All right, thank you. Welcome back from lunch. Thank you for joining us on the next session here at the Jefferies Healthcare Conference. I am pleased to have our next session with Beam Therapeutics. Up here is the president, Giuseppe Ciaramella?
That's right.
Close enough?
Close enough.
Close enough. But importantly, Beam is progressing and enrolling in a important sickle cell program, which we'll talk about. And importantly, there's been a new focus on your second program-
Mm-hmm.
—as well, in AAT, which we'll talk about, and certainly there's been some controversy around, you know, safety, and whether or not there's any risks with the platform. So I would love to delve into all of those. So maybe it would be great if you could just make some opening comments about where Beam stands today and the progress on your sickle cell program, and where you are with AAT, and then we'll get into some of the details.
Absolutely, and, first of all, thank you for the invitation. It's great to be here-
Yeah
-and to share some updates. So just to give you background of Beam is a next generation gene editing company. They use base editing to focus on really on two main franchises. One is the hematology franchise, of which sickle cell is obviously the front leader, and the gene editing for liver disease, initially with alpha-1 being one of them, but also GSD-1a-
GSD, yeah
the second program. So sickle cell disease, we are currently in the clinic. We have disclosed we have completed the sentinel cohort, which-
Which is like 3+ patients?
Three-
Yeah, three.
3+ patients.
Okay.
Yeah. And then also announced that we've actually initiated the expansion cohort, following review by an independent data safety monitor of the three sentinel data. And so we're pleased to say that the conduct of the trial is going very well. It's meeting all of our expectation. The trial design is very similar to what you might have seen from Vertex or Bluebird. It's essentially designed to be a pivotal trial, which will enroll a total of 45 patients. We estimate on the basis of the conversations and the BLA filing that Vertex has done, is that between 20 and 30 patients with the certain follow-up will be sufficient actually to support the BLA.
20-30-ish to support the BLA-
We know-
Ultimately, we're enrolling 45.
We're enrolling 45, and we know 20 was not sufficient as such with Vertex. They went with 30, but there may be an opportunity to maybe find a middle ground there.
Okay.
But yeah, so, we are also on track for our guidance, that we will be disclosing some of the clinical data later on this year.
Okay
... on a meaningful number of patients, which will include certainly the three sentinels, but also beyond that. And the, again, the trial has already incorporated several sites, several individuals on trial, and so we feel confident that we will be able to provide the meaningful clinical information.
Meaningful is like, well, certainly more than three.
More than three, and also with the follow-up, right?
Yeah.
The first patient we announced was dosed early this year.
Okay
... toward the end of this year will be almost close to 12 months of-
Yep
-follow-up.
Okay.
So that's the meaningful is not only the number, but also-
Follow-up
-some individuals-
Yep
-with the-
Okay
-appropriate follow-up. So yeah.
So making progress on sickle cell, and again, we'll be looking for an update there. Keeping it high level before I get into the details, tell us about your AAT program.
Mm-hmm.
This would be in vivo-
Correct
-not ex vivo, so we're dosing into the patient. Tell us about AAT and what you're trying to address, because this would be different than the other AAT programs out there, whether Vertex, whether Inhibrx, which got-
Correct.
-sold. That deal just closed. And Arrowhead-
Mm-hmm
-Takeda, which is a different program, but-
Yes
What are you trying to do?
So, we have an open CTA actually for this program in the U.K., and we're on track-
Okay
-to dose actually our first patient before the end of this month.
Okay.
In this case, what we're doing, we're using the power of the single base pair correction that base editing affords to correct the single point mutation that causes the disease. This protein is normally expressed in the liver, but as a consequence of the single amino acid change, this protein basically misfolds and accumulates in the liver, causing toxicity in the liver. But perhaps equally, if not more importantly, prevents this protein from being secreted from the liver and going to the lung, where it protects the lung from elastase and other proteases.
So by fixing the gene in situ, like we are planning to do, we are essentially fixing not only the liver issue, but also the lung, because we project to actually restore circulating level of active alpha-1, certainly targeting at least some of the normal levels that are starting around 20 micromolar on the basis of some genetic evidence. Perhaps even more importantly, though, by fixing it in situ, we preserve basically the endogenous regulatory paradigm of that protein. So the promoter will be the identical promoter, the wild type promoter. The reason why this is important is because you need alpha-1 protein the most when you have an infection in the lungs, because obviously you need to protect that. In fact, under those circumstances, during an infection, alpha-1's levels increase as high as threefold over baseline.
Hmm.
And so the restoration of that is really can only be possible if you are fixing the gene in situ. Protein replacement therapy, for instance, cannot do that because essentially you will have peaks and troughs which are not necessarily aligned to an infection. The same even Inhibrx, for that matter, will not be able to do that. And other strategies like siRNA knockout, for instance, will be in a way eliminating even more circulating levels of alpha-1. And gene therapy approaches like, for instance, Intellia, which is trying to insert a cDNA in a protective locus also will not do that because it will utilize a different promoter.
Mm.
We feel that-
Mm
Not only the basal level, which is obviously important, but this regulatory ability of restoring higher level of alpha-1 during infection, we think is actually very important to protect the lung.
You're restoring the natural biological function-
Yes, essentially.
-which is broken. The others are either trying to block it, which is not doing anything-
Yeah.
But just blocking something bad. It's not restoring it, obviously, not getting into the lungs.
Correct.
And obviously, not restoring the natural increases and decreases as you have an infection because that gene therapy is different.
Is different.
Yeah. Okay, so, let's start with that because it is a topic of high importance because AAT, it's in vivo-
Mm-hmm
... it's important. It is about-- you're about to treat a patient-
Correct.
You just said. And so tell us about the types of patients you're enrolling. Are there specific protocols? Is the dose that you're using a therapeutic dose, and would you expect that you're gonna get high levels of AAT in this first patient?
Yeah, the first patient will be challenging, but the design of the study is a typical single ascending dose, very similar to studies that you may have seen with Intellia, for instance, and others.
Okay.
Where, essentially, we're exploring 3-4 doses, but with some flexibility of modulating the dose regimen that we will look at, depending on some of the emerging data. Even the very first dose, and this is by regulatory demand, will be a dose that we expect to bring some clinical benefit. It's unethical actually to go in patients with a dose that we know would not be at least providing some benefit.
Right.
It's unlikely that it will be the optimal dose because we need to obviously be careful also from a single dose ascending-
Mm, mm
... in order to be able to progress to a higher doses. The dose levels are very typical of dose levels that you would expect to see with an LNP product, which range up to 1 mg/kg.
Okay.
In preclinical studies, we have shown that we can achieve clinically relevant upregulation of active alpha-1 AAT at doses of as little as 0.25 mg/kg.
Okay.
But we can see a maximal saturating level of dosing from doses as high as 0.5 and higher.
Okay. So, in preclinical, like, non-human primates?
In preclinical, so non-human primates do not have the single point mutation.
Okay.
But what we have, not only the mouse, which is typically the model that-
Okay
... most people use, but we have developed a bespoke rat model-
Okay
... where we have essentially swapped the rat SERPINA1 gene for the human one, one to one.
Okay.
Which is not the case with the mouse model, where there are about 13 copies of the human gene, and also the mouse gene has been preserved.
Okay.
In this case, essentially, we have reproduced a more-
Okay
... closely genomic background.
In that model, 0.25 mgs per kg was producing enough editing.
Mm-hmm.
Give me a number, how much editing happens?
The very minimum that we expect is required is between 20%-25%, will be enough to be able to do that.
Sure. So, if there is, I was going to say, I know that 20%-25% of editing of the cells-
Mm-hmm
... will get you to therapeutic levels.
Mm-hmm.
At 0.25, how much editing do you get in the rat model?
So, you are in about 30% editing rate. So you're-
Okay, so you're in that zone.
You're in that zone.
30% of the rat cells are edited, and that yields 20 micromolar of AAT?
It should be within the range, between-
Okay.
... 15 and 20 micromolar.
All right. That's excellent.
So-
That's excellent data.
... obviously, yeah, and then we by increasing the level-
Yeah.
... we get to saturating levels of editing. Saturating, remember, we measure the editing in the whole liver, and the whole liver is only about 60% of the hepatocytes, which are the relevant cells. So 60% editing is potentially it's essentially 100% of the hepatocyte.
Wow.
And we can see those kind of levels when we go-
The hepatocytes are only 60% of the cells.
of the entire liver mass.
Okay.
So, you can get to those levels of editing when you go to 0.5 and 0.75.
Okay. So, even at 0.25, you get enough editing that should lead to very strong levels of AAT in a rat. Now, I can't recall the prior, but the prior analogies were that Intellia and others-
Mm-hmm
... have shown that remarkably, in human in vivo dosing, that they were getting at, the same doses, higher editing and efficiency, weird, that you actually get even better data in human. Maybe that's because of the LNP or maybe, I don't know. But that, that means that it's conservative, because if you're doing 1 mg per kg in a human, in the UK-
Mm-hmm
... and the animal was 0.25 mg/kg, and you're already getting therapeutic levels that are strong, wouldn't 1 mg/kg get you at least that level?
Yeah. The reason why Intellia saw an improvement from non-human primate to human is because the guide that they were using was more potent for the human sequence than it was for the non-human.
For just that program?
For just that program, so-
Which was, remind me, TTR?
TTR.
TTR, right.
It was in that case.
Okay.
So, you know, the translatability of how the will depend to a great extent on the guide. We do expect to see some improvements on the potency of our human guide relative to the, but it's not identical to what, you know, Intellia had.
Okay.
So we think that basically in the range that I described, which is 0.25-0.75, you know, up to 1, is a valid range of doses that we can explore, which are similar by the way, to the ones that others have seen, so-
I think you're being conservative.
Well-
I'm hearing 4 times the dose, 1 mg per kg versus 0.25.
No, 1 mg, 1 mg per kg is the highest. I'm not saying that we'll-
Oh, that's not the s-
Yeah.
I thought that was the starting dose.
No, no, no. No, no, no.
Oh.
We have not revealed the starting dose.
Yeah.
We're in the same range that others have looked at, which is up to 1 milligram per kilogram.
Oh, okay. Well, like what did Verve use for their starting doses?
The starting dose, I don't remember for them, but I think it was 0.3-
0.3?
0.1. Actually-
0.1.
0.1, then 0.3, then 0.45.
Okay.
So-
And so you're not disclosing the starting dose, but it's in the ranges of these things.
It's in-
The highest would've been one as a starter—who's used one as a starting dose?
Nobody has used one as a starting dose.
Okay.
To my knowledge, there's no one that has ever dosed-
Okay
... LNPs higher than 1.25 mg.
Got it, got it, got it.
It just-
Point, point being that that's at least in the starting dose already of what the rat showed.
Correct.
That rat showed was already giving great levels of AAT editing, so that would be predictive of why even a low starting dose, similar to 0.25-
Correct.
... and in the zone of the others, should get you to therapeutic doses. How much of that? We'll see, but you should be getting increases in AAT.
So we-
At some point.
... we have, we have basically, you know, confidence from the preclinical model, that shows the similar level of editing both in mouse and the rat. So we have translatability in two species.
Yeah.
And then we've done PK in the non-human primate, 'cause obviously in that case we can't do the edit, but we can certainly measure the amount of LNP, the amount of RNA that we give at the different doses. So we can create essentially a PK/PD model that gives us a prediction of human dose, and that's what we used. The additional level of confidence comes also from the fact that we're using LNPs, and even if we were unable to achieve the ideal levels with a single dose, we have the opportunity to come back with a second or a third, because the edit that you make essentially will be there, and you can accumulate additional editing on top of that.
It really gives us, you know, confidence because we have not only a strong preclinical package, but also at the clinical level, the opportunity to modulate the number of doses so that we can get to the desired level of outcome.
Yes. Let me drill down on that a little more, 'cause this is important. So, you said basically you could redose if-
If necessary.
If necessary.
We're not planning to, but-
Yeah
... but we have the opportunity to.
Okay. Now, importantly, the market is watching this carefully because Verve using the Beam single base pair editing technology-
Mm-hmm.
... albeit with a one or two different LNPs, as I recall.
Correct.
Because they were targeting one receptor, and then also a second liver receptor-
Mm-hmm.
... to get it into the liver, but they have two different ones. One of them initially had some one or two off adverse events when that data came out in November of last year, since they were at the Jefferies conference.
Mm-hmm.
Stock traded up because the PCSK9 levels did get knocked down.
Mm-hmm.
It was edited out, but then there were some safety questions. Then the second result, they recently announced that there was a hold on the second, correct me if I'm wrong, partial hold?
No, there was no hold. Actually, they voluntarily stopped that particular LNP-
They voluntarily-
Because-
... stopped it, okay.
They saw, essentially, what was classified as Grade 3 transient elevation of LFT.
Grade 3 transient LFT, okay.
Also, they're in the patient background that has some heterogeneity in the LDL receptor.
Mm.
... which is an important receptor for the uptake of LNP. In fact, I would say that the important thing to understand in the context of our program is that even if we saw what Verve have seen-
Mm.
... it would not be a dose-limiting, basically, event for us.
Okay.
That's because every LNP, actually, at a certain dose will see, and you will see transient elevation of LFT. And if they resolve within two weeks, and they occur early on post-dosing, those are actually not really clinically relevant, and they can be managed, and they are essentially a temporary high accumulation of fat in the liver that leads to essentially a transient inflammatory response.
Let's walk out. This is important.
Mm-hmm.
... because a lot of people said, I mean, the market reacted, and said, "Okay, Verve had this, voluntary pause.
They-
I don't know whether the term used.
No. Verve basically had in play-
Yeah.
... two different LNP formulations.
Yes.
One called, they call it 101-
Right
... which is, a more, standard LNP-
Yep
... which utilizes an LNP, an ionizable lipid, and I'll come back to that.
Yeah.
There are three other components which are typically of an LNP.
Okay.
This is a cholesterol, there is another lipid, and then there is PEG.
Okay.
That LNP formulation is 100% dependent for uptake to a receptor, which is called LDL receptor.
LDL Receptor, okay.
The issue with the patient population that Verve are targeting is that in most cases, there are, they can be heterozygous for that.
Mm-hmm.
And so that can contribute to some variability to the data, which is likely-
Well, less receptors.
Less receptors.
Okay, yeah.
But actually, in a subset of the population, there are homozygous negative.... So basically, they cannot use that LNP to address the patient population.
Okay.
The alternative formulation that they had to develop-
The second one, yep.
The 102 uses GalNAc.
GalNAc.
GalNAc is an alternative to bypass basically that receptor.
Okay. Yeah, it gets in without using the LDLR-
Without using the LDLR receptor.
Okay.
They already announced that because of the heterogeneity in the population, that ultimately they wanted to wait for one or two data in order to make a choice.
Yes.
between those two.
Okay.
Now, since they saw this transient elevation, they, I think-
With the GalNAc one?
No, with the LNP only-
Oh.
-which potentially contributed also by the heterogeneity that they see with LDLR. Then they made what I believe was a strategic decision to say, "We're actually gonna cut to the chase and just go with 102." That's gonna-
Thank you. So yeah-
So-
To clear up, the first 101 had the thing last year. They kept going forward. They also used 102. 101 then had a transient increase. They paused that, said, "Why are we even messing with that?" Plus, the receptors are regulated-
Yeah.
For PCSK9, let's use GalNAc. The one you're using is different but similar to 101.
Different but similar.
Thank you.
It will be an LDL receptor-
Yes.
-dependent, typical LNP. The relevance to us, the important thing-
Yes.
is what Verve is seeing is really the only relevant thing is actually the positive that you just described. If we were able to reproduce the level of editing that they have seen, it would already give us the-
Yes.
the clinical
I believe they have, what, 60% editing or something like that?
I believe-
Of the eligible cells.
Of the eligible cells.
Yeah.
And that-
That produced significant knockdown of PCSK9. With 25% editing, you should be getting high levels of AAT. So even with a fraction of the editing that has already been shown with PCSK9, you should be getting high levels of AAT, even with a fraction editing.
Even with a fraction, yeah.
So the only thing is, can they do it safely?
Yeah.
Your point is, the thing that they saw, which kind of freaked the market out, you would say if they have a transient increase in LFT, you're gonna watch it for two weeks.
If it's resolved-
It's probably gonna go away. That is not a concern-
It's not a-
nor a material disclosure for B.
Is not a DLT. You know, dose limiting toxicity.
Okay.
It's not a DLT. Now, we have data to suggest that we probably might, you know, the transient elevation, typically you'll see with any LNP, so-
Mm.
We can't exclude that we will see them, but it, we're likely to be in that kind of scenario of transient elevations. And as you pointed out, potentially our editor is a little bit more potent than what Verve is seeing. The other thing that is important to note, the ionizable lipid is different from the one that Verve has used.
Okay.
It's an analog of the one that they use-
Mm.
but it's not identical.
Right.
And, you know, different chemical structures can actually have a different effect. We've also put the LNP together with our own proprietary formulation process, which is not the same as Verve, and we think that that brings some advantages of, you know, how well the particle is formed and so on and so forth. So we have a lot of reason to believe that we're actually in a situation where actually what Verve have seen-
Yeah.
even though some
Yeah.
You know, there's been some correlations.
Can you explain? 'Cause I don't think the market understands. Do you believe that there's some has to do with fat, and what was the fat doing that's causing-
Yeah.
the transient increase?
That's typically what happens with LNPs.
Yeah.
is, if you think about it, the amount of lipid ratio to-
Okay.
-your RNA-
Yeah.
-is between 10 and 20 times.
Okay.
If you say one milligram of RNA-
Yeah.
-it's 20 milligrams of fat.
Okay.
Okay? Per kilogram-
Okay.
that you are dosing.
Okay.
This is like a huge Big Mac that all of a sudden you're just ingesting.
It's that much cholesterol.
Because there is, it's just-
It's a fatty LNP.
It's a fatty LNP.
Yeah, okay.
Now there is some additional contribution that can come from,
Understood.
... the RNA, how you formulate the LNP.
Understood.
You know, where the particular transient elevation occurs in terms-
Understood.
of dose might vary and
Which literally has to do with the amount of cholesterol-
It-
And the fat that's being injected. If you multiply that out times milligrams per kilogram-
That is really one of the things-
It's like a cheeseburger going in-
Yeah.
That's what you're saying. Okay.
It's not the only thing-
Okay.
because there are other components to it.
Yeah.
As I said, some can occur at lower doses than others.
Got it.
but typically you would expect
Interesting.
-of any LNP.
The key here, getting back to the point about Beam, is that this is mechanistically makes sense.
Mm-hmm.
That's not a safety concern, that you believe that that's transient.
Sure.
And that once that settles out, you're gonna watch the patient. That would not be a DLT, not technically be a reason to pause, and you will continue to dose patients in the U.K. And so what would we have? What's going on from this month throughout the summer, and would you put out data on a bunch of patients at the end of the year?
Yeah. So we eventually we will disclose data. We have not provided guidance as exactly when that is going to happen. As you can imagine, you know, we want to have a meaningful clinical disclosure.
Yeah.
But similar to others like Intellia, where there is a couple of cohorts of data, some actually even three, will take between 12 and 18 months if you look at when that disclosure has actually happened, with them, so-
Okay, so let me come back-
Yeah.
... 'cause I actually feel, just, clarify, that Beam has suggested or, that there could be data on a few patients end of the year or early 2025. That's not true?
We said that 2025 is probably a likely
Got it.
-uh, scenario.
So sometime in 2025, there'd be-
Sometime in 2025, there will be data.
Got it.
The most aggressive would be early 2025.
Got it.
The most conservative would be later in 2025.
Got it. Some other healthcare conference in San Francisco in order to-
We'll see. San Francisco, I'm not sure, but-
Not San Francisco.
Maybe we'll find another conference.
Got it. Got it.
The reality at the moment, it's difficult for us to provide guidance in a-
Understood.
From a clinical point of view.
By the way, the sentinel cohort is that you have to dose the patient then wait months?
There is a bit, there is a bit of a sentinel cohort, but we don't necessarily need to wait months. UK is a little bit more flexible on, on some of those parameters, and so there is a little bit of flexibility in there, but, you still need to do a sentinel dose.
Got it. Very good. Giuseppe, thank you so much for running through that with us. Super helpful clarifying things. Congrats on getting ready to dose that patient AAT.
Thank you very much.
We continue to follow up and some data in 2025.
Thank you so much.
Sickle cell data later this year. Thank you.
Absolutely. Thank you.
Very good.