To our 7th Gene Editing, Gene Therapy Summit. It is really great to have this happen again. I wanted to take this opportunity to thank all the investors, companies, and also you know, especially our event team and the corporate access team who made this event possible. With that, I would like to introduce our next presenting company, Beam Therapeutics. With us today, we have John Evans, Chief Executive Officer. John, thank you very much for giving us this opportunity.
Thank you for having me.
Yeah. Maybe before we dive into the specific questions, do you wanted to give a quick overview?
Sure. Yeah. Beam Therapeutics is a next generation gene-editing company. We're working on a new form of CRISPR, called base editing, which we think improves on what is possible. It uses CRISPR to target within the genome, but not to edit. The edit is then made by a second component called a Deaminase, which basically does a very precise chemical modification of the DNA to alter one letter to another at a very programmable spot, which gives this incredibly flexible and versatile tool to make very precise, very high efficiency changes within the genome, doing everything from silencing genes, to turning them on, to modifying their function, to correcting them if there's a spelling error in them.
We have taken a very broad strategy to exploit this technology and bring it to patients wherever we can, looking at delivering it outside of the body in blood cells and T-cells, delivering it into the body using lipid nanoparticles or viral vectors, and building a real integrated stack of capabilities from the editing, to the delivery, to even manufacturing a facility that we're building internally, to try to have all under one roof, all the things we need to make a really compelling set of medicines that could be potentially one-time cures for patients suffering from serious diseases.
That's great. Maybe we'll start with your lead indication
Mm-hmm
BEAM-101 in sickle cell disease. I know the first patient enrolled in November 2022 and recently withdraw due to non-medical reasons. Can you elaborate a little bit on how that will impact your data update timing?
This is patient number 1. Unfortunately, patient number 1 had to withdraw. It was truly idiosyncratic. There was basically just a very dramatic life change for this person that made it impossible for them to continue. The investigator then withdrew them. It wasn't like if we waited a month, they could've come back in. It was, it was bigger than that. As you noted, it was not related to the drug. We hadn't treated them yet. It wasn't related to the procedures we were doing. It wasn't even that they had changed their minds about seeking therapy or gene editing or anything like that. It was, it was truly on the personal side. We wouldn't expect this to happen again. It was, it was a kind of one-off. Unfortunate.
We had been through several rounds of mobilization with the patient, so we actually have cells. There would be a conversation about could we ever treat this patient in the future. If they could come back, we'd like to. They obviously went through a long journey with us, but not right now. In terms of the impact, you know, we had already enrolled two more patients, so they were of course, going to be patients 2 and 3. Now one of them will have to serve as patient 1. You know, the first dose will come later, you know, than it would've, and I think that's the impact.
The good news is that we had been working since the fall on really accelerating and broadening the BEAM-101 program, basically taking advantage of the fact that it looks like Vertex is sort of showing that there is a path to market with one trial, as we would've hoped. We can design, and we have designed BEACON really to achieve that. We're powering this not just for the sentinel cohort, but really for the full expansion. Since then, we've been really building this out, so we have already five sites open. I think we'll have, you know, double-digit types of sites by the end of the year, opening. We have patients now in view, and looking to get into the trial. We can do a lot of things in parallel, right?
We can, you know, literally enroll multiple patients. We can think about the screening, the transfusions, the mobilizations, just getting all of that done in parallel. The bottom line is I think if we can do this right, we can make up the time so that we really aren't much later, if at all, into the expansion phase, and certainly the final BLA filing doesn't have to be much later either. That's our current assessment.
Mm-hmm.
Obviously the first dose will come later, but, you know, through going in parallel on multiple patients, I think we can keep the timelines in. We've sort of said, continue to think we will fully enroll the sentinel this year. We will add more patients this year, who will then contribute to the expansion phase, and we will be able to have data in 2024 on multiple patients. That's been our guidance, and we're able to reiterate that.
Okay. That's good. you know, you mentioned that you wanted to, especially we have a precedence of, say, Vertex/ CRISPR's program, see how they quickly evolving into the pivotal program.
Mm-hmm.
One key data point is, you know, one is the number of patient, right, 45-ish.
Mm-hmm.
The other is the primary endpoint.
Yep.
When I look at, I think last night, look at ClinicalTrials.gov, the primary endpoint still did not change. Like, do you need to change your primary endpoint in order to like, to, you know, VOE events and then, like, the Criteria in order to be aligned with the approvable endpoint with the agency? Maybe have you discussed with the agency, and do you plan to do that at some point?
Yes. We absolutely would discuss it with the agency. What we have done so far with the BEACON trial is we've put in everything we can think of.
Mm-hmm
based on what we've seen outside in of what others are doing in terms of both number of patients. You know, clearly it's about a total N. You know, we've guessed 45. Within that, there's clearly a kind of a benchmark analysis of a certain number of patients who've gone for a certain amount of time follow-up. We've estimated it's anywhere in the 20-25 range for 12-15 months is just a ballpark.
Mm-hmm.
Then obviously the choice of endpoint itself, you know, building around vaso-occlusive crisis reduction.
Mm-hmm.
There are nuances around that which we would potentially be able to update. The good news is we'll basically get a beautiful view into that by the end of the year in terms of the Vertex FDA interaction for approval. Potentially Bluebird bio as well. We will be able to basically take that information and incorporate it into the trial and make any tweaks we need to. Also, of course, as you say, we will talk to the FDA as well, at some point and get their final input. I think it'll be pretty close to what this looks like. I think that those sorts of tweaks don't slow down the trial in any way.
Mm-hmm.
We'll just sort of, you know, make those modifications. You know, we continue to be fairly confident that it should then me be true that we have a, you know, rapid path to the first filing based on BEACON as the dataset.
Mm-hmm. You mentioned, you know, also Bluebird.
Mm-hmm.
I can think of like Bluebird, CRISPR, and we have Editas also already modify all these, the endpoint, and moving also very quickly. It is a very competitive space, you know. Any thoughts like how would you differentiate? I know every program, you know, when they present is that ours will be the best.
Mm.
Like, how would you differentiate? And, you know, especially giving, say maybe third or fourth to the market
Yeah.
Like how do you differentiate and then take some market share?
I mean, first of all, just to say I think competition is great for patients, right? It raises the bar, they will benefit. I think there's nothing bad about that. It is a crowded space, but it's a lot less crowded than it was, right? Even in the last six months, we've obviously seen Sangamo, Novartis and Intellia, and then Graphite drop out.
Mm-hmm.
It is narrowing actually. You know, I think no healthy drug category has fewer than three or four entrants in general in it, in my opinion. We welcome the competition. I think that our base case view of the world would be that, both Bluebird and CRISPR will get approved, CRISPR Vertex.
Mm.
They will start to build this market out. We will obviously enter several years later. Editas is definitely there in the mix. They, as you say, they are going fast. That's kind of the optical illusion of these trials.
Mm-hmm.
They seem very slow to start, and then they seem very fast later.
Mm-hmm.
It's just because of how, you know, it sort of gradually builds up. You know, we expect the Editas sort of pattern to play out with us as well. I think obviously in the case of Editas, you have another nuclease
Mm-hmm
relative to the Vertex program. You have a different target, which is the HBG locus, which is also where we're targeting, but they're using a cutter for that. You know, so far the clinical data looks fairly comparable to the Vertex program, but we'll have to see, you know, more follow-up, more data there. I think in our case, obviously, we do believe we are bringing a best-in-class editor forward that'll have clear differentiation. We have very clearly in the preclinical models, we have higher levels of editing than these players. We're up at, you know, above 90%. We have higher levels of F, which is the upregulation we're aiming for, over 60%. We have therefore lower levels of sickle protein, down to 40% or lower.
We're just having effectively a deeper cure than what others may be able to offer. We would look for, obviously, not vaso-occlusive crisis. You know, everybody's sort of fully getting rid of those, which is good news. For differentiation, we would look to things like hemolysis, you know, blood markers of inflammation, things like, you know, pain, you know, stroke, organ damage are sort of some of the longer term ideas where, you know, we would expect that, you know, a better editing product will have some of these visible clinical markers. As a reminder, patients aren't dying of vaso-occlusive crisis. They're dying of all these other things accumulating over time. We do think a deeper cure is gonna be important here.
Of course, you know, there's an entire next stage of the story for us, which is our next generation versions, where we're gonna bring forward better conditioning, which uniquely builds on base editing's ability to do precise modifications, to do the ESCAPE technology, which lets us use an antibody conditioning agent to selectively get rid of old cells, but leave alone new cells. We think that is another potential game changer where really base editing has a unique advantage. We may be able to port all of that in vivo, delivering the initial edit using a lipid nanoparticle, but then again, maybe using the antibody in combination with it to select for those cells. We see this as really a three-wave life cycle strategy and, you know, BEAM-101 is just the beginning of it.
Mm-hmm. Okay, very good. I'm pretty sure you've also done tons of marketing as well. When we talk to some doctors, it seems like patient willingness to take this new drug class is a little bit hesitant. Like how do you see this? We know that the total population actually is very big.
Mm-hmm.
The patient willingness and even also the doctor as well, like maybe lack of understanding, like how do you see this evolving?
Yeah
over time?
No, I think that's exactly accurate. I mean, if you think about it, the cure is great. You know, everybody wants to get the permanent change to their genes, and they're very excited about that. The challenge is the transplant and the use of chemo, and I think everyone is very clear about that. Busulfan is the chemo we all will use. it, you know, it is chemo, right? it's the standard of care in transplant. It's a, it's a great trade if you have a very severe disease and you are very motivated to get rid of that disease. a lot of patients with sickle are maybe more moderate, and they can survive for longer without needing to feel like they need to do that. that's where the hesitance would come in.
I think we've always sort of said that this wave one with busulfan is a minority of the market, but it's not zero. There are a lot of patients who are desperate to get out of their disease and for whom that chemo transplant process is very exciting. They are lined up for our trials, and they're lined up for therapy. The real question that we will all answer over the next, you know, several years is exactly how many of those people are there and what size is that market. I would just note that the pricing, you know, looks like it is lining up to be anywhere in the $2 million-$3 million range based on even ICER, let alone
Mm-hmm
competitor dynamics. You know, it doesn't take that many patients, a year to potentially contribute to a potentially multi-billion dollar a year market. Of, you know, even this sort of first -gen chemo. I think we do anticipate something like that playing out.
Mm.
Now I think for the commercial launch, I would, you know, I would say, you know, we're cautious. I don't know that'll be an S-curve launch. I think it'll be more steadily grown as, you know, Vertex and Bluebird and others sort of start to establish the footprint of sites who are capable of doing this, the referral networks, much like the autologous CAR T field has evolved. Over time, we do expect it to grow and then be a kind of sustainable model. Nonetheless, there are 100,000 patients with sickle in the U.S.
Mm.
Clearly, you know, despite everything I just said, there's gonna be a lot of patients left to still treat, and that's what we are aiming for with our wave two, wave three products.
Mm-hmm. Okay. Actually, going back to your, let's say, wave one, the current conditioning regimen, the pivotal, or registration trial readiness
Mm-hmm.
How's the preparation regarding the manufacturing part?
Yep.
Regarding CMC and then also, you know, say align with the FDA, potency assay, release assay.
Yep. Yeah. One of the other things we said in the fall was this commitment to bring BEAM-101 forward, we're basically doing all of the registration enabling work now.
Mm-hmm.
You know, sometimes middle of development, you sort of say, "Oh, I'm gonna go for it, now I have all this work to do"
Mm.
To finalize the commercial process, get those assays done. Then you have to have a certain number of patients who are on those final assay forms before you can file, and so it creates a delay. We're gonna try to avoid that, so we're doing all that work now. Yes, all the assays are in process that we need. Then manufacturing, we're currently using an external manufacturing facility, but we have built North Carolina up, and we do anticipate moving to that by the end of the year, as a GMP-ready operation to do the sort of cell processing and manufacturing. In the process, we're gonna kinda lock down those final validation forms of our process, so that which would be kind of commercial grade.
The beautiful thing about that strategy is basically North Carolina is also a potential launch facility. I mean, we can basically start manufacturing it now, do much of the expansion cohort out of North Carolina, and then basically exact same process would be what we would launch with. There would be no comparability questions or bridging processes you'd need with the FDA.
Mm-hmm.
I think again, that is all designed to make the BLA stage of this program as smooth as possible.
For North Carolina site, like how many patient, like percentage of, say, 45 patient, how many patient you think you need to treat in order to be able to clear with the FDA?
Yeah, that's always a negotiating point. You know, the FDA, there's not like a hard and fast line. I think that at this point I would anticipate the vast majority of patients being out of North Carolina.
I see.
We would be most likely in excess. I guess the nuance would be how long it takes us to finalize those validation step assays.
Mm-hmm.
It's not so much just out of North Carolina, but how many patients were on those final set of assays.
Mm-hmm.
And, you know, maybe that'll come online sometime next year. I think we'll see. I think bottom line is our assessment is we should have plenty of patients on everything locked down and final out of North Carolina to support a filing.
Okay. Regarding your wave three
Mm-hmm.
The conditioning regimen in vivo delivery using, HSC-targeted lipid nanoparticle, what's the update there or status there?
Yeah. Nothing recent on that one. We continue to be very excited about it. I think we've shown before, LNPs that can target the bone marrow, the HSCs, and at least deliver a payload. We're now adapting that into a base editor format. I guess but the relevant update given, as I said, it may even interact with the ESCAPE technology, we did publish at ASGCT just this month, an update on ESCAPE, which basically shows a kind of mouse transplant. You know, we're sort of, You know, it's human cells, but it's in a mouse.
We're basically showing all the steps that we anticipate taking both in wave 2 and potentially in wave 3, where you condition with the antibody, you then edit the cells, you bring them in, and you show that in the presence of the antibody, the edited, you know, therapeutically corrected and escaped cells grow out and become the dominant population. You know, we think it's a beautiful proof of concept that continues to be de-risked and we're, you know, very excited about the future of that program.
Great. We have a few more minutes. You do have other programs.
Mm-hmm.
I wanted to ask you, the in vivo program, the GSD1a.
Mm-hmm.
You did show the mouse data update, and then maybe like, you know, from the mouse data, how do you, say, translate or identify the right dose, for human?
Yep. Yeah. I think the beautiful thing about both GSD and Alpha-1, which our second program for Beam Therapeutics is, you know, they are relatively low bars for editing, actually. GSD is probably the lowest in terms of we've estimated, you know, no more than 10% is probably needed to have a therapeutic impact, and correction of this condition. We are clearly in excess of that in our preclinical models. That's really good news. You know, dose projection for a correction is a little more challenging than for a knockdown because you don't have, you know, a mutant model in a primate, right? I think we have very good LNP data now to really give us a sense of, you know, for a given editor, how potent are we in primates?
We are able to kinda put all that together and get pretty comfortable. I think that, yeah, so 301 looks like we think we have a very good chance there to deliver that, you know, that editing, you know, well in excess of what's needed. We'll be looking for, you know, normalization of metabolic parameters, then ultimately glucose challenge, right? How do we show that fasting, you can then survive the fasting because you're now you have a functioning pathway in your liver.
Mm-hmm.
Alpha-1, you know, maybe a little higher bar for editing. Maybe it's more like 20% or more, in that ballpark. Again, with having improved the potency a lot on our Alpha-1 editors, we feel very confident that, again, single dose, we have the potential to deliver a, you know, potentially normalization of Alpha-1 levels and start to resolve the liver phenotype as well, which is a first in the industry in terms of a single therapy addressing both the liver and the lung phenotypes, as a single regimen.
The IND, likely you have two in the next maybe 12 months, right?
Mm-hmm.
Their submission.
Mm-hmm.
We saw Intellia clear their IND, and then your partner, Verve
Mm-hmm
is still try to get their IND clear.
Yep.
like, what kind of learning you can get, I know you are in the active preparation for that package.
Yep.
What data package, you know, like, how do you prepare to have, you know, the successful IND?
Yeah
submission?
Absolutely. We've talked about this a lot. I mean, we see a clear path with the FDA. There's no question the FDA is asking for a more thorough package than maybe other jurisdictions, and that's been some of the delay of the field just getting this piece of things going.
Mm.
It's coming. You know, you've seen Intellia get open. We thought that would happen. I expect TGR will be open this year. I think Verve will get open as well.
Mm-hmm.
We did a pre-IND meeting with the FDA on GSD last year. We have the same feedback. I think it's very clear. It's really just all about how thoroughly you're checking your off-target profile in different tissues, and that's fine. We can do that. With GSD, we're expecting to file both in the U.S. and ex-U.S. in some order, basically starting with there will be an FDA filing there. You know, the patients are here in the U.S. We know the sites. They're genotyped. Alpha-1 is right on the heels of GSD. They're really moving neck and neck right now. With Alpha-1, we probably will go ex-U.S. first for a different reason.
We actually wanna have patients who have no protein replacement, so no Alpha-1 protein that is exogenously added to their blood, so that we can see a really clear up regulation on therapy, and then we would generate some of that data and then come back into the U.S., where protein replacement is more ubiquitously used. Bottom line is I think, you know, in vivo gene editing is coming to the U.S., and, you know, we think it's just a matter of operationalizing it. We don't see a roadblock there.
Mm-hmm. Okay. Will you announce once it cleared, or will?
Yeah, good question. We have in the past, we've announced once it's clear.
Okay.
That's been our practice so far.
Very good. We're running out of time. Thank you very much for the discussion. We look forward to the updates.
Thank you very much.
Thank you.