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 yeah, in terms of timelines, the one other point and guidance that we provided is that we feel that we are on track basically for dosing the first patients by the end of the first half of this year. So end of June at the latest, start of that. So obviously, you know, on track on that and obviously pending positive approval from the MHRA, but we are pretty optimistic that we should see that.
Mm-hmm. Will you announce it when it's accepted?
We haven't guided yet, but I think, you know, it's obviously the guidance is that we're waiting for the CTA, so it's likely that you will, we will let you know that, you know, whether it's been approved or not.
Mm-hmm. So maybe, you know, walk us through, say, if CTA got accepted and then how quick you can run the study and like, maybe the thought process there.
Yeah. I would say, you know-
And then also initial dose.
Yeah. So, as I mentioned, you know, 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, you know, the feedback to the end of June, you know, will be two-three months, that will be needed in order for us to activate the various 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've actually are 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 what is giving us the confidence to guide on the first dosing and by the end of the first half.
Okay. So when we look at the preclinical data, and you do have a little bit, I think that, you know, you do have a bystanding factor with the 5G + 7G. For CTA, maybe a little bit more straightforward for the U.S., you know, R&D in the future, do you think that that will introduce extra, say, scrutiny from FDA regarding, say, assessment of 5G + 7G modification and then the safety? And I know you did show the efficacy part, right?
Obviously, we will know for ... 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 would 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 a G, in 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 elastase, both in terms of secretion propensity from the cells, and it's basically identical, right? So we just don't see any biological way in which the two proteins are different from each other.
In fact, the biology would suggest that, you know, it's really the 342 amino acid that is really what is causing this protein to misfold. There are also two individuals that are heterozygotes for that particular mutation, it's a naturally occurring SNP in human databases. So again, there's also evidence that occurs in humans relatively infrequently, but it does occur, and it doesn't seem to be causing any issue. Obviously, we'll see what happens with the FDA, but I, I would expect then at that point, the concern would need to be articulated into a biological potential consequence. At that moment, I don't see any rationale for that.
Mm-hmm. So you are also preparing 301 in GSD1a, R&D package, right, in the U.S.?
That's right.
Yeah. So you submit a CTA for the AATD. Any differences, you know, regarding the data preparation, the package, you know, when you prepare these two?
No, they're essentially identical. In fact i f 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, you know, pharmacology, CMC, essentially safety, right? And that's the package that we are putting together. And for GSD1a, for the 301 program, we've guided and we remain on track for filing the IND by the end of the first half of this year.
Will you announce it when the R&D cleared? Or submitted?
Possibly. We haven't decided yet. So we'll, you know, we'll obviously see. I can't remember what we did last time, to be honest, but maybe how we will... we'll try and be consistent in the way we handle this thing.
Okay, that's fair. Maybe also, you know, the initial dose and, you know, what you are thinking-
Yeah. 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 or Verve or others where it's essentially a single, ascending dose strategy.
Where there will be three or four different doses that we will look at. In both cases, because they are genetic diseases, it's actually both unethical and not sort of advised 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 timelines to data, particularly, you know, 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 as a comparator, Intellia disclosed data after 12 months on two cohort of patients. Verve disclosed data after 18 months on three cohorts. We're probably gonna be somewhere in that range. And so you could expect for 302, to see some data as a 2025 event. If we're lucky, probably earlier, maybe a little bit later on in 2025, if we're not.
Okay, that's very helpful. I think the last, maybe minute or two, ask about your manufacturing.
Sure. Yeah, so we have a manufacturing facility in North Carolina. The site is a 100,000 sq ft 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 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, you know, 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, of 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 and be more agile to the different changes that might come from time to time. The good news about the autologous process that we've been optimizing for is that it's highly automated. And what that allows us to do is essentially pretty much all the way already commercial ready, I would say, with the exception of optimization of some of the potency assays that will be needed when we launch. So that we, you know, we can actually stick with the same process all the way.
That's really important, so that doesn't hopefully cause any delays during the course of the program, which unfortunately was, you know, something that you saw between CRISPR and Vertex. When Vertex took over the program, there was about nine 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.