Good afternoon, everyone. My name is Gena Wang. I'm a Senior Biotech Analyst at the Barclays. Welcome to Barclays' 27th Global Healthcare Conference. Together with me, we have John Evans, Chief Executive Officer from Beam Therapeutics. Thank you very much for giving us the opportunity.
Thanks. Great to be here.
I know yesterday you just announced today's Tuesday, right? Yeah. Yesterday morning, you just announced a very big data update. Maybe you know give us a high-level overview, and then also the data, and we can dive into the questions.
Perfect. Yeah, so it's great to be here. So Beam, as you know, is working on a next-generation kind of gene editing called base editing. It uses the same power of CRISPR to do precision gene targeting. But once we get to the target spot, we're not doing the traditional cutting that you get with nuclease editing, the first-generation tools, but we're doing a much more precise single base change. This gives us precision and control. It's also gentler on the cells. So when we thought about how to apply this tool, we can actually use it to do things like knocking down genes, turning them on, activating them. Our own BEAM-101 in sickle cell disease activates the fetal hemoglobin gene more robustly than others have done before. So it's a very versatile tool.
At the same time, one of the most exciting applications of the technology, because we can make a precise change without disrupting the sequence in the chromosome, is to actually go in and rewrite the genome and correct mutations. I can tell you that top of our list from the beginning was to go after alpha-1 antitrypsin deficiency for that application. AATD is a very severe disease. You have a single point mutation, one-letter misspelling in all patients who have this, almost all patients who have this severe disease. There are 100,000 people in the U.S. who have two copies of that one-point mutation, and then they have the disease. They have low levels of alpha-1 in their bloodstream, which causes lung progressive emphysema because they are missing that alpha-1 protein to protect their lungs when they get an infection, and the immune system mounts a response.
They also have liver failure because the mutant form of the protein is building up in their liver, and it's causing damage over time. It is really a two-sided disease, and there's really very little for these patients. With BEAM-302, we designed a base editor that can go directly to that one spot in the genome and for the first time in history actually rewrite a broken mutated gene back to normal. That's what we're doing. Yesterday, as you noted, we shared the very first glimpse of data into that drug. It's, of course, an open-label trial. We're still in the dose escalation phase, so we're just in the middle of the beginning of this. Nonetheless, we've been through three dose cohorts so far. We've had 15 mg, 30 mg, and 60 mg given to three patients each.
We were able to show really the entire range of outcomes we were hoping to see with this drug. We saw first safe and well tolerated across all dose cohorts. This is LNP in vivo delivery. It's a simple infusion. We saw dose-responsive increases in total AAT. At the top cohort, we were indeed above the therapeutic threshold of 11 μM, showing that we've really moved these patients out of the disease category into something that looks much more like a normal carrier of the disease, someone who only has maybe one mutant copy rather than two. We are raising AAT because we're creating the normal form of the protein because we've rewritten the gene. At the same time, we're dropping the amount of toxic protein in the body quite significantly, up to 78%. The ratio of the good-to-bad protein is reaching very high numbers.
Finally, we were able to show that all the protein we're creating is functional. There's a variety of assays we can do that show that the new protein we're creating does what it needs to do in the body. That was all the things we were hoping to have happen with this drug. From here, we have lots more to do. We're still developing it. We're going to continue to expand the trial and push farther. Already, I think we have a potential therapeutic in view.
Right, right. I totally agree with you on that part. Yeah. For me, given such a good safety, why can't you dose higher? Why are you so cautious, only dose up 20%-30% for the first dose?
Yeah. We can dose higher. I mean, the safety will allow us to. We jumped 30 mg between the second and third dose cohort from 30% to 60%. I think that from there, we do want to shade back down the increments that we go in. That is just because as you get the therapeutic and higher doses, you just want to be seeing the safety evolve in a slightly more careful way rather than jump too far and get surprised. I mean, safety is really important here. Again, the enrollment has been so fast. We do not need to be in a rush on that. We are enrolling very swiftly. We have a great clinical site network. It should be fairly easy to get that next cohort enrolled. Again, depending on what that looks like, we will make a decision of where we go from there.
Now it goes back to the AAT protein expression, right? I think the stock reaction and the feedback, of course, the market yesterday was horrible. Some of the investor feedback, what I got is also they think they are looking for even higher, even though the first three already certainly hit the minimum threshold and actually pretty promising direction. What they are looking for is, what is the potential to even dose higher? The goal is, would that be possible, reaching close to 20 μM? Maybe first question is based on your feedback, maybe physician or scientifically, how that can translate to clinical benefit. I'm pretty sure you wish you also the lung function later in the year. How do you think about the numbers? Are we too fixated on, say, 11, 12 μM, 14 μM versus 20 μM?
How much actually that in terms of the protein level differences can translate to incremental functional benefit?
Great questions. I'll answer it in two ways. One is I think we probably are going to end up being too fixated on specific numbers because I think there's a very strong argument that we are already out of disease. We're into the normal range. There is no diagnosed person with AATD who is the ZZ genotype who has 11 or 12. It just doesn't exist. I think there's a lot of good evidence that we've already achieved. We think we're in the range of the carriers in this case. Someone who has just one copy of the mutant protein, the Z protein, and the other copy is normal, we call that M. MZ is the category there. They don't have disease. They don't have progressive disease. They may have very low risk of emphysema if they smoke.
That is maybe one consideration. Other than that, they are never going to progress. If we have really gotten patients there, I think that we have had already a transformative effect. It would be very difficult actually to show a difference between where we are now and a higher number. All that said, we will go higher. I think there is no reason not to. We have that capability. In fact, there are a few different things you can look at in our data set. One is even at the 60 mg dose, we are probably marginally underreporting our efficacy because we had a fairly low baseline level. Patients were about 4.4 μM versus you often see fives and sixes. We were delivering an almost 3x fold change in the alpha-1 levels, 2.8.
It's easy to imagine gathering more patients, having more patients at that slightly higher level, 3x times 5 to 6 would be up in the mid to high teens. I think that even the 60 mg dose may get us in those directions. If you look at that fold change chart, we're also really at the steep part of the dose response curve. With LNPs, you have a sort of sigmoidal shape of the curve. We think we're right in the middle of that curve right now. Incrementally higher doses, we expect will continue to unlock more efficacy here. The dynamic range, I think, is going to be important. The bottom line is we're going to keep going. I mean, this was the very first data set. We couldn't be happier with what it shows.
We're going to keep on going because the safety is so strong that it really enables us to push for those higher numbers. I think that they'll be achievable.
I think regarding the 2.8, close to three-fold increase from the baseline, I have a slightly different view. Is that because of baseline so low, so it's easier to show higher multiple, the increase? If baseline a little bit higher, like I think 30 mg was a 5.4, and we saw like 1.9 increase. What is the right way to think about? I mean, my calculation using linear increase correlation, if using the same baseline, 4.4, the 15 mg and a 60 mg. If you do the linear correlation and then roughly translate to, say, 75 mg would translate to like 14.3 μM.
Yeah. I think that I would not do that, I would say. I think if you look at the fold change chart that we've provided, the error bars are very tight. It shows you that there's a real effect there. I think that what we should be thinking about is a certain amount of LNP dose is given. The first step for the LNP is it has to saturate the liver. The reason you have a kind of flat dose response in the beginning, at low doses, is you may not have fully saturated the liver. Once you've done that, now you're just driving up the concentration in all the cells, all the hepatocytes, and that's going to drive your editing rate up. We think we're there. We think we're in the steep part of that curve.
The reality is patients, the reason the baseline matters is patients just do have different set points for alpha-1. They may be low or medium or high. You apply the fold change to those patients, and they get that robust change. We are controlling for the baseline levels with that fold change chart. The bottom line is I think that we do not think the baseline matters for the fold change. We think fold change is really about how many alleles have we edited in the liver at the end of the day. We have a reasonable proxy for that. If we look at the proportion in circulation of M versus Z, we know from clinical genetics, again, that carriers, I keep pointing to that group of people, they have one copy of M, one copy of Z.
They are 50% of the gene is M, 50% of the gene is Z. In circulation, because their Z does not get out of the liver very well, they are actually more like 80-20. We are actually at that level or above in our proportions in circulation. We reported 88% M in the latest follow-up point. That would suggest that we are getting maybe about 50% of the alleles being edited. We are kind of in that MZ genotype range. That very clearly also suggests that there is more room to run here. I do not think we are close to the end of our curve in terms of dynamic range of adding more dose.
Okay. If you do not have a safety issue, what would be the ideal, your goal to reach, say, M-AAT protein level?
I think I wouldn't want to set a number. I think that because I think we already have an approvable drug, but I think that as you go higher, you start to think about numbers in the 15-20 range. I think that those are certainly in view. Now you're into the kind of high MZ or basically into normal levels.
Okay. Very helpful. I think even before data update and we discussed in the past, we still get tons of investor questions on the lipid nanoparticle. Yours compared to the Verve, especially given the previous safety issue. Maybe can you take this opportunity to talk about your lipid nanoparticle and how similar or different your current one is and you also have internal other.
Great point. The LNP is, of course, critical here. This is in vivo editing. It's a simple infusion. It's hard to overstate what a powerful thing that is. Cost of goods is low. They're redosable, titratable. It's really an amazing system for accessing hepatocytes. We did really our own work on this. The ionizable lipid is in-licensed from Acuitas. We also have some of our own ionizable lipids that we can use for the future. It was all Beam work to put the other components together, process development, formulation, and manufacturing. Manufacturing these carefully really does matter in terms of how they perform in the body. I think the team did a really superb job. This is a kind of a Beam proprietary system here. It is now, we think, fully de-risked.
We have a great safety margin here, very little in terms of LFT changes, and very dose responsive and clearly reaching full efficacy. That is an asset, both in alpha-1, because it allows us to do what we were just talking about, which is push the dose and explore higher levels of efficacy in the near term, which we're excited about. Also, now it's a platform that we've really validated Beam's approach to in vivo delivery. We can now do many other things targeting the liver. That's, of course, a big strategic part of our portfolio. Certainly, immediately with BEAM-301, our glycogen storage disease program uses exactly the same LNP, has a low bar for editing. I think that you'd have to say that has a high probability of technical success at this point.
We are ramping up additional liver programs to follow. I like to think of it as almost a conveyor belt at this point of sort of preclinical programs that now can move forward. This is when, in my eyes, it gets really fun because the platform leverage that we now have can apply. We've done all the work. A new filing for a new program, you just have a tweak to the editor, a new guide RNA, same LNP, same manufacturing, same off-target set of assays, and you have a new product. The ability to now get leverage from our investment to date and create a string of new programs, all of which should have high probability of success, at least of getting to phase I safely and getting to a certain amount of editing is now in place.
That's a big part of our strategy going forward.
For this lipid nanoparticle, is that the unique part? Is the ionizable lipids there that make a difference, like better safety, the delivery efficiency?
I think no. I think that's one part of the puzzle, for sure. And we like this one, and we're using it for 301 and 302. But as I said, we have our own as well that are at least as safe and potent. We can swap those in and out over time. I actually think the special sauce, if you will, is much beyond that. I think that LNPs are validated, but they're not trivial in terms of how to make them work. You really have to have a lot of know-how. It's all about how well do they come together, how well is the payload packaged, is it uniform, are you getting small particles so the biodistribution is predictable. These things make a big difference, and they are completely functions, actually, of the process development and the manufacturing process. That's all being proprietary.
In fact, these LNPs that you're seeing with BEAM-302 were manufactured in North Carolina at our facility by our team. That is all in-house know-how.
Okay. Good. Kind of going back to the AATD program, there are two assays you have conducted to test both the total protein and the functional protein. Do you think that that will be sufficient for the FDA, the bystander editing generated functional protein? Can you foresee any additional data or testing that FDA would like to see, given you did introduce additional mutation there?
Yeah, I can't. I think that that is the definitive assay that you want to check. What you're noting is base editing has this signature. We turn the Z mutation into the normal allele at that position. It's called M. With the base editor, this version, we get some amounts of what I call the canonical sequence. We create some amounts of that change plus another amino acid change. What we've been able to show is that that is normal. It's a silent change. There are actually people who have that SNP in the world. It's a site that has several SNPs in the population. Most importantly, it's functional. We've shown that several times preclinically. Now we've shown that clinically as well.
The functional assay is really the critical point, where the whole point of having alpha-1 levels in your blood is that they are functional, that they inhibit neutrophil elastase and stop it from degrading your lung tissue. I do think that is the important assay. Really, it's the constellation of all the assays. What the FDA will want to see is, okay, total AAT is going up past these thresholds. What's the composition of the AAT? As we've shown, we're reaching 88% M. Out of the 12.4 μM, that means we've got 11 μM of M and just 1+ μM of Z left over. That's a huge change in the quality of the AAT that is circulating. Really important to think about that.
As opposed to, for instance, augmentation therapy, where you're adding some extra on top, you still have all the Z there. And Z, we do think, is a bad actor, not just in the liver, but systemically. It creates polymers. It interferes with the action of the M protein. So there's a lot of problems there. The FDA wants to see total AAT. They want to see how much M are you producing. We're in the double digits now. They want to see how much Z is left. We're down to maybe 1 μM of Z left, and we can drive it further down. They want to see functional. In our case, at the top dose level, the functional assay readout was overlapping with the total, which shows you that we have, again, converted nearly all of the total AAT to M.
All of the M that we're creating with and without any variant is functional by those assays. I think that all of that together is exactly what the FDA would want to be seeing.
Okay. Regarding the regulatory path, I mean, this is a relatively new space. Do you think it's possible to use biomarker? Or do you think, say, lung function FEV1, which should be pretty quick to measure, what could be likely path there?
Yeah. The beauty of precision medicines like this is they show themselves early, which we've just done. This is, we think, clearly a potential medicine. Because you are fixing the root cause of the disease, any endpoint is available to you because you know that you will work on those endpoints. Obviously, we favor those that get this drug to patients quicker. I think that this is a perfect setup for something more accelerated. There are different flavors of that.
At the end of the day, in my experience as a drug developer, you do find that when you're on the core driver of the disease and you're reversing it and you have a lot of biomarkers that are telling the same story in a coherent way that you have reversed the disease, especially when you have clinical genetics like we do, which show you that the phenotype we're now creating is a non-disease phenotype and is therefore predictive of clinical benefit, that is usually enough to drive that accelerated approval conversation. We will absolutely be exploring that. I think that we're cautiously optimistic that that sort of thing will be available to us. Nonetheless, we also would think about running other kinds of studies to generate those other longer-term endpoints. We want to create a strong value story here for the product.
We are confident that the drug would succeed in those trials because we've reversed the disease at its root cause. For the lung, that would be things like, can you measure lung function over time and show that there's no more progression of disease? Things like CT densitometry are available, literally measuring destruction of lung tissue over time. Those are achievable endpoints. In the liver, there's been a lot of work with the RNAi knockdown field to show resolution of aggregates and change over time in liver function. The liver, in particular, can regenerate. It's a fairly dynamic organ. We would expect, again, already, the amount of knockdown we have here to start alleviating the pressure on the liver and allow it to start healing itself. That's another angle that we can create.
I think overall, the answer is yes, we do think there's more accelerated pathways here. I expect us to be able to generate important functional data over time.
Okay. Regarding the part B study, I think you didn't mention that dose could be lower. Maybe any thoughts on the initial dose?
Yeah, so part B, we have no reason to expect a different tolerability or efficacy signal in part B. When we've dosed animals that have cirrhotic livers or have late-stage disease, we didn't see any differences there. With an LNP, which is delivered to the liver, we just felt that it was prudent to start by excluding those patients. It's the minority of patients. Maybe it's 15%-20% of them who have this sort of very heavy liver involvement. You wouldn't want to confound your initial safety signal with questions about whether the liver was playing a role. I think it's just cleaner this way. We now know that part A has delivered a very clean safety profile, very well tolerated. That's great. Now we get to go and check, is there any difference in patients who have heavy AATD-driven liver involvement?
Formally, it is another dose escalation. You will step back down and kind of titrate up just the way we've done in the part A. That said, we may not need to completely repeat all of the doses, I think, especially with this tolerability profile. We will work with our safety committee and decide exactly which doses to test.
Okay. That would be one of the 15, 30, 60, or it could be even lower?
Oh, you wouldn't need to go lower. I'm sort of arguing we may not need to go all the way back down to 15 even.
I see.
That, again, that would be 60. That'll be something we have to debate.
Okay. Good. I know we only have one minute left to maybe quickly give an update on the sickle cell program. You show very impressive data.
Thank you. Yes. BEAM-101 is our other program that I feel confident is a potential medicine. It showed, we think, best-in-class profile at ASH with superior hematology readouts with 60/40 ratio, reaching that, again, carrier kind of trait profile, and also fully resolving anemia in those patients and having fewer cycles of mobilization and faster time to engraftment. That trial is fully enrolled on the adult side. We are adding adolescents now, and they are on study. That puts us in a great position to move quickly. We'll have new data at EHA, most likely at ASH as well. I think if we can see continuation of those strong benefits, do we see with larger N, are we still getting good mobilization cycles and fast time to engraftment in that same hematology profile? Does that best-in-class profile continue to firm up?
We'd like to see that. The other metric we've been tracking there is the 30th patient dosed, somewhat of an arbitrary midpoint checkpoint in terms of doses. The reason we chose it is that the Vertex approval for Casgevy was ultimately on 30 patients with the 15-month follow-up to check for how many vaso-occlusive crises were given. If we were to get the same package from the FDA, that 30th patient will sort of start the clock for follow-up, after which point we could write it up and bring it to the FDA for a filing. We're not so far off on that program, and that's moving quite quickly as well.
Okay. Will you announce when you dose the 30th patient?
Yes. We'll probably give maybe, I don't know if it's the day of, but we'll certainly update the guidance when that's happened, yes.
Great. Thank you very much. We look forward to the multiple updates later this year.
Thank you very much.
Okay. Thank you.