Good afternoon. Thank you for joining us for another session at the 44th J.P. Morgan Healthcare Conference. I'm Brian Cheng, one of the senior biotechnologists here at the firm. On stage, we have the CEO of Beam Therapeutics. I'll now pass the mic to their CEO, John Evans, for a short presentation followed by a live audience Q&A. John, the stage is yours.
Thank you very much. So yes, my name is John Evans. I'm here to tell you about Beam Therapeutics and some of our medicines. And I'm going to talk about the power of predictability in the technology that we're using. So as a reminder, I will be making forward-looking statements today. So at Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. This is gene editing for rare and common disorders. This means the potential for one-time curative therapies with lifelong effects. And this is a platform that can potentially create a large number of medicines over time. So it's been a remarkable 12 months for base editing. And I just want to walk you through some key events. So at the very end of 2024, we revealed data of base editing for severe sickle cell disease, showing dramatic results.
Shown here is Brandon, patient number one on that trial, who was treated at Boston Children's Hospital. Just a couple of months later, in March, we published the first data for base editing in alpha-1 antitrypsin deficiency using BEAM-302. This is in vivo editing this time. And now, for the first time, we're literally rewriting a broken gene back to normal, which has never been done before. Two months after that, a team at the Children's Hospital of Philadelphia published dramatic results where they created a customized base editor for a baby named KJ, who the editor was only developed over the course of about six months while the baby was being born. And it worked. So you have three very different settings, very different contexts. And yet base editing went three for three, with dramatic results. And that's not an accident.
And I think it's a sign of the predictability and the power that this technology can bring. So at Beam, we're not surprised. So Beam was founded around this technology. It's a simple concept, but it has many profound implications. So with base editing, we're using CRISPR to target within the genome precisely. But once we get there, we're not going to make a double-stranded break or a cut. We're instead going to make a single-letter change in the gene. And we are going to have total control of those strands. This has a couple of outcomes. So first, we're going to have consistent gene sequence outcomes. So we're going to know the gene sequence that is going to result from our edit in every case. Second, this will be, of course, durable. We're going to have lifelong correction, one-time curative potential.
And finally, because we're not making the double-stranded break, we're going to have less genotoxicity. The cells are going to be healthier, potentially happier than in traditional gene editing. So you put all that together. And what we believe we're going to have is more predictable and reproducible outcomes for patients. So if that's possible, what could that mean? So we think that the products that we're going to create here that have that predictability are going to have profound ripple effects across the healthcare and biotech ecosystems. So first, the predictability that we're predicting here is going to mean streamlined R&D cycles. That means reduced development risk. We're going to be able to predict that this drug ought to work every time. That's going to shorten timelines and make our investment more effective. Second, regulatory acceleration.
The FDA is more than willing to work with you to move programs to patients faster so long as the science is really clear. And here it is. And we're already seeing this FDA open up the door to more flexibility for these kinds of medicines. Third, physician confidence. These are not drugs where you might get a 10% or 20% response rate. These are drugs where everybody responds and everyone has a profound impact from this editing. That's going to mean predictable safety, durability, and efficacy that can give physicians confidence. Of course, patients are also very interested in that same kind of predictability. And they're eager to be done with their disease. They want to get that benefit and hold on to it.
And the unique part about lifelong cures is the patient doesn't have to worry now about maybe their insurance is going to change or they're going to lose access to their chronic medication. They're going to get that benefit. And they're going to be able to rely on that benefit for the rest of their lives. Finally, payers. We all know we need to be more efficient in our healthcare spend. And we're so confident that the profound changes and the lifelong changes that we're going to provide here are going to reduce lifetime healthcare utilization costs across the healthcare system with outcomes to back it over the long term. Payers are going to be very supportive of that. And we think that'll be another tailwind in favor of this kind of therapy. So beyond that, there are also advantages to Beam as we build a company around this technology.
So this is a true platform. So what does that mean? That means that base editing is easily adaptable. Once we've made it work in one target, one cell type, it's very quick to then put it onto the next target. And you have an entirely new program. Delivery technology, things like the LNP we use to deliver to the liver. That's reusable. If it works once, it's going to work again and again. That's going to mean consistent preclinical and clinical outcomes. Manufacturing is highly scalable. And the more we do it, especially at Beam, where we're doing it internally on our own team, our own facility in North Carolina, the better we are at it. And finally, as I said, the flexible regulatory frameworks that are emerging. So this flywheel is now spinning faster and faster.
And the confidence that we're generating is only going to go up from here. So I think the evidence for this vision is already clear. At Beam, we have multiple growing high-value franchises in view. Because of the success of these early programs, we are eager to now double down and expand the pipeline, bringing more programs in that can take advantage of the de-risking and validation we've already established. And this platform is going to generate excess value beyond even what we can capitalize on ourselves. And that's going to be substrate for some really exciting and creative platform partnerships. So of course, none of that can be done without a foundation of financial strength. And we have that at Beam. So Beam has $1.25 billion in cash at the end of the year.
That gives us runway now into 2029, which will carry us through the launch of Risto-cel, our sickle cell disease product, as well as full execution of the pivotal development plan for BEAM-302. We remain focused on our spend strategy, managing expenses over the long term. The commercialization of Risto-cel and sickle cell is actually quite efficient, and as I said, and I'm going to go into this in more detail, the development pathway for 302 is also efficient as well. All of this gives us a very clear path to value creation with a wholly owned pipeline addressing significant markets, and behind that, a sustainable growth engine based on this platform, so 2025, I think, was the year that all of this became visible. This has been our vision and dream for the eight years since we founded the company, but I think 2025 was really the proof.
So as I said, first human proof of concept ever for an in vivo correction of a gene in alpha-1 with 302, continued differentiation of Risto-cel and sickle cell disease. Now, FDA regulatory alignment on the path to market for both of those programs, as I will describe, exceeding our clinical enrollment, advancing our next wave programs, a very significant financing early in the year, and as I said, now runway into 2029. So we're very excited leaving the year and couldn't be more eager to see what comes next. So let me dive in now to some specifics, and I'll talk a little bit first about our liver programs and then turn to hematology. So in liver, the lead program here, as I think everyone knows, is our alpha-1 program, BEAM-302. This is a potential best-in-class and first-in-class program, disease-modifying for alpha-1 antitrypsin deficiency.
Because of its success, we're very excited now to expand the pipeline and bring more assets forward. We will be announcing another liver program soon. All this is built on our industry-leading LNP capabilities, enabling delivery to the liver. And so far, LNPs have been well tolerated clinically. Finally, this entire area has platform synergies that make it perfect for the kinds of novel regulatory pathways that the FDA is flashing the green light on so we can go faster and faster and reach more and more patients. So now let me dive into alpha-1. So alpha-1 antitrypsin deficiency is a severe genetic disease characterized in almost all patients by a single-letter misspelling in the SERPINA1 gene, which makes the protein alpha-1 antitrypsin. So that G to A point mutation, we call it the Z mutation.
And patients who have two copies of that mutation, it's called the ZZ genotype, have the disease. So when you have this disease, you get two problems. First, you have a progressive lung disease. That's caused by low levels in your body of the alpha-1 protein, which is designed to protect your lungs when you're infected. And in addition, what little alpha-1 protein you have is the Z form of the protein. It's a mutant form. And it is not as effective. It actually causes problems. It can cause inflammation and aggregation. In addition, there's a progressive liver disease. And that is caused by the fact that that Z protein is actually building up in the liver in a toxic way. It's causing aggregation and accumulation. And that causes a progressive liver disease and gradual liver failure. There are very few therapeutic options for patients. They are generally unsatisfactory.
We clearly need to do better. And nothing addresses the full spectrum of the disease. So that's what BEAM-302 is designed to do. So with BEAM-302, we're going to use base editing to correct the single-letter misspelling in this gene and turn it back to normal. That'll address the root cause of the disease and restore physiologic control of alpha-1. So what would success look like? We would see the liver producing the normal form of this protein for the first time. We call that the M form. If we're doing that, we would, of course, significantly reduce the amount of Z in the body, which is the bad actor. We would see total alpha-1 levels rise above the 11-micromolar protective threshold. It would rise because the M form is so much better secreted from the liver than the Z form.
And we know 11 micromolar is protective because clinical genetics tells us that patients with this disease where you have two copies of Z have alpha-1 levels in the four to six range. No one has 11 or above. If you're in the teens, 10-20, you're generally a carrier. You might have only one copy of Z. And you have no progressive disease. You're safe. We would also, of course, want to know that the AT we produce is functional. And finally, this is an inducible gene. So when you get sick, you create a lot more. And we'd want to see that the AT increases with inflammation. All of this would be in a durable single-course treatment, one time for life, addressing both lung and liver. So it sounds very exciting. And it turns out that's exactly what we've shown with BEAM-302 so far.
So here, this is the data that we showed in March. This is the 60 mg cohort. And you see on the left-hand side, total AT levels indeed rising above 11, here reaching 12.4 micromolar. And that's at day 28 after a single dose on day zero. We also then show significant reduction of the Z protein because we're literally converting Z genes into M genes, here showing almost 80% reduction again at day 28. Finally, the composition of the AT in the body has shifted. You see here going from 0% at baseline to 91% M in circulation again at day 28. So all of this is truly indicative that we've achieved those therapeutic goals, that we've converted these patients from disease to carrier where they shouldn't have any progression anymore. We really believe this could be a functional cure. So what have we been doing since then?
The trial is very active, so we're hard at work exploring. We're treating more patients at 60. We've gone up to 75 mg. We're going to try two 60 mg doses, all just to explore different variations of dose and schedule. We're also running a Part B in patients who have very sick livers. This is a minority of the population, but given that our program is liver-directed, we want to make sure there's no change in safety and efficacy in that population, and all of this is to identify the optimal dose and schedule for a pivotal study. We look forward to getting updated clinical data across all of these cohorts, and that is expected by the end of the first quarter of this year. Clearly, we believe this is the most advanced genetic and disease-modifying program for alpha-1 in the clinic.
We've actually treated over 25 patients at this point and still going. And there is quite significant patient and physician enthusiasm. Excitingly, I can now add FDA alignment to the list for BEAM-302. So the timeline goes like this. So in March, we showed the clinical proof of concept, that 60 mg data, got the IND open in the U.S. shortly thereafter. And that data was submitted to the FDA for RMAT designation. So RMAT may be less familiar. But it's basically the breakthrough designation for gene and cell therapies. And to get that, the FDA will review your data and has to decide that, yes, this is worthy of trying to work with you to accelerate the program to get to patients faster because RMAT allows you to have multiple meetings with the FDA in a sort of continuous manner. And so they said yes. They invited us in.
So we've been working with them ever since. And I'm happy to say that in Q4, we did indeed reach alignment with the FDA on a potential accelerated approval pathway for this drug in alpha-1. What does that look like? The primary endpoint is expected to be based on AT biomarker, so levels of alpha-1, functional alpha-1, M levels, Z levels, all the things we've already shown, measured over 12 months. So clearly, we want to be able to show we've changed AT physiology and that it's durable. We anticipate enrolling approximately 50 additional patients in an expansion of the existing phase I/II trial. So that's going to be a very efficient approach. We're already open in many countries and sites around the world. And we think this will be very easy to implement.
We were also accepted into the FDA's CDRP program, which is basically designed to give CMC consulting advice to companies and programs that are on expedited pathways with the FDA. So great progress. We're so excited to bring BEAM-302 to patients with alpha-1 who really desperately need new options as quickly as we can. So one quick update on our next program in the liver. This is BEAM-301 for glycogen storage disease Ia, patients with the R83C mutation. So this is a very orphan disease. Patients have to continuously take in cornstarch every few hours, including overnight, or they can potentially die of hypoglycemia. So this is much slower to enroll because it's much more rare. But we're actually making good progress here. And now we do plan to report our initial clinical data from this program by year-end.
Third in the liver, as I said before, we look forward to sharing an additional liver program that will be added into this portfolio. And that will come out in the first half of this year. So we look forward to that as well. But now let me turn our attention over to the hematology franchise. So here, as you may know, our major focus is sickle cell disease. And we now see an opportunity for really a pair of complementary approaches, one near-term ex vivo approach that is a near-term commercial opportunity, and then longer-term an in vivo delivery approach to achieve maximum scalability and reach all patients. So for ex vivo, we're focused on the severe sickle cell market. This is about 10,000 patients in the U.S. We believe it's really poised for growth at this point going forward.
We see very clear clinical differentiation for Risto-cel based both on the mechanism of base editing and on our very advanced manufacturing process. For next-gen technology, we do still have the ESCAPE program that is very exciting and can be used in a wide variety of places. But at this point, in vivo delivery to hematopoietic stem cells has made enough progress that we're moving that into our preferred position as the platform for our next sickle cell program after Risto-cel. On Risto-cel itself, as I said, we see three major areas of differentiation. First, we're achieving deeper resolution of this disease. We're trying to raise fetal hemoglobin to higher levels to protect these cells. We're achieving over 60% F, that's higher than anyone else is achieving in the field. And at the same time, we're driving sickle protein down below 40%.
So those numbers are comparable to sickle trait, a carrier. And that tells us that we're finally achieving a normalization of the biology for these patients. We're also fully resolving anemia. And markers of hemolysis and oxygen delivery are normalized or improved. Second, patients are spending less time in the hospital after the transplant. We think because the base editing doesn't make that double-stranded break, the cells may be a little more viable, a little more ready to turn on more quickly. And we're seeing rapid neutrophil and platelet engraftment. When you get the transplant, you have to wait until those cells appear again from your new graft before you can go home. And so this could mean an overall safer transplant journey and, of course, a faster time to return to life. Finally, predictability is about not just editing or delivery. It's also about things like manufacturing.
And we're seeing that. So we have a very advanced process. At this point, patients are seeing a median of one collection cycle for mobilizing those cells that we can make a dose out of. We're seeing consistently high yields and viability. And we really think that's a function of both the base editing mechanism as well as the fact that we have our own facility in North Carolina allowing us to have our internal team do all of the manufacturing and release in a seamless way. So we get a lot of questions about the market for this drug and sort of where is it and have the launches gone as expected from some of the other players in the field. So our perspective is there's actually a lot to like about what we've seen so far. So first, there's patient interest.
There are waiting lists in most of the major centers. Patients are eager to participate. Treatment centers, there are 70-plus centers where whole teams of people have trained themselves to get ready to do this work, so they are motivated. On the other end of the spectrum, patient outcomes have been positive, and payer, we believe that there have been no payment rejections to date as far as we have heard. It's still very bespoke, but that's going to get more systematized over time. The major issue, we believe, has been in that cell collection manufacturing process. These are challenging processes. So we hear reports of inefficient or unpredictable processes, patients facing multiple cell collection cycles with a lot of uncertainty, and then manufacturing slot limitations as they try to work through that, so we expect some of these things can be improved.
But they're clearly holding back the market as of today. So that creates an opportunity for Risto-cel. And in fact, the data we're already seeing in Beam shows that we actually address these problems quite directly. So if you focus in on the collection and manufacturing steps of this process, as I said, one cycle per patient median, we're actually running if you start from the beginning of mobilization to when we release the drug, it's about three months. From the beginning of mobilization to when the patient receives the drug, that sort of vein-to-vein time, that's four and a half months with high predictability. And that's for the majority of patients. At that point, you benefit now from the faster time to engraftment, under 20 days for neutrophil and platelets to turn on and get you home.
So in total, we're looking at four to six months for the entire journey to potentially cure yourself of sickle cell disease. So clearly, we believe this would be very attractive and bode well for Risto-cel's uptake within the market. But in fact, we think we can actually grow the market because you can use an existing amount of clinical infrastructure and potentially, with numbers like these, treat more patients. So we're very excited about the potential of the program and its differentiation. So what have we been doing with this? So we've actually been engaging with regulators continuously also on this program through 2025. We do have clarity on that BLA package now. And it's very consistent with what we had been expecting. We've actually completed manufacturing of all doses on the trial. Dosing of the final patients will sort of occur through the beginning of this year.
And so at this point, we are able to guide that we plan to submit the Risto-cel BLA package as early as the end of this year. In parallel, we'll be initiating our commercial build. And as I said before, it will be a very efficient build. Again, there are 70-plus centers we need to focus on. We're already doing the manufacturing out of North Carolina. That facility can go commercial. It was always designed to. So this is not a big lift. This is an upgrade and a scale-up of the things that we're already doing quite well. So couldn't be more excited about the potential of Risto-cel for sickle cell disease. And that's for that 10,000 sickest patients for whom a transplant makes sense. Let me turn our attention now to what are we going to do for the rest of this population?
We're not satisfied only treating 10%, and so here we're looking at this next wave and we are prioritizing in vivo delivery using lipid nanoparticles, so this is really building on breakthroughs that have been made recently on how to make these sort of particles reach these cells in the marrow. We do still have the ESCAPE technology, which we've talked a lot about. It's a powerful approach. BEAM- 103, the antibody, is in the clinic and advancing. We can always do it ex vivo and pursue a sort of non-genotoxic transplant, but at this point we think the in vivo approach is going to go faster and is ready to accelerate, and we have the optionality, of course, to use ESCAPE with it if we choose. So why now? At this point, we believe Beam actually now has all of the capabilities needed to do this.
That includes the LNP, of course, as you saw from our liver portfolio. We have many potent lipids in hand and proprietary LNP processes. But importantly, now we can do extrahepatic delivery. That takes two things. So one is you make modifications to the LNP to detarget the liver, which is where LNPs usually want to go. And then you add targeting binders that can enable cell-specific delivery in vivo. So in addition to that, of course, we have the efficiency and potency of the base editing payload. And as I said, the option to use ESCAPE as well. So the proof points for why we think this is ready now. We've actually been working on this for several years.
A company that we helped start called Orbital has been using Beam reagents to do this exact approach to deliver LNPs to T cells in the body for autoimmune disease. They showed really beautiful NHP proof of concept last year. That program is now progressing to clinical studies and was actually acquired by BMS for $1.5 billion. In parallel to that work, we have been working on the HSC delivery side. HSCs are going to be a little harder than T cells, but not a very different concept and at this point, we have multiple HSC targeting LNPs in hand and identified. The development scale-up for that program is already largely in place and we are in lead optimization, so stay tuned. We look forward to updating you on this exciting program as it advances as well, so let me spend one moment now on our partnerships.
This has been a strategy we've taken to really drive both value creation for the company as well as therapeutic impact. At this point, our partnerships have resulted in over $900 million in non-dilutive funding for Beam over the course of our eight years in existence and, by the way, gained rights to both innovative and complementary technologies for us to use. In addition, it's allowed us to move some of our science, be it delivery technology, editing technology, or otherwise, towards patients in areas that we were not going to be able to get to ourselves. It's been a big success. We couldn't be more happy with this. I think you should expect this to be a big part of our business model going forward. We expect to continue with this track record.
I'll now close just by talking a little bit about what we expect for 2026. As we noted, the headline here is we're going to be pursuing a path to approval for both of our lead programs. For BEAM-302 and alpha-1 antitrypsin deficiency, we'll be reporting updated phase I/II data and giving a little more clarity on the timing for our pivotal development program by the end of Q1 this year. For Risto-cel and sickle cell disease, we plan to submit that BLA as early as year-end this year. Building on the success of those programs, we're now also quite eager to take advantage of that. If this technology is as predictable and reproducible as I think it is, then we're very excited to do more for patients.
We'll be disclosing along those lines another liver-targeted genetic disease program in the first half of this year. We'll be reporting the initial data for BEAM-301 and GSDIa by year-end. On the hematology side, we'll be completing the BEAM -103 healthy volunteer study in the first half of this year and then advancing that in vivo editing program, all while maintaining financial strength with $1.25 billion in cash and, as I said, runway through into 2029, including the anticipated launch of Risto-cel and the execution of the 302 pivotal development plan. Really, we're at the point where we have the funding we need to get to that commercial transition and begin generating sales as a company. It's a remarkable place to have gotten to. We couldn't be more excited about it.
So I'll close by saying thank you for your time, but also thanking the patients and families who have partnered with us on this journey. They are on our minds all the time. They are waiting for better and curative, potentially therapeutic options. And in addition to helping them, we want to get to more patients and more diseases. The impact we can have, I think, with these technologies is quite profound. And we look forward to working with you all to move this forward. So with that, thank you. And we'll take some questions.
Great. Well, let's start the Q&A. For those who are in the audience, if you have any questions, feel free to raise your hand. For those joining us virtually, you can also submit questions on the portal. I want to start off with on what happened. I think the news really caught us by surprise in a really good way. What a great surprise to kick off the week. Can you walk me through the interactions that you have had with the agency? How do we get to the accelerated approval path now in place? I think I also get this question of, have they seen data from the higher dose? Have they seen the double-dose cohort? Can you just kind of walk me through what they have, what kind of interactions you have had with the agency?
Yeah. I think in many ways, I think this is a classic accelerated approval program. FDA likes it when you have your own mechanism. We know the problem here. It's the mutation. We have a mechanism that directly fixes what's wrong, and then they want to see that the science they're showing is consistent with that, and all of the biomarkers I just described are going in the right direction, consistent with that functional cure, so I actually think that the FDA has been thinking about an accelerated approval pathway themselves for some time. To answer your second question, they have seen the only things that they saw to make these decisions and put us on this pathway was the same things that we've shown today, so it's the same data set that we shared back in March. They haven't seen some of those newer, more recent things.
Those will come out at the end of Q1. The timeline I described, I think, is really descriptive. That data came out in March. We had RMAT designation with the FDA by April, I think it was. And again, RMAT is explicitly about, we want to work with you to find a way to go faster to get to patients. I think everything else was really just working with them on the details. I don't think it was a big picture disagreement. It was more, OK, what does this cohort look like? What's the follow-up? How do we manage variability? All the classic development questions that come up.
Great, and then maybe just turning to the primary endpoint of the trial. We noticed that the press release says biomarkers, plural. How should we think about the selected biomarkers? Are these known biomarkers to those of us who have been trafficking in alpha-1? How should we think about just the selection of it?
Yeah. Maybe I'll take it. First of all, my name is Pino Ciaramella. I'm President of Beam, and it's great for your interest and participation today, so a couple of things, maybe just to complete the prior conversation. I think actually it was really pleasant for us to see that we could come to this agreement with the FDA, but it wasn't completely a surprise. In fact, in the pre-IND conversation that we had, they did open the door to an accelerated approval on the basis of biomarkers, and the biomarkers fundamentally are essentially exactly what you've seen. As John mentioned, the data package that you've seen has been disclosed is exactly the same that the FDA has seen, and essentially, we'll be obviously totally AT, but we'll also be functional AT. We'll obviously be interested in the levels of M relative to Z.
All of those will be the kind of biomarkers we'll do. There's nothing new that we need to develop or novel assays that the FDA has requested on that. It's really just a confirmation of what we've seen, but in an extended data set.
Great. Any questions from the audience?
Hi. Thank you for being here today and sharing your perspective. As you think about base editing technology scaling, what do you think the biggest bottleneck is going to be? Is it capital? Is it talent? Is it operational know-how? Something else?
Yeah. That's a great question. So the question was, how are we going to scale base editing technology? Just from a pure manufacturing perspective, it is highly scalable. These are synthetic, easily manufactured intermediates. We're doing it ourselves in North Carolina. I think that it really just takes the time to develop the science and the evidence base that we can do this safely, that we can do it with efficacy, that we understand how to deliver to a certain organ. And then once you've done that, doing it the next time is going to be much more predictable and more repeatable. So I think we're just building that track record now.
You can hear from my presentation that we do feel like we're kind of at that inflection point where now we have enough of that evidence and foundation built that we can start to shift it into higher gear and do more things in parallel.
Yeah. I would say certainly from a manufacturing point of view, we deliver the base editor as a messenger RNA and enveloped into an LNP. It's exactly the same technology to some extent as what has been developed with vaccines for mRNA. And you have seen there have been literally billions of doses have been able to manufacture at very managed cost. So I think the scalability from a manufacturing point of view is not an issue. Really, then it depends on how many tissues you can successfully deliver. And I still believe that delivery is somewhat of a rate-limiting step in how many tissues you can actually afford that. The good news is that the LNP technology actually is making progress in going to other tissues and other cell types, particularly with now the ability to target different cell types by coating the LNP with different moieties.
I think the field is moving along. The strength of the base editing is the predictability that we just said. We know that if we can deliver to the cell that we want, we know what the outcome is going to be.
Just turning to the first quarter updates by the end of this first quarter, what is expectation? And what do you ultimately want to see, especially among the new cohorts? The 75 make the double-dose cohort. And we're also going to see liver plus minus lung disease patients. So ultimately, what do you want to see so that you have the best view going into the expansion part of the study?
Yeah. Great question, so I think as we try to communicate, we're very confident we have a potential drug here at the 60 mg data, and I think the FDA agrees as far as we can tell. So really, what we want to do in addition to moving it forward is do a few last checks to make sure we have the right path going forward. So one of those is to make sure we've optimized dose and schedule. So we've clearly edited a substantial portion of the liver here with the 90% M that you see, the 80% reduction in Z. At the same time, we haven't edited all of the liver because there's still some Z there. So we want to make sure we don't leave efficacy on the table, and so the 75 mg cohort, the two times 60, we're actually adding more 60s.
All of this is just designed to test for, is there additional efficacy to be gained, higher levels that could be achieved without compromising safety? We wouldn't want to do that. And so that's sort of one set of data that we're going to get. And that'll inform sort of a final recommended dose and schedule. Is it 60, or is it one of these other flavors? But importantly, all of them we expect to be therapeutic and plausible. And then in the liver cohort, this sort of part B of the trial, we're asking a different question, which is, as we know, alpha-1 patients are on a spectrum from liver and lung involvement. So in part A, we excluded patients with really sick livers because this is a liver-delivered therapy. So just to be conservative, we wanted to first target patients who didn't have sick livers.
And then in part B, we're testing in those patients. And so we want to see there is, does the safety and efficacy look similar in those patients as in the part A? If it does, we will collapse them back together and just treat everybody as one group. If for some reason it looked different, then we would have a different modified approach to treating those patients. So that's the second big question we want to ask. And I think we'll have plenty of data, I think, to have a conversation about both of those questions at the end of Q1.
Great. I want to touch on a relatively frequently asked question, which is, is 20 micromolar the new bar? We have been hearing 11 micromolar is the protective threshold for a long time. And if you look at some of the older agents, that's where it should be. What's your take on that? There seems to be a bit of a debate on where it should be to get meaningful benefits in a clinic.
Yeah. Maybe I'll start then, Pino, and if you want to expand, but remember, the disease is in that four to six range. A carrier is in the 10- 20 range, and carriers don't have the disease. So I think the difference between 11 and 20 would be undetectable from a clinical perspective, so I think at the end of the day, the reason 11 is the number that people focus on is that's the breakpoint where you would stop seeing symptoms. I think that's what ultimately matters. Of course, if you can go higher, you would.
Yeah. Yeah. Of course, 20 is the sort of, typically, 20 and above is where normal double M sort of phenotype lives, but as John says, basically, as long as you are out of the disease and you are in the 10 and above, you essentially do not show any progression of the disease, so really, what our technology and the data that we have already shared does is to set these individuals as essentially heterozygous, and as a consequence of that, they're not expected to have progressive disease, and not only that, we've demonstrated with the old biomarkers that we have disclosed is that the functionality of the gene has now been restored, so you essentially eliminated the cause of the progression of the disease from the body, so we think that 11 micromolar is really the threshold to be worried about.
And then, of course, you try and generate as much as possible. But the reality, being able to demonstrate clinically the benefit of a difference will be very challenging.
Let me add one other point because people sometimes are comparing us with augmentation, which is a very different paradigm. The numbers we're sharing, so the 12 and a half micromolar at 60 mg, that's a floor, not a ceiling. And so because this is an inducible gene, we would expect when you get sick, the gene will turn on. And you'll actually go up from there. Whereas augmentation, exogenous protein that you put in is basically washing out. And it's not regulated. So you're not ever going to get more until you get another dose. So I think it's important also to keep track of the very different sort of profile of the AT levels in the body based on these mechanisms.
In the last two minutes, we have one quick one on GSDIa. I don't think we touch on that quite a lot. We're going to get some data, first glance of data this year. Where should we focus?
I think GSDIa is really an important disease with very strong medical need. And the R83C mutation in particular we're targeting is the most severe form of that disease. What we're hoping to demonstrate is that a proof of concept that we've essentially restored the glucostasis in these individuals and also rectified many of the negative biomarkers that are associated with disease, like for instance, enlargement of the liver, high level of triglyceride, cholesterol, and so on. And this is obviously an ultra-rare disease. And therefore, there are fewer patients. But we expect demand, the opportunity for obviously high prices, but also the ability with very small number of patients' data set to hopefully achieve a licensure very relatively quickly as part of that.
So we think it is a program that has benefit both certainly from an unmet medical need, but also potentially from a small commercial opportunity that will be a meaningful one. So that's what we're hoping to be able to show you that progress.
Looking forward to it. Thank you so much for our time, and that's all we have for today. Thank you.
Thank you.