Great. Great. Thanks, everyone, for being here. My name is Yanan Zhu. I am one of the biotech analysts here at Wells Fargo. It is my great pleasure to be joined by John Evans, CEO of Beam Therapeutics. Thanks, John.
Thanks, Yanan. Thanks for having me.
Wonderful. I was just wondering, can you kick us off by providing an overview of the company and its initiatives?
Yes, sure. Beam is a platform company developing a really novel and innovative technology called base editing. Here we are doing genetic correction of genes at the single letter level. We use CRISPR to target flexibly within the genome, and that is a quite powerful system. If you change the guide RNA that does the targeting, you have an entirely new mutation that you can target using the same machinery. But then, unlike old CRISPR, we do not make double-stranded breaks, so we are not editing by cutting the genome. We are editing instead by using a deaminase to do single letter changes, so very precise modifications. That gives us the power and the uniformity and the predictability of modifying the genome one letter at a time. We are using this in a wide variety of different places, delivering to blood.
We are treating sickle cell disease, initially ex vivo, with our risto-cel product. That will eventually, hopefully, move in vivo over time. Then in the liver, using lipid nanoparticles to deliver. We are treating alpha-1 antitrypsin deficiency, a very high unmet need disease where, again, a single letter misspelling causes the disease. It is a perfect application for base editor to go in and change that one letter. Then we are looking at other metabolic disorders, including PKU, GSD1A, and others, where again, we are going to go in, find single letter misspellings, turn them back to normal with the base editor. All of these treatments are potential one-time functional cures for these patients so that they get the therapy and that is it. They shouldn't have the disease anymore if we have done our job.
Great. Thanks for that overview. I think this morning you presented some new data at ERS and also at a company event. Could you share with us what are the incremental data presented today?
Broadly consistent. We gave a top-line version of this data earlier in the year, in April/May timeframe. This was our first visit to an academic conference, so now communicating with the investigators and the treating physicians in this field. I think major headlines are drug continues to look like we are getting patients into that functional cure zone that we want. So we are getting patients above what is called the protective threshold in alpha-1. The disease is characterized by a deficiency in this protein, alpha-1 antitrypsin. Patients are living in the mid-single digits for their micromolar levels of this important protein, and this important protein is needed to protect your lungs from degradation. We are getting patients into the mid-teens. Every patient is at or above this protective threshold, which is 11 micromolar.
Where that comes from is we know that there are no patients who have this disease who live at 11 or above. They are all in the single digits. So we know we have relieved that issue. Today, we basically were able to give a thorough summary of the dose escalation phase, part A and part B, with single-dose treatment. We are showing now durability of these effects across 18 months or more with these patients. So consistent with that idea of this is a one-time intervention. We are showing dramatic reduction of the toxic protein, the Z protein, over 80%. We are now able to show additional functional parameters. So we had functional data in today's update showing that the AAT that we are producing, the normalized form, it is called the M form, is fully functional. We showed that.
We also showed a reduction in human neutrophil elastase, which is a measure of this potentially problematic process that we are lowering by having the protective M around. We also showed a reduction for the first time in Z-AAT polymers. Z is commonly thought to be a problem in the liver. It builds up to toxic levels and causes liver toxicity. But unfortunately, when it is secreted, it also polymerizes in the body, and those polymerized forms can also cause systemic damage. They cause inflammation. They also interfere with alpha-1's ability to inhibit elastase activity. All of that data set is now really coming together to show the strong functionality of the blood we are producing. In general, we are getting over 90% M and under 10% Z. The shift from an all Z patient to now dominantly an M patient is quite dramatic. All of that came together into the update today.
Got it. In terms of AAT levels, compared with what you have shown in the April/May timeframe, the number back then was 16.1, I think, and today's number was 14.4 for the 60 mg part A patients. I was wondering, does that reflect a change in level, or is that just a measurement unit or something like that?
Yeah. A little bit of both. Our original report, I think, for 60 mg was in the 12 and a half range, right? Then we were at 16, now 14 and a half. I think, first, this is a protein that moves around. There is a fair amount of up and down in levels in patients. We are also mixing multiple different assay formats. Today's update was in turbidimetry, which is the classic thing that investigators are used to. For an academic conference, we felt that was appropriate. But last time, that 16 number was with LC-MS. It is just a different assay. That will ultimately be the thing we also use for filing with the FDA because it is a quantitative assay. It is also what we use when we want to discriminate the M and the Z forms, okay?
All of that together said, I think at the end of the day, we think this is the same data. We're clearly in the mid-teens. Every patient is at 11 or above. I don't think there's a meaningful difference between 14 and a half and 16, and I expect these numbers to continue to fluctuate over time. By and large, the level we're reaching looks very durable, and I expect it to hold.
Okay. Got it. You also reported Part B data. This was quite a lot more data compared with last time, right? Because these are the patient with the liver manifestations, right? Yeah. Can you talk about in liver disease patients, whether the efficacy has any difference that you can tell? Also touch on safety, and give us a sense of how prevalent liver disease really is.
Yep. So, really, probably every patient with alpha-1 has some amount of liver involvement, because all they're making is Z, and we know that Z is not secreting, and it's sort of building up in the liver and causing toxicity. We know that in most patients, the lung phenotype leads, and the liver trails. That may be because the liver is able to regenerate itself to some degree. It's a fairly plastic organ, whereas lung tissue, once you start to lose it's gone. You asked about the market or the kind of the prevalence. By and large, only about 10% of patients with alpha-1 are kind of pure liver phenotype. It's kind of an unusual population. So 90%, we would say, have some degree of lung involvement, and then a range of liver involvement below that.
Out of that, I would say maybe 15% or so are lung and liver, kind of equally severe. Then the rest are mostly lung with some lower liver burden. So it's a minority. But we're dosing with an LNP. It's a population that we want to study carefully and just make sure that the safety looks consistent. Then obviously, efficacy-wise, are we getting to the hepatocytes in the same way, et cetera. So I think if you look at the data we revealed today, as you said, there's five patients, so it's a pretty important increase in the number of liver patients. Efficacy looks very similar, right?
We were getting, again, up into the mid-teens, I think in the 13s range, and that's up from a baseline of about 4.7, so you're just about tripling the alpha-1 levels, and that's similar to what we see in the lung patients. Safety, by and large, very well tolerated. All Grade 1 LFTs with one exception. We had one patient who had a Grade 3 LFT. These are biochemical findings. Just to unpack that a little bit, patient basically went up in their AST/ALT. Within a few weeks, they went back down. There was never any bilirubin, so there's no liver injury signal. Never hospitalized. This is just sort of lab findings. No change to the path forward for the drug. No different monitoring needed. Looks good.
Okay. This is the first Grade 3 finding for liver enzyme. Is this related to the fact that the patients already have underlying liver condition? When you think about enrolling more patients in the future, what kind of consideration does this bring?
Yeah. A liver patient, like the Part B patients that we're studying here, where we've done FibroScan, and we know that they have a more severely burdened liver, let's say. They generally live often in the Grade 1. They sit above usually the upper limit of normal, just as a background. Whereas I think the Part A lung patients are usually high normal, but they're probably still below the upper limit of normal in general. This was one of our liver patients. From there, you put a bunch of lipid in, and the liver can show you that kind of biochemical response, and that's what we saw here. Again, I think in general, as long as it's just AST/ALT, right? You're just detecting those enzymes. You're not seeing bilirubin change, which is the functional measure of liver function, right?
As long as it's just those lab tests, then Grade 3 and below is very much in the noise for these sorts of LNP therapies. I think Grade 4 and above, you start to consider things, and obviously bilirubin is a big deal. We obviously didn't see that. Again, as I said, no change to how we're proceeding and continue to enroll these patients in Cohort C.
Got it. Is there anything to be considered in terms of the timing of the observation?
Not really. It is within the kind of mix of what we have seen for the Grade 1s that we have been seeing as well. It started a couple of weeks into the dose, then resolves a couple of weeks after starting. Again, no intervention, no hospitalization, outpatient completely.
Okay, got it. I was wondering if you can comment on some data from other companies also presented at ERS. This is YolTech Therapeutics' data.
They had a poster there.
Can you share your thoughts on that data?
Yeah. I think we've sort of shown that I think DNA editing is going to be a very attractive category, and base editing is obviously a perfect fit for this disease. We do expect there will be competition, and that's standard. I think we have a good couple year lead here. We're starting to see these newer entrants start to come on the scene. YolTech is one. There's also Tessera, and then, behind that, just filing now would be CRISPR and then Prime. There will be a set of these. With the YolTech data, they are using base editing, which of course, is the technology that we have pioneered and where we have a really leading position, I think. That's quite important. They have at least one patient who has nice high AAT levels in the maybe mid-20s.
Their mean was lower, maybe around 20, which kind of implies that the other two patients are probably in the teens, more comparable to what we're getting. I think it's too early to tell exactly where they're going to land, but I think at the end of the day, it goes back to, I think once you're at where we're at, where you're getting everybody above 11 and in the teens and you look like not a patient, but maybe the parent of a patient, right? So a carrier. I think you've achieved all the clinical benefit there is to achieve. I'm not aware of any clinical argument to going any higher, and I don't know how much higher those other players are going to get either.
Got it. Thank you. Let's talk about your pivotal cohort effort.
Yep.
You dosed your first patient in July in the pivotal cohort. If I can backtrack one step, I think in Part A, you also have Part A expansion for the 16 meg.
Yep.
There are six patients there, right?
Yep.
Now that you're enrolling your pivotal cohort, what purpose does that cohort serve, and will we see data from that expansion cohort?
Yeah, great question. Basically, when you're doing an accelerated approval push, you sort of want to keep the machinery rolling constantly. We have these expansion cohorts where we can keep adding patients. That's been ongoing. Now, of course, we're going to mostly direct patients to the Cohort C, which is the pivotal cohort. Yes, at some point we'll have some of that data to share as well. There's no expectation on when. Today was really the kind of full story of the dose escalation phase and how we got to the dose and sort of where we're going next. I think at this point we've treated quite a good number of patients. I think the signal is very robust. I think the safety understanding is getting quite strong, and it puts us in, again, I think, a good position to now confidently go into that pivotal cohort
Okay
and enroll.
Okay, great. Can you comment on the progress in your enrollment into the pivotal cohort?
Yes. It's going well. We have our first patient dosed in July. We had guided to second half, so obviously there's a lot of enthusiasm there. I think the operations is in great shape. We have, I think, 14 sites in six countries. Again, investigators are very eager to participate. We've had a lot of waiting list patients raise their hand for interest. So, going well. I think, at the end of the day, in terms of expectations for enrollment, I think we can't give guidance just yet. But I always say that the BEACON trial took about a year to enroll once we got out of the Sentinel cohorts. This will be a similar number of patients out of a similar-sized population. I think we might be able to go faster than that given what I'm seeing, but we'll see.
Got it. So in terms of patients' willingness to get a one-and-done therapy, do you get some feedback from the ground?
We do. I think this has probably exceeded expectations, honestly. We've always felt that a DNA curative edit here would be popular. But also there's a lot of different classes of agents and a lot of different people trying to bring new solutions to this field. And I think what has become clear to me is that the idea of a one-and-done, as long as you have the profile we have, which is getting you to a protected level, lowering your Z, increasing your M. Inducible, we haven't talked about that, but just the ability that when you're sick, it goes up even further to give you even more protection. That's the way the gene normally works. And given that we're correcting it in its normal location, we get that, and we showed that in a patient who got an upper respiratory tract infection.
You put all of that together, and that is a very popular profile with patients. If you think about these patients who are diagnosed, they have been living on augmentation their whole lives since diagnosis. And this is a weekly infusion, very burdensome to their lives to kind of maintain what even then is actually an inadequate amount of protection. They're getting total AAT kind of mid-teens. They're adding about 11 of M. They're not reducing Z. And it's not inducible, right?
So when they get sick, they're stuck with what they have. They can't go up any further, unlike us. So for us, we're inducible. We're lowering the Z. Those are quite improvements. And so these patients are really, frankly, sick of it. It's been a long time. And so I think any chronic medicine has been a little bit of a hard sell. The one-and-done looks very attractive. Now, within that, obviously, there will be early adopters and late adopters and all the normal, I think, cycle will play out. But the overall enthusiasm level, I think, has been pretty striking.
Okay, great to learn that. Let's talk about the bar for success again. I think you talked about this before, but it has been since JP Morgan when you aligned with the FDA, right? So it has been half a year. Can you remind us or provide any update with your more recent FDA interaction regarding the primary endpoint and what the bar is for approval?
Yes. I think as we said back in JP Morgan, we do have alignment with the FDA for an accelerated approval path here. I think they are working with us in a great way and by the way, it has been very consistent, a similar team, consistent reviewers. So we are just so appreciative of what they have done. I would also say very consistent today as it was then. There has been a good amount of consistency there. We have not, as you know, disclosed the specific ordering of endpoints and exactly what that agreement is, just that is just from a competitive intelligence perspective, something we are holding to our vest. But it is really the constellation of all of the things we have talked about together. So obviously, total AAT matters. Your M, your Z levels, your functional AAT, inducibility, like these are all things that are important.
Many other of the functional assays that I have mentioned become relevant as well. The reason all of it together is important is because they tell a story that, again, as I said at the open, we have clearly taken a patient who has the profile of a diseased patient, a ZZ with 100% of their AAT is Z protein, and it is in the mid-single digits. We have really converted them to what is clearly at least a carrier phenotype, where they are now total AAT is in the teens, they are 93% M and very little Z is left, Z has been reduced by 83, 84%, and then it is clearly inducible, and it is clearly all functional.
I think what that tells you when you are FDA is you are looking for the evidence that you can then use to predict clinical benefit. That is what accelerated approval is. It is really that profile that we know from the genetics should no longer be a diseased profile. It should now be a stable profile. That is, I think, the basis for the confidence that they need to work with us on an accelerated approval.
Got it. That makes a lot of sense. Thank you. Maybe switching gears for the PKU program. You announced this program fairly recently, and this is IND cleared. You are in a clinic. Can you talk about the level of your excitement with this program, and how big is the opportunity, and how do you think BEAM-304 can be positioned in the treatment landscape?
Great question. The level of my excitement is high. This really becomes, I think, the third leg of the stool for the company from a commercial perspective. That is important. We clearly see the sickle franchise as having blockbuster potential. Alpha-1 clearly has blockbuster potential. But so does PKU, and that is really important for a company like us, where we are looking to make gene editing into a sustainable business. It is also a very efficient path in the clinic. We will be starting dosing patients around year-end, early next year. That goes a few cohorts of dose escalation to establish safety, right? That will be an important first step. But once we have established a dose, we should have a path directly into an expansion cohort, which could be registration enabling, right? We will try to treat some number of patients, maybe it is another 50 or so.
Here we are just measuring phenylalanine lowering, which is the deficiency here. They cannot process phenylalanine. Then some amount of diet normalization, and that is a full approvable endpoint. No confirmatory trial. That would be the whole journey. That is a very efficient and predictable clinical pathway. As far as I know, we are the only DNA editing players in PKU right now. It is a perfect indication for us. Then really cool about PKU as well is we are using this novel platform approach with the FDA. We got the IND open, which we announced mid-year.
Here, the FDA for the first time, as far as we know in industry, is doing this sort of new kind of rules within CRISPR and genetic medicine where we actually have multiple editors in the same product, so that depending on which patient you are, depending on which mutation you have, we give you one of two different editors. That is the initial IND we have now. We can add to that. We can add a third, a fourth, a fifth, and all just be part of one package, not have to redo things every time. That is really exciting because it allows us to increasingly create individualized curative therapies for each patient while treating the same disease. The FDA's causal mechanism pathway guidance really talks to this. I am quite excited about that.
Our first two editors cover, we think about 45% of patients would have one or the other of these two alleles. It is the R408W allele, and then there is one more. Again, we think we can add more alleles over time into this package and treat more and more patients within this community. Then as with sickle and Alpha-1, this would be a one-time intervention to potentially give you lifelong normalization, ideally, of your phenylalanine metabolism.
Okay. Got it. I guess you have not guided on potential timeline to firsthand human data on this program yet, right?
We have not. Obviously, it is open-label trial, so we will be accumulating it over time. I generally say on average 12 to 18 months before even starting to expect data is usually a good rule of thumb. We will see as we get into it.
Got it. Maybe talk about bar for success on efficacy. There are approved therapies out there. What is the bar here?
Yeah. This has been one of these diseases, like alpha-1, where it really needs better therapies, and it hasn't been easy despite a lot of effort. You have KUVAN, which is like a cofactor, but that only works in the milder cases of PKU. More recently, you have SEPHIENCE from PTC, which can maybe get you more out of any functional enzyme that you have left there. But even that is not curative. You still have some amount of diet restriction, and not all patients are in control.
I think there's real room here to improve, and if you look at our preclinical models, which we have shared, at a relatively low clinically meaningful dose, around 0.3 mg per kg, for instance, we were getting full normalization, with stability and durability of phenylalanine levels. I think we'll see what we get, but my ambition here is to provide as close to a full normalization as we can. That's the promise of gene editing.
Got it. That's great to hear. That sounds like there's some efficacy advantage to look forward to.
Yes. As with all of our other programs, again, not giving guidance yet on when the data might arrive, but it is true that the first data set should tell us not just safety. These are precision medicines, so the very first data set should show us how is it tolerated, but also is it working, because we are treating patients with intent to cure from the very beginning. So the first data set ought to be pretty informative as to whether we have a drug and a franchise.
Right. Just continuing on, for the in vivo editing franchise, GSD1A, I think you have data coming this year.
Help us understand the study design and what data could we expect.
Yes. So GSD1A, our BEAM-301 is editing the R83C mutation, again, a single point mutation in this gene that we are trying to correct back to normal. This is a really terrifying disease where you cannot fast because what is broken is the machinery to take stored energy from your liver in the form of glycogen and turn it back into blood sugar, glucose. We all use that every time we fast between meals and when we go to sleep for eight hours and we are not eating, your liver is keeping your blood sugar up. So these patients cannot do that, so they are basically constantly crashing and going hypoglycemic, so they have to eat something every couple hours, and particularly they take this sort of cornstarch that is a slow-digesting source of glucose. So their glucose levels are just crashing and then spiking and crashing and spiking.
And literally, if you sleep through one of those feedings overnight, you can die. You slip into a coma, and you never recover. So it is a crazy situation. And again, a relatively low amount of editing would restore the ability to do that glucose production out of the liver, and we see that in animal models. So this is the most prevalent mutation in this population. It is an ultra-rare population. We think there is probably 300 patients with this mutation out of maybe 1,000 total. And what we would like to see, we will have a couple of cohorts worth of dose escalation, so stay tuned for that. And again, the goal here is to show some real impact on the metabolism of these patients. We would look at things like cornstarch utilization, right? That was used by the Ultragenyx drug. Ultimately, the gold standard here would be time to hypoglycemia, right?
That is the fasting duration. So at baseline, if you take them off cornstarch, how long until they go hypoglycemic? It is generally a couple of hours. And then after the treatment, do you extend that? And so that is what we will be looking for. And that, again, should be ultimately an approvable endpoint for full approval.
Got it. So, I see. So in terms of the data points that we will see this year, can you outline those endpoints for us?
Yeah. So I think, again, the ones I just mentioned, so it would be sort of cornstarch utilization, time to hypoglycemia. I think those are the gold standard endpoints here, and could be comparable to other agents in the field, which will be hopefully helpful to investors. And then obviously safety, how it is performed.
Okay. Obviously, there is the Ultragenyx gene therapy approved, as you mentioned earlier. Do you think there is room to improve with a gene editing approach?
Yeah, I do. I am so happy that product did get approved. I think this is a population that really needs more options, and as you noted, we are only coming to at least initially treat one mutation, which is the R83C. There are other patients who do not have that mutation. So the more options for these patients, the better. All that said, I think that product does leave some room to improve. So it is an AAV product, which means some patients will have preexisting immunity, which blocks them from receiving it. That is not the case with LNP therapies like ours. Then for those treated, they got a 44% reduction in cornstarch, which is a real improvement. But you can see the FDA is thinking of this as potentially an accelerated approval, then they need to come back with more data to convince them for that full approval.
That is because the cornstarch reduction, I think, is maybe a softer endpoint, and maybe the effect size is something that maybe the FDA wants to see a little bit more. So I think that is where I think both cornstarch reduction, but also time to hypoglycemia is maybe the endpoints that we will be looking for.
Got it. Super helpful. Let us talk about sickle cell.
This is a program that you already have. You are in phase. You will file
by year-end.
Yes.
Let's talk about what are the items remaining for the filing, and then also touch on the commercial experience for CASGEVY so far and what are the lessons learned and how do you foresee your launch?
Yeah, great question. Everything is going well. We are doing validation runs and PPQs and all of that. Very much on track. The timeline is really driven by, we have treated 50 patients, but we think it is the 30 patients that were similar to the CASGEVY label that we need. We treated number 30 July of last year. 15 months to measure the VLC 12 endpoint puts us into October. That is your data cut, and then you basically write it up as fast as you can. We think it is around December, that is hence the guidance of end of year and we will see if we can hit it. I think we are in good shape to. I think that we then would be positioned to enter a market that is actually starting to grow. CASGEVY is doing better now. Genetics with LYFGENIA, I think, is doing quite well.
They announced they were profitable this year, so they are making money with that drug. Patient demand is really high, and yet we do hear from sites that they do want more. I think they are looking for new options. Particularly, there has been a lot of difficulty with manufacturing some of these products, and that is real-world issues that they are working through. We know that risto-cel has real advantages there. Our vein-to-vein time from the median patient from the start of mobilization to when we deliver them a dose and they dose it in the transplant has been four and a half months. We think that is quite a bit faster than what is being seen with other products, and that was with our own manufacturing facility, our own team releasing the drug, and that will continue to be the case on the commercial market.
On top of all that, we get higher levels of F, lower levels of sickle protein, faster time to engraftment than what has been reported before. I think in general, it looks like a best-in-class profile for a market that is just beginning to really get into gear, and we think can be quite meaningful.
Got it. You are ready to or do you plan to launch it yourself?
Yes.
Build a sales force?
Yes, we are fully ready for that. It is just not that big an effort. We need to scale up the North Carolina production line a little bit, and then grow it over time as capacity in the market increases. There are 50, 60, 70 centers that we will be focused on. A small team can do that. We will be doing that. We did a financing, a really exciting financing with Sixth Street, where we have access to a $500 million facility. We are projecting we will take down about $300 million of that, about $100 a year, and that fully covers our commercialization build-up costs for the product, and the product can then fully pay back the cost of that financing and the principal later. It makes risto-cel effectively self-financing, which we are quite pleased with.
This will launch by the end of next year and be making money in the end of the decade. For a company like us, that is quite important. From there, we are also hard at work on next gen products. This is to treat really the 10% of patients who are sick enough to go through a transplant. But from there, we have an in vivo program that we are quite excited about that will be coming at some point. That, of course, can then create access to genetic cure for hopefully all sickle patients, and that would be 100,000 patients in the U.S. Again, we think that the sickle franchise is a very important one for Beam's future as well.
Yeah, definitely look forward to progress on the in vivo front. Unfortunately, that is all the time we have for today, so maybe another time. Thank you, John, for a very helpful session.
Thank you, Yanan.
Thanks, everyone.