Okay, great. Thank you. All right. Well, good morning. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan, and our next presenting company is Beam Therapeutics. Presenting on behalf of the company, it's my pleasure to welcome CEO John Evans. There's going to be a Q&A session after the presentation. If you want to ask a question, just raise your hand, we'll get a mic over to you. For folks joining via webcast, you can also submit questions by just hitting the Ask a Question icon. So, with that, John.
All right. Thank you, Eric. Okay, so welcome, everybody. My name is John Evans. I'm very excited to be here to tell you a little bit about Beam Therapeutics and our effort to create new precision genetic medicines in the field of base editing. 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. We see real potential for one-time curative therapies, which could be truly disruptive in medicine. We believe gene editing is going to be a treatment for both rare but ultimately also more common diseases. We believe that because these technologies are programmable, they can be true platforms, not just creating one program, but creating multiple medicines rapidly over time.
So to give you a quick tutorial on gene editing, so the state-of-the-art to date in gene editing have been what we call nucleases, most famously, CRISPR. So what these tools have done is solve one very important problem, which is, how do you target within the genome precisely? There are three billion letters in all of your genomes, A, G, C, and T. We want to find one address for editing, and they do it very well. The challenge is, once they get there, there's only one thing that they can do, and that's to cut. It's like having the scissors for the genome. When you make that cut, it's a genotoxic event for the cell, but more importantly, you can't control what happens next. The cell puts the pieces back together again, but with damage.
You have literally random insertions and deletions at the target site. So this means that you basically lack control over what's going to happen to the gene sequence. So base editing was designed to fix that problem. So with base editing, we keep that same precision targeting that you get with CRISPR, but now we're going to do an enzymatic-based conversion when we get to that target site. Simple chemical change, turning one letter from another, either A - G or C - T. This is very efficient, but more importantly, it's predictable. So now we know exactly what sequence will result when we've made the edit. That really opens the aperture for thinking therapeutically about reprogramming genes to do a wide variety of different things. So this is what the gene editor looks like when you're doing base editing. So we use the CRISPR protein.
It's targeted with a guide RNA, just like normal CRISPR, but now we have a deaminase attached to it, which does the chemical modification. And on the right-hand side, you see all the different kinds of edits that we can make here, with this controlled and precise system. So now we can think about correcting mutations, literally taking something that is spelled wrong in the gene and turning it back to normal for the first time. We can, of course, think about silencing proteins, activating proteins, modifying proteins, literally changing a protein's function by changing a single amino acid in the protein. And, and actually, we can also do multiplex editing.
Because we don't cut, we can actually stack edits on top of each other as much as we want without creating chromosomal damage, and that allows us to target multiple pathways at the same time, letting us intervene in more complex biology. There are actually examples of all of these types of editing already in Beam's pipeline and with our partners. In many ways, I think that we are at the very early innings of what is possible in this field. We've been building a truly comprehensive and integrated platform of technologies to make these medicines a reality. Of course, it starts with base editing, the A and the C base editors I described, world-class guide RNA and messenger RNA capabilities.
For delivery, we use cell therapy, ex vivo editing of blood stem cells or T cells, or lipid nanoparticles going in vivo to the liver or potentially other tissues as well over time. Finally, we enable all of this with GMP manufacturing. These are very complex medicines to make. We have established our own in-house GMP manufacturing facility in North Carolina. I believe it's the biggest in the gene editing industry, and that is already now doing runs as we speak. Importantly, this is a modular platform, okay? What that means is that we're already applying it to our current pipeline products, but as we get new ideas, we can pull all of the tools we need right out of this platform and quickly move new programs forward for patients. So here's the pipeline.
So as you can see, a wide variety of different kinds of delivery, different kinds of editing being exploited here. Leading the way is BEAM-101 for sickle cell disease, followed by the ESCAPE version, which is a next-generation version for sickle, which I'll describe soon. In the liver, we're doing in vivo editing, BEAM-302 for alpha-1 antitrypsin deficiency, BEAM-301 for Glycogen Storage Disease Ia. We have BEAM-201, our quad-edited CAR T cell for T-cell leukemias and lymphomas, and then our major alliances with Pfizer and Apellis starting to bear fruit, with lead programs targeting the liver, now moving forward into lead optimization. We're actually doing many more things as well, than just this at Beam, but these are the programs getting the most activity right now.
So I wanted to double-click on a couple of areas here and give you a sense of why we're so excited about these two big drivers, I think, of value creation and patient impact for BEAM over the near term. So first, with sickle cell disease and hematology. So we really believe in the best-in-class potential of BEAM-101 for sickle cell, and I'll show you some of that data in a moment. Importantly, we're operating with what we believe is now an increased probability of success for any ex vivo gene editing of blood cells, as well as for upregulating fetal hemoglobin in sickle cell Disease, based on what we've seen in the field.
We now have a validated FDA regulatory pathway to approval for this kind of agent, and our next-generation version, ESCAPE, has the potential to eliminate chemotherapy altogether from the equation, which could dramatically expand the reach of base editing to many more patients. Ultimately, if these technologies work, this is a true platform in hematology, where the kinds of things we're doing here to help patients with sickle cell disease can help patients with a wide variety of other disorders. The same basic logic is true in alpha-1 as well. So with alpha-1, we have best-in-class potential, clearly with BEAM-302. We have, again, an increased probability of technical success, based on the success of in vivo LNP-based gene editing in the liver. We have potential for rapid clinical proof of concept, raising alpha-1 levels, lowering Z protein levels.
This will be the first and only clinical stage program in alpha-1, with the potential to be a one-time treatment that benefits both lung and liver disease and is under normal regulation. Again, if we're successful here, this is a platform for creating a large number of liver-targeted base editing programs over the long term. So these two franchises, I think, are gonna be very important to Beam over the coming years. So 2023 was a truly transformative year for CRISPR gene editing, for base editing, and for Beam. Hopefully, you've been following some of the exciting news. In the gene editing field, we had the first in vivo INDs cleared by the FDA. We had the first in vivo liver base editing data published, and we had the first CRISPR-based product approved in sickle cell Disease.
So tremendous wins at our back in gene editing. So at Beam, our job is to take that next generation of this technology forward. So we achieved the first patient's dose with a base editor therapy in the United States. We did that initially with BEAM-201, dosed in Q3. And then today, we're very excited to announce that we did, in fact, dose a patient with BEAM-101 in sickle cell disease, and they were successfully engrafted all in Q4. We did a very strategic deal in which Lilly acquired Beam's rights in the Verve programs. That provided a lot of capital for us. We prioritized our portfolio, really highlighting into those couple of value-driving areas in sickle cell and alpha-1 that I mentioned.
Those decisions have put us in position to announce again today with a revision, that we do expect our cash balance to last us into 2027. So that's a great place to be, given all of the things that I think this pipeline can accomplish over the next three years. So 2024 is the beginning of that journey, and this is gonna be a very dense year of catalysts for the company, very action-packed. So walking you through some of these things. So Beam- 101. Coming off our first patient dose, we do anticipate being able to complete the sentinel dosing and initiate expansion dosing in the first half of this year. That puts us in great position to present clinical data on multiple patients in the second half of 2024.
ESCAPE, this very exciting next-generation program that we're working on, has been making great progress. We're in late lead optimization, and again, excited to announce today that we anticipate being able to initiate phase I enabling preclinical studies in 2024, putting us on a definitive path towards the clinic. In vivo, with BEAM-302, we had a goal of filing for phase I in the first quarter of this year, and I'm thrilled again to announce today that we've actually already done that. So that is complete. BEAM-302 CTA has been filed in the U.K. We have additional countries to be filed shortly. All of that puts us in position to initiate a clinical trial for BEAM-302 in the first half of the year.
BEAM-301 will follow shortly thereafter. This is for Glycogen Storage Disease Type Ia. Again, looking to file a U.S. IND this time on the later parts of the first half. Finally, BEAM-201, our quad-edited T-cell program, gonna be a lower priority for the company going forward based on the prioritization decisions that we've made. But nonetheless, ongoing trial, we do anticipate being able to present clinical data in the second half of the year. All right, so let me now walk through a couple of stories just to give you a little more detail on some of these areas that I wanted to highlight. The first one I will do is sickle cell disease.
So it's been obviously an incredibly exciting period for sickle cell patients with the approvals of the first gene therapies, one-time therapies to they've had truly transformative effects for these patients. But I'd pose the question: What if we can do better? Can we create even better one-time cures for these patients, or are we really gonna stop here? I think clearly our team feels strongly that the answer is yes, we can do better, and the technologies that Beam has assembled are gonna unlock that vision. So the path really looks like this. So this is a multi-wave strategy. It begins with the most severe patients. So this is gonna start with BEAM-101, where we're doing precise upregulation of fetal hemoglobin, potentially best-in-class profile, non-cutting, non-viral. Following that will be wave two with ESCAPE.
So this is to add an extra edit that will allow us to pursue non-genotoxic conditioning, getting rid of chemotherapy. That would allow a much broader range of disease severity and ages to be treated and expands the market dramatically. Finally, of course, our long-term vision is to do all of this in vivo, to deliver these, editing tools with lipid nanoparticles directly to the stem cells, avoiding the need for transplant altogether. At that point, really, every patient is eligible for this kind of therapy, and we could even go global if you think about the incredible global burden of disease that this disease represents. So a quick primer, on sickle cell disease and what BEAM-101 can do.
So as you know, this is caused by a mutation in the adult hemoglobin gene, that has caused the expression of the sickle form of hemoglobin. And what that does is under low oxygen conditions, it can polymerize and cause rods that deform the shape of the sickle of the red blood cell, causing this sickling shape, which then clogs in your capillaries and causes vaso-occlusive pain crisis, organ damage, and ultimately significantly shorter survival for these patients. So what we want to do is we want to go in and turn on the genes for fetal hemoglobin that are off after birth. We can do this more directly than anyone else because we don't cut, and we can install single letter changes in the on/off switches for those genes that will turn them on really robustly.
Once you have that extra level of F, you then will protect the cells from the sickle protein, and they will function normally. So BEAM-101 has the potential to be a more efficient editor, leading to greater and more uniform induction of F, more reduction of the sickle protein, and more normalization of hemoglobin. We're also investing in wholly owned manufacturing and process development and the overall patient experience, making sure that we can deliver the best possible regimen for these patients. So this is the data that backs up my claim about best-in-class. This is the same animal model that has been used by others in the field. You can compare them directly. On the left-hand side, you see that very high efficiency that we're getting from base editors of over 90% editing.
But importantly, in the middle, because of the high number of cells edited, but also that uniform production of the same edit in every cell, and we've literally chosen the edit that gives us the highest dynamic response from the gene, we get the highest level of F of anyone in the industry, of over 60%. And compare that to, say, the Vertex product, where the preclinical data was in the mid-30% range. Okay, so that strong upregulation of F also leads to a lowering of S more than others, and so we're seeing S levels at 40% or less. As a reminder, these are human cells, so this is practically the clinical product. We're just putting it into a mouse rather than a human.
And so that, you know, gives us a lot of confidence in the potential translation of this profile. So the translation is going to happen in this trial. This is the BEACON trial. This has been designed explicitly to be a potential registration-enabling trial. We really believe that should be possible, and the FDA's decisions late last year give us increasing confidence that that is indeed gonna happen. As you know, a transplant is a long and complicated process, so patients must go through transfusion, mobilization, manufacturing, all before you can condition, which is where you get rid of the old cells, dose in the new edited cells, and then engraft. So we're moving in parallel on the first part of this, with many patients now on trial, moving through the preparatory steps of this process.
Now we have indeed successfully dosed our first patient with 101. We're moving on to patient two now, and once we finish all three sentinel patients, we can then dose as many patients as are ready in the expansion phase of the cohort. We've actually completed manufacturing for multiple additional patients beyond patient 1 already, so great momentum in this trial, and we do anticipate, again, dosing some expansion patients all in the first half of this year, putting us on track to present data in the second half of this year on multiple patients with long-term follow-up. So a lot of momentum here for BEAM-101, and can't wait to show you what it can do. So let me, let me just highlight this next-generation version called ESCAPE.
So with ESCAPE, what we can do is we can take that same potentially transformative edit I talked about with BEAM-101, that will take care of the sickle cell disease, and we can add a second edit. And that second edit is going to be on a receptor on the surface of the blood stem cell. And this is something that only base editing can do, because if you use a nuclease, you would just knock out the receptor. You would scramble the gene. But the base editor can make a single base change, changing a single amino acid on that receptor, where you're only altering the epitope of binding for an antibody. All right?
What that allows us to do is, for the first time, use antibody-based conditioning rather than chemotherapy, to get rid of the old disease cells, and in such a way that it will bind to old cells and kill them off, but it will now not bind the edited escape cells and leave them alone, and they will grow, okay? So this, for the first time, lets us have in the body at the same time, the graft and the conditioning agent, okay? That is a huge breakthrough in the pursuit of this field to change transplant and conditioning. So on the right-hand side, you see that in action, you see a mixed population of cells, both edited and unedited, and as we add antibody, we dramatically shift the population towards edited cells and wipe out the rest of the unedited colonies.
So very, very excited about what this potential breakthrough can do for patients with sickle cell disease. We now are on track to initiate phase I enabling studies in 2024, which would put us on a definitive path to the clinic. Finally, wave three, of course, is the goal to go in vivo. We'd love to deliver lipid nanoparticles with base editors to blood stem cells. We've shown before messenger RNA payload delivery in primates at clinically relevant doses of 1 mg per kg or less. The research now is to adapt that to a base-editing payload, which is much larger and more complex. That work is ongoing, and the ultimate goal here is to, again, remove the transplant altogether. This, of course, would be a truly scalable single shot kind of cure that could potentially go global.
So hopefully, you have a sense from this story about why I'm so excited about this wave of innovation coming from BEAM, what we can do for patients with sickle cell disease, as well as what it would mean for other hematology conditions if these technologies work. There's a very broad aperture of medical impact that we can potentially make if this really happens. All right, so now I'm going to tell you the second story, which I'm so excited about with BEAM. You know, we're doing a lot of exciting things in gene editing. We're knocking proteins out, we're activating them. But I would ask the question of: what if we could go back to that original dream of gene editing, which is to fix what's broken?
That's exactly what we're gonna try to do with the next two programs I described. This will be the first time in the industry that we're gonna try to correct disease-causing mutations in the body. This starts with BEAM-302. This is treating alpha-1 antitrypsin deficiency. This is a disease where you have a single letter misspelling in a gene. It's called the Z mutation. Patients who have the ZZ genotype have the severe form of this disease. There's probably 100,000 patients with the ZZ genotype in the U.S., largely underdiagnosed. That's an upward revision from previous estimates from us.
The problem is the Z protein is building up in your liver, causing liver failure, as well as not secreting to the bloodstream, where it's supposed to be protecting your lungs from degradation by proteases when you have inflammatory or infection events. So BEAM-302 is designed to go directly to the cause of the disease, turning that one letter A back to G, back to normal, as a one-time event. That would both stop production of protein in the liver that is being toxic. It would start secreting normal protein to protect the lung, and it would be under normal regulation, okay? This is a gene that wants to surge in response to infection. And by fixing the gene where it normally lives in the genome, we enable that to continue happening, and that's not true of all other therapies in this field.
So really, BEAM-302 is doing all the things that we would like it to do, to be a really transformative therapy for this patient population. So late last fall, we published some data showing this in action. So you can see here on the left, really robust editing at achievable clinical doses. And then on the right-hand side, you see the effect, exactly what you'd want to see. We're literally converting allele by allele from a mutant gene copy to a normal gene copy. So now you're increasingly secreting normal, corrected alpha-1, and you are eliminating or driving away the Z form of the protein. And again, these dose levels we believe are quite achievable in humans. That's really important in the LNP field, to always be thinking about that dose translation.
So, this is the trial that will show what it can do in people. So this is BEAM-302's phase I/II trial that we're now starting up. It will have a standard dose exploration of over four dose cohorts. We're gonna initially start in lung patients, and then in Part B, we'll be looking at mixed lung-liver patients who have more of a mixed phenotype to make sure we understand the profile of the drug in the full spectrum of the disease. All this is to identify the optimal dose for the pivotal study. So as a reminder, this is an opportunity for the first time to demonstrate proof of concept of in the body, correcting a disease-causal mutation. So as I said, we've been accelerating this program continuously for the last year.
The CTA has already been submitted in the U.K. We have additional country filings to follow, all putting us in position to start this trial, in the first half of this year. The second story I want to tell you, in the liver, is for BEAM-301. So this is targeting a disease called Glycogen Storage Disease Ia. Here, patients can't convert stored energy, which is in the form of glycogen in their liver, back to glucose to maintain blood sugar. And, patients with the R83C mutation have the most severe, form of this disease. And so what they have to do is literally take cornstarch supplementation, every few hours, or they can die of hypoglycemia, and that includes overnight. And if you were to miss one of those feedings, you could potentially, pass away.
So we estimate about 300 patients with this mutation in the U.S. That's also a revised estimate based on some updated epidemiology, but very severe patient population. Of course, more patients ex-U.S. needing therapy as well. So BEAM-301 is designed to go, again, directly to the cause of the disease, turn that one letter back to normal, restoring enzyme activity, restoring glucose metabolism. We think there is a very low bar for success here. About 10% editing is probably sufficient to restore normal metabolism. And success looks like this. So this is a preclinical model of that mutation. We showed that untreated mice with this mutation are dead in a couple of weeks, whereas with one dose of BEAM-301, you see a very significant improvement over the long-term survival of these mice.
So this is a rare disease. We know where these patients are in the U.S. We'll be beginning the clinical trials in the U.S. That'll be a U.S. IND filing, in the latter part of the first half of this year. So let me finally just say a little bit about our business development strategy. So, we've had a very creative, pipeline and platform strategy. Having accumulated so much technology under one roof, we really want to make sure we, we get the most advantage of that. We've done strategic deals, now totaling, about $675 million of capital that we've been able to invest, obviously, in our own capabilities, but also to put great programs in the hands of our partners. The Pfizer deal, a landmark deal, that was a couple of years ago.
That collaboration is going very strong. And then this last fall, the Lilly deal, where they acquired our rights in the Verve programs for a significant amount of capital upfront, and a significant amount of still earnable capital as Verve continues to execute. Then the Apellis and Sana deals as well. As a reminder, in Pfizer and Apellis, we continue to have opt-in rights to any one product out of those collaborations, creating additional strategic value for the company, and you saw that on the pipeline chart starting to come into focus. We've also done the innovator deals, as I call them, where we're trying to really gain rights to complementary technologies and continue to expand that toolkit.
So we did a deal with Prime Medicine, where we have exclusive access to prime editing for any AG or CT change, as well as for sickle cell disease, basically, any place that base editors also work. And then Orbital, a newer company, where we have a significant equity stake, and we have access to IP coming out of their investment in the next generation of RNA, as well as delivery technologies. And, you know, certainly as we seek to expand the application of base editors to more and more diseases, we think that could be a very helpful collaboration as well. So in closing, I'll just leave you again with this vision of what 2024 is gonna be for Beam. This is a true inflection point year for the company.
Leading the way, BEAM-101, with now really a lot of momentum and a very clear path, both to data and ultimately, potentially, to approval. Followed by ESCAPE, you know, this game-changing technology that could finally unlock the potential of transplant with non-genotoxic conditioning in sickle cell disease and beyond. Then in vivo, starting to finally talk about fixing mutations, starting with BEAM-302 for this huge patient population that desperately needs new options with alpha-1 antitrypsin deficiency, followed by BEAM-301 for GSD Ia. And of course, BEAM-201 as well. The first quad editing cell therapy in cancer, hoping to show what multiplex editing can do for cell therapies, presenting data later this year as well.
Behind all of this, now having built that full engine of capabilities all together, we see a really clear, sustainable innovation engine that can drive value creation for the company going forward, and hopefully maximize our impact for patients with so many different diseases who desperately need new options. With that, I will thank you very much for the time, and very happy to take questions.
All right. Well, thanks, John. And just as a reminder, for those with questions, you know, we have mics that will circulate. I'll start things off on Beam- 101 and the sickle cell program. And John, really just kind of to ask you to unpack what a higher quality cure looks like or feels like from a patient's perspective when you talk about that potential being on the table for with 101. And maybe just, you know, given that the trial is now underway, whether there are sort of early-term, you know, clinical endpoints that might predict for, you know, a higher quality outcome long term.
Yeah. I mean, a higher quality, obviously, deeper, you know, cure. I mean, I think that it is quite clear that we have higher levels of editing, that we're getting more F, we're having less S. So I think that biochemical profile is already clearly superior. I think from there, we'd like to see, you know, improvement. Obviously, vaso-occlusive crises, we want to eliminate those. They're not completely eliminated from, for instance, the Vertex product, so we'd like to go farther there. Hemoglobin function, hemolysis, again, not fully resolved. We'd like to see some improvements there. Time to engraftment, you know, and even the process, you know, we've worked really hard on the process to be as efficient as possible.
So, I think there's a lot of ways that this could show up, all, you know, visible in the short to medium term. Of course, long term, we're focused on things like organ damage and mortality. We want to deliver patients as full a correction as possible. That will take a little longer to mature.
In terms of that process, I presume you're talking about manufacturing. I guess, are there ways in which, I guess, material ways in which your manufacturing process with 101 differs from that of Vertex's Casgevy and of Lyfgenia? I'm thinking about sort of the amount of, you know, starting CD34+ material and the like.
Yep. I'll have Pino. Maybe, Pino, describe yourself and then, go ahead.
Yeah. Hi. My name is Pino Ciaramella. I'm the President, Beam, also responsible for manufacturing and other functions. And yeah, in general, I, I would say that the process that we deploy is not dissimilar from the process that others have used, but what we have done is to optimize the process very much with the high degree of automation as part of the entire manufacturing process. And what that buys us is a couple of different things. One is obviously the reliability, which, frankly, in this kind of setting, is very important for the patient experience, and potentially also buys us a greater yield overall of high-quality cells that might be able to minimize the number of mobilizations that we actually need to do.
Even though the manufacturing process per se is similar but automated to the full extent that we possibly can, the overall patient experience might hopefully be better because there may be a faster way to actually bin dose. Obviously, as more and more patients will come through the trial, we'll be able to reassure ourselves that that's the case.
Having now completed manufacturing product for a number of patients so far begs a lot of questions. I guess one is just sort of, you know, the manufacturing success rate that you're achieving. And then as maybe a follow-on to that, I guess, how should we be thinking about sort of any gating steps to, you know, treating subsequent patients now having treated one and seen engraftment?
Yeah. So I think we're gonna generally not be in the business of giving patient-by-patient updates or lot-by-lot updates. I think suffice it to say, as Pino said, we have a lot of confidence in the process, and I think it's performing well, as well as both in our manufacturing partners externally and now becoming internal at North Carolina. So I think we. Again, I think that clinical map we showed, I think we're in great position to execute on that this year, to deliver what should be a really meaningful clinical update in the second half of the year. We really wanted to bring forward data when there's a real story to tell, and we can show, you know, the full picture of what the drug can do, even as it accelerates through into the latter parts of the trial.
Yeah, in terms of the manufacturing so far, I would say that we are really very pleased with the consistency that we see from the products actually that we've generated on several patients already. Of course, you know, we need to do many more in order to confirm and continue to do that, but so far we are very, very pleased.
Yeah.
I mean, it's early days right now since the first movers have been approved here, but I guess, is there any, you know, material headwind, do you think, from being able to enroll the expansion portion of BEAM-101 with the two commercial products on the market?
Yeah, you know, I, I think we, we haven't anticipated that. We don't see anything yet. I think actually, if anything, the enthusiasm for the BEACON trial seems to be high and growing. So I think we feel a lot of confidence there. There are a lot of patients with sickle cell disease who desperately need therapy. Clinical trials are actually fairly easy to get going as opposed to a commercial pay reimbursement, and there's a lot of infrastructure that is gonna get set up there. And again, we're only looking for 45 patients here, so I think , we have a lot of confidence in being able to enroll the trial.
Okay. On BEAM-302 in AATD, I think it was pretty well laid out in the presentation, but, like, I think it might be still useful to kind of make the contrast with 302 and sort of the other, some of the other therapeutic strategies that have either been, that are either available, right?
Mm-hmm.
In the case of enzyme replacement therapy or that have been in development. I guess, you know, how does your approach sort of, you know, the, you know, the full nature of the disease, perhaps, relative to some other interventions?
Yeah, I think, I mean, because it's such an unmet need and it's such a big population, it is desperately in need of therapy. There's a lot of people who are trying, but it is also a big challenge to really get something to work. And so there's a variety of different approaches. Some of them are focused only on the liver, say, the RNAi knockdown. Of course, that's not gonna help with the lung. You have, you know, RNA editing, where it's trying to do both. You know, the question there, of course, it's still a chronic therapy, and what the efficacy will be. You have some other gene editing approaches, maybe knocking in the gene elsewhere in the genome, but of course, that won't be under its normal regulation and more of an unprecedented approach.
You know, there's b ut despite all of the different players out there, there isn't anyone that can do the set of things I described for 302. I think that's why we're so excited about the differentiation of the program, because we're the ones going directly to the broken gene and with a one-time therapy, trying to fix it.
Okay.
Yeah, we're effecting restoring the production of the natural protein in the liver, which is where it actually is manufactured. So we're essentially replacing, bringing back the body to be able to make that protein, how it's supposed to be made, including preserving the regulation, basically, of the protein that could respond actually to the need of increased production during the course of an infection or inflammation, for instance, which is very difficult to do even with a you know like a gene therapy approach, where you may not necessarily be in the natural locus of where the gene is produced.
Is there any risk of autoimmunogenicity, immunogenicity as a result of, you know, kind of expressing the corrected, the wild-type version of the protein, where a patient hasn't seen it?
Yeah. What I have learned about immunogenicity is that you can never say never. And so I'm not gonna say never, but I would say that the likelihood of that as a consequence of a single amino acid restoration back within the context of an entire human sequence of amino acids is gonna have to be pretty low.
Okay.
I would add to that, that patients have generally seen augmentation therapy, so that would be a normal protein.
Yeah.
And just in general, on that point, because it comes up a lot, you know, that would apply to any gene therapy, right? Any time or approach and replacement. And I actually don't know of any examples where it's been observed, so I think just generally, I think the background worry there is pretty low.
That's a good point. Okay. And I guess, so maybe just setting expectations or orienting us a little bit more around the, the phase I program. You talk about sort of, you know, focusing initially on lung patients. I mean, and so I guess the rationale, for doing that, and just sort of how those patients might sort of present relative to those with kind of both, lung and liver phenotypes?
Yeah.
Might be helpful.
It's really just a thoughtful clinical design to make sure we can sort of understand each part of how the drug is behaving in a well-defined patient population. So to start with, we're gonna focus on lung. You know, this is a liver-directed LNP therapy, right? So there's, you know, that's. Mostly for safety, all we're measuring is the acute effects of the LNP. There's not really an acute effect of the base editor that you're expecting to see. So, you know, lung patients is sort of a first baseline, and then we'll mix in patients who have more diseased liver and just make sure we fully understand the dose, kinetics and safety profile there as well.
And so how quickly after, you know, achieving editing in the liver, would you expect to see corrected, I guess, M protein in this case, in the serum? And, you know, perhaps use that as a, you know, well, yeah, I guess, a proxy for the amount of editing that you're achieving and also, you know, inform dose selection, I guess, in subsequent phases of development.
Right. Yeah. So in terms of the production, the approach is actually we would expect to see that within days. I mean, if you look at some of the data that we generate in the preclinical models, you know, you certainly, you know, a week or so would probably start to give you an indication of the restoration of circulating levels. And yes, that obviously can be an important biomarker for us to follow. As I said, we are in this unique situation in which we're restoring the production of essentially the wild-type protein, and so we can certainly use that. However, of course, you know, in terms of biomarkers, we will continue to have the conversation with regulators as to what ultimately will be part of the pivotal trial.
But I think the levels of alpha-1 will be very telling, both in terms of conduct of the program, but as well as eventually, potentially being an important biomarker, even for maybe an accelerated approval.
Yeah, that pretty much anticipates my follow-up question. Really, it's a, you know, very forward-looking question around sort of what the pivotal path the regulatory avenue would be here towards approval. Certainly, you know, the most favorable path, I guess, would be being able to use a surrogate endpoint of serum protein, perhaps, I guess. But if a functional endpoint is sort of the base case of what would be required, I guess, where maybe you could sort of offer some initial comments around what endpoint I think you'd want to base an initial pivotal program around?
Yeah. I'm thrilled that we're already having that conversation and getting those questions, which is awesome. I would say, you know, there's a journey ahead, and we'll certainly be working with the community as well as with the regulators. The good news is this has been an area of focus for the FDA and for the community, both patient groups as well as investigators, for quite some time. So there's a lot of different ideas about the right kinds of clinical designs and endpoints that we can draw on. There's a lot of biology that we will have access to. As you noted, obviously, the blood levels are very measurable, and then, of course, lung function, liver function over time. So I actually think there's a wide range of possibilities.
Obviously, yes, biomarker-driven approvals will be certainly something we look at, as well as I'm sure doing other functional tests over time. So a lot ahead. I think our first job is to generate a really high-quality phase one data set and show what the drug can do.
Okay, great. Well, let me pause for any questions from the floor, and if there aren't any, I think we'll leave it there for time. So thanks very much, John. You know, really appreciate it.
Thank you.
Thank you.
Thank you.
You're welcome.