Welcome to the Metagenomi Hemophilia A Preclinical Data Update Call. Last night, we issued a press release with preclinical data for our lead program in Hemophilia A. This release can be found on the investor section of our website at ir.metagenomi.co. Joining us on the call today with prepared remarks is our Chief Executive Officer and Founder, Dr. Brian Thomas, and our Senior Vice President of Preclinical Research, Dr. Alan Brooks. During the live Q&A session, they will be joined by Dr. Sarah Noonberg, our Chief Medical Officer, as well as Dr. Glenn Pierce, international thought leader in Hemophilia A and member of the Metagenomi Scientific Advisory Board.
At this time, I'd like to take a minute to remind listeners that during the call, Metagenomi management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. All information presented on this call is current as of today, and Metagenomi undertakes no duty to update this information unless required by law. I would now like to hand the call over to our CEO, Dr. Brian Thomas. Brian, please go ahead.
Thank you, Simon, and thank you all for joining us today. At Metagenomi, we are harnessing the power of metagenomics, unlocking four billion years of microbial evolution on this planet to discover and develop a suite of novel gene editing tools and translate these into curative genetic medicines. We continue to advance our internal and collaboration programs with a broad range of technologies to support our goal of being able to address any disease by enabling any therapeutic genome edit in the human genome. Today marks an important milestone for Metagenomi, supporting our recent decision to declare MGX-001 as our development candidate for Hemophilia A and share details on our Factor VIII durability study in non-human primates. MGX-001 is on track for an IND filing in 2026, consistent with our prior guidance.
Recall that Hemophilia A is a blood clotting disorder caused by a genetic deficiency in Factor VIII protein. We conducted our non-human primate study in response to a competitive landscape where gene therapies have been unable to achieve long-term persistence of Factor VIII expression in patients. We are excited to announce the results of this study, which establishes proof of concept of site-specific gene integration and durable expression of Factor VIII in non-human primates over 12 months. The results we have announced today provide early validation of our platform for targeted large gene integration. It also supports our plan to leverage the MGX-001 platform to pursue additional therapies for secreted protein disorders. Our goal for MGX-001 is to provide a one-time curative treatment for adults and children with Hemophilia A.
We believe the achievement of 12 months of durable Factor VIII expression in non-human primates is suggestive of the potential for a lifelong cure. I am pleased now to turn the call over to Alan Brooks, our Senior Vice President and Head of Preclinical Research, to walk you through our non-human primate study design and results in detail, as well as lay out our next steps toward advancing MGX-001 into the clinic. Alan, over to you.
Thank you, Brian. It is a pleasure to provide you all with an update on our progress in creating a potentially curative therapy for adults and children with Hemophilia A. Before moving into the data, I'd like to first begin with a brief introduction to the disease. Hemophilia is the most common X-linked bleeding disorder and is caused by a number of different mutations in the Factor VIII gene, leading to a loss of functional Factor VIII protein. As Factor VIII is a critical component of the body's coagulation cascade, patients with a significant loss of Factor VIII protein are not able to form a normal clot in response to even a minor vascular injury. While spontaneous intracranial bleeding is the most concerning clinical manifestation of severe Hemophilia A, patients are also at risk of lifelong bleeding into their joints, leading to cumulative joint damage.
Importantly, the risk of joint bleeds has been shown to be highly correlated to the level of Factor VIII protein activity in the blood, as shown in the graph. The risk of clinically apparent joint bleeding is very high in severe hemophilia, defined as Factor VIII activity below 1%, and drops off significantly with moderate hemophilia, defined as Factor VIII levels between 1% and 5%. Once Factor VIII levels improve to about 10%-15%, the risk of clinically apparent joint bleeding is quite low, setting an important benchmark for future therapeutics with curative intent. The standard of care for patients with hemophilia has evolved dramatically over the years, beginning with efforts to improve survival with plasma-based products administered in the setting of major bleeding events.
The therapeutic landscape experienced a major advance about forty years ago with the initial identification of the Factor VIII gene and publication of the Factor VIII cDNA sequence. This milestone not only transformed the care of patients with recombinant Factor VIII products, but really rallied the hemophilia community around the desire and potential for a true cure... Although extended half-life Factor VIII products and Factor VIII mimetic agents have succeeded in improving the burden of therapy and minimizing spontaneous bleeds, breakthrough bleeding is a continued challenge in this patient population. More recently, the first Factor VIII AAV gene therapy was approved for adults with severe hemophilia, and while Factor VIII levels in a therapeutically relevant range can be achieved, clinical data has demonstrated that Factor VIII levels decline over time and thus provide only a temporary cure.
The goal of gene editing is to continue to build on this substantial progress with a one-time treatment, leading to a permanent cure for adults and children with Hemophilia A. Despite the benefits of gene therapy for hemophilia, there are significant challenges with this approach that can be overcome with a gene editing approach. These challenges can be categorized as ensuring persistence of the DNA encoding the Factor VIII gene and ensuring persistence of expression of the therapeutic Factor VIII protein. Focusing first on persistence of the Factor VIII DNA, a key distinction is that AAV-based gene therapies deliver episomal DNA copies of the Factor VIII gene, meaning they are not integrated into the genome and can therefore be lost or diluted as the hepatocytes in the liver divide or die off.
As such, an AAV-based gene therapy is not suitable for pediatric patients, given the rapid growth of the liver in childhood. With our gene editing approach, the Factor VIII gene is integrated into the human genome at a specific safe harbor site so that the Factor VIII gene is maintained as hepatocytes divide. Therefore, gene editing can potentially be applied to both adults and children with Hemophilia A. Next, in terms of persistence of the therapeutic Factor VIII protein, AAV-based gene therapies utilize an engineered non-native promoter that, along with the episomal location, can trigger cellular mechanisms leading to transcriptional silencing or hepatocyte stress that result in the loss of Factor VIII expression over time, as supported by recent scientific publications. By contrast, our gene editing approach utilizes an endogenous promoter in its natural chromosomal context that should avoid transcriptional silencing.
Further, the lack of the exogenous promoter results in a Factor VIII construct within the normal packaging limit for AAV, which enables more efficient AAV packaging and enhanced genome integrity that should streamline manufacturing and improve Factor VIII protein expression. In summary, the key factors distinguishing our gene editing approach from AAV gene therapy approaches are the permanent site-specific integration in the genome and the use of an endogenous, highly active promoter in its native open chromatin context. Both of these factors are expected to overcome important challenges seen in the clinic with AAV-based gene therapies. When we first initiated our gene editing approach for Hemophilia A, we identified the following components as critical for success, especially in light of the evolving treatment landscape. Most importantly, the therapy needs to give rise to durable Factor VIII expression at levels sufficient for a functional cure.
As you will see on the next slide, our approach is to integrate a Factor VIII gene into the genome of hepatocytes, and this integration must occur at the site we have selected. The therapy also needs to be tolerable as a one-time treatment, not require prolonged corticosteroid use, have no identified off-target editing, and have a low risk of development of anti-Factor VIII antibodies. Other critical criteria are suitability for children as well as adults, pharmacoeconomic benefits for payers, suitability for outpatient administration, and support from the Hemophilia A community. We believe that meeting these criteria will allow treated patients to live a normal life with a hemophilia-free mindset. So now let's move on to a description of MGX-001, our investigational gene-editing therapy for Hemophilia A. MGX-001 is a two-component system comprised of an LNP and an AAV drug product.
The LNP delivers a novel gene-editing nuclease that makes an efficient and specific cut at a safe harbor locus in the first intron of the albumin gene, whereas the AAV delivers a Factor VIII donor DNA template that is then inserted at that cut site. Importantly, the strength and constitutive nature of the native albumin promoter can give rise to high levels of Factor VIII expression, even at low integration rates, which ensures that albumin levels are not affected. In summary, our approach is a site-specific integration of the Factor VIII gene that is then expressed off the native albumin promoter, which is distinct from gene therapy, in which an episomal Factor VIII gene is driven off an exogenous promoter. As has been demonstrated with the clinical development of Roctavian, a major limitation of gene therapy for Hemophilia A has been loss of expression of Factor VIII over time.
For this reason, one of our earliest non-human primate studies was designed to test whether site-specific gene integration at the albumin safe harbor locus can provide circulating Factor VIII levels that are durable over time. In order to do so, we needed to use a surrogate Factor VIII construct containing the Factor VIII sequence from the same non-human primate species, that being cynomolgus macaques, so that the animals would not mount an immune response against the expressed Factor VIII protein. Additionally, we made a single amino acid change that has no impact on Factor VIII activity but allows us to specifically quantify the recombinant Factor VIII protein, even in the presence of the endogenous levels of cynomolgus Factor VIII.... The design for this non-human primate study is illustrated on the slide.
Three male Cynomolgus monkeys, selected for the absence of anti-AAV antibodies, underwent a baseline liver biopsy and then were treated with the AAV Factor VIII virus on day 1, followed by the lipid nanoparticle on day 35. Both the AAV and LNP were given intravenously, and each were preceded by a single dose of dexamethasone. No other corticosteroids were administered during the study period. The animals were then followed for Cynomolgus Factor VIII activity levels and safety parameters for 12 months. Additionally, the animals underwent liver biopsies on day 7 and day 70 to measure editing, efficiency, integration, and mRNA levels. The study remains ongoing, and we anticipate continuing to follow these animals for up to 2 years. We are pleased to share the exciting results from the first 12 months of this ongoing study.
Importantly, the graph to the left demonstrates that Factor VIII activity levels do not decrease over time, and all three animals are expressing Factor VIII levels at a range expected to be associated with curative or near curative effects. I also want to emphasize that this study was one of our very first non-human primate studies, where we made our best estimate of LNP and AAV doses and did not incorporate ongoing learnings about dose finding or use higher grade manufacturing processes. Importantly, this study uses an older version of the Factor VIII gene, whereas our development candidate incorporates both a bioengineered Factor VIII that increases the amount of Factor VIII produced per integration event and a improved version of the nuclease mRNA.
Yet despite those caveats, at one year, we see two of three animals consistently in the normal to near normal range of Factor VIII and one in the mild hemophilia range. At the 12-month data point, these values are approximately 82%, 9%, and 41% for animals 1001, 1002, and 1003, respectively. Furthermore, when comparing mean values across the three to six-month time period and the nine to 12-month time period, values are highly consistent and also consistent with our earlier data release out to four and a half months. As previously reported, day seven biopsy data demonstrated gene integration in the correct forward orientation between 0.7% - 2.9%, which correlated with Factor VIII activity levels.
Safety data from these animals is also highly consistent with our earlier 4.5 months data release, with notable findings limited to transient and moderate transaminase elevations after AAV and LNP administration that do not recur with long-term follow-up. Notably, there are no elevations of total bilirubin and no significant changes to albumin levels, consistent with a low level of site-specific Factor VIII integration into the albumin locus. There have been no adverse clinical observations to date, and the animals have been healthy and continue to gain weight as expected. Establishing non-human primate proof of concept for site-specific integration and Factor VIII expression that is durable over one year was a major milestone for our gene editing program and an important validation of our metagenomics-based platform.
We have invested significant effort in optimizing key components of the AAV and LNP with the goal of maximizing potency and minimizing toxicity. These components include those anticipated to be relevant for both efficacy and safety in the clinic and have been incorporated into the development candidate. To summarize key aspects of optimization relevant for efficacy in the clinic, we selected the novel MG29-1 nuclease, a Type V CRISPR enzyme based on its editing efficiency and inherent specificity. We performed mRNA sequence optimization to enhance expression and nuclear localization in support of lowering the dose of LNP required. We performed a series of experiments to select the optimal guide RNA sequence, spacer length, and chemical modifications to enhance potency while retaining high specificity.
We have opted to use a bioengineered B domain deleted Factor VIII construct to enhance Factor VIII activity, and we have optimized the ratio of the different LNP components and evaluated the timing between AAV and LNP administration. Similarly, to summarize key aspects relevant for safety in the clinic, we have performed a suite of orthogonal specificity assays, as outlined in the FDA guidance documents, that demonstrate no measurable off-target editing to date. Our LNP delivery components were designed to target hepatocytes in the liver in order to minimize on-target editing outside of the liver. We have evaluated and continue to evaluate both short and long-term safety parameters in non-GLP studies. We remain cognizant of the importance of minimizing any immunogenicity risk. Accordingly, our Factor VIII gene has been codon optimized to remove CpG residues, and the bioengineered construct has been designed to minimize the risk of immunogenicity.
I'll now end this presentation by summarizing our current status, as well as planned next steps to bring MGX-001 into the clinic. To date, we have performed multiple rodent and non-human primate studies that demonstrate integration and expression of Factor VIII from the albumin locus, including our planned clinical candidate that contains human Factor VIII, incorporating the bioengineered variant.... We've engaged with the FDA through an INTERACT meeting to discuss data required to support an IND and first-in-human studies. We continue to broaden our community of experts and advisors and have held two international clinical advisory board meetings. We have initiated GLP and GMP manufacturing to support future IND-enabling studies and clinical material supply.
Looking forward, we will be continuing to follow the ongoing non-human primate study for a period of up to two years, provide additional data on the durability of this gene editing approach and differentiation from gene therapy approaches. We will soon be initiating dose response studies in non-human primates to define the minimally effective doses of AAV and LNP. We will continue to engage hemophilia experts and advocacy groups, as well as continue with planned scientific presentations of our technology. We continue our manufacturing efforts of all components, and importantly, we expect additional engagement of FDA and ex-U.S. regulatory agencies in preparation for planned regulatory filings in 2026. In all, this has been a very exciting time for Metagenomi in reaching this important milestone and validating our novel metagenomics-derived gene editing platform.
We look forward to providing additional updates on our Hemophilia A program, as well as other pipeline programs in the future. With this, I would like to hand the call back to Brian.
Thank you, Alan, for this great overview. As we transition into the Q&A portion, I would like to remind everyone that we will be joined now by Dr. Sarah Noonberg, our Chief Medical Officer, and we have the honor of also being joined by Dr. Glenn Pierce. Dr. Pierce is an internationally recognized hemophilia physician-scientist who has spent more than three decades in research and clinical development, as well as advocacy roles. Dr. Pierce has been actively involved in the approval of six therapies for Hemophilia A and many other programs in various stages of preclinical and clinical development. He's currently the Vice President, Medical for the World Federation of Hemophilia. Operator, please open the line for questions.
Thank you. At this time, we'll be conducting a question and answer session. For those joined by phone, if you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. We also ask if you could, please ask one question and one follow-up, and then re-queue for any additional questions. One moment while we pull for questions. Our first question today is from Maury Raycroft of Jefferies. Please proceed with your question.
Hi, good morning. Congrats on the update, and thanks for taking my questions. I'll start with asking about dosing. Wondering if you could talk more about your, your learnings from dose findings from these data. And it seems like the 001 and 003 NHP expression increases over time beyond day 70. Is it possible you're getting a gradual increase in number of cells that have the integrated gene over time? And how are you assessing that?
Yeah, thank you for that question. So to address your first part, we have some dose-finding information from rodent studies only at this point. Our pivotal DRF studies are planned towards the end of this year in NHPs. So until we have that data, it's not really reasonable to comment on what we know about dosing at this time.
However, this is Sarah Noonberg. I would add that we are incorporating in MGX-001 a bioengineered variant that we believe will enhance Factor VIII expression, and this will actually be able to lower both the LNP and the AAV dose. You know, and that's a primary reason for incorporating that variant. So we believe that, you know, relative to gene therapies and even this experiment here, we'll be able to use lower doses, and that will have important safety implications.
Yeah. To answer your second question, we don't have an explanation currently for that apparent increase in Factor VIII over time. It could be a biologic phenomenon. It could be to do with the physiology of the animals, the fact that they're growing. These are not adult animals at the current time. We're gonna continue to monitor that for the next year, as we said, so we're going out potentially two years with this study, and we don't have data currently on integration frequency.
Got it. Okay, all helpful. Maybe just as a quick follow-up, if you can talk more about as it relates to pediatric patients, are you planning experiments to use lower doses in younger NHPs or rodent models? And then how will you track how cells are propagated over time to optimize those for pediatric patients?
Yeah. We'll start our clinical development in adults like most gene therapy programs and others. But as we get experience in adults, as well as additional non-clinical data, we'll then be able to extrapolate and plan for pediatric studies. But, you know, importantly for gene editing, being integrated into the human genome and being propagated as cells divide, we believe, unlike gene therapy, this is going to be a suitable approach for pediatric patients. This is a major, you know, value driver for the program.
The next question is from Joseph Thome of TD Cowen. Please proceed with your question.
Hi there. Good morning. Congrats on the update, and thank you for taking our questions. Maybe the first one, just as you look between the three NHPs, is there anything aside from the gene integration, maybe to explain the spread in factor expression that you're seeing there? Is it anything with the ALT elevations at the beginning, or anything else that you can point to? And then maybe just a follow-on question, potentially for Dr. Pierce or the company, but you know, given his exposure to the space, can you talk a little bit about just the overall commercial appetite for a long-acting Hemophilia A therapy?
Obviously, the current gene therapies do have that impact with roll-off, but for the hemophilia B gene therapies, we don't necessarily see that same level of roll-off, and yet it does seem like the, you know, the ones that are happening fairly gradual as well. Can you just talk a little bit about broadly how you're thinking about this commercially? Thank you.
Yeah. To answer your first question, we don't see anything else in that study that would explain the difference in factor levels. There's a clear correlation to integration frequency, as you might expect.
And then the second question for Dr. Pierce.
Yes. Hi, this is Glenn Pierce. Thank you for the question. With regard to the Factor VIII gene therapies, I think we've learned a lot over the past 10 years or so since they've gone into human beings, and some of what we've learned, we can't fully explain. We don't really understand what the loss of activity is in these gene therapies. We do recognize that there is significant toxicity, and it's thought that some of that toxicity is ER stress, that has been well documented since 2008 or so, with the Factor VIII gene product, as it goes through the endoplasmic reticulum and Golgi apparatus.
And some of that is also due to the amount of viral capsid, AAV capsid, that is being delivered to patients, which is in the quadrillion range for most patients. And so that is causing its own unique stress with a whole series of innate immune responses that can go out for months. Whether that contributes to the loss of Factor VIII or simply to the intermediate-term toxicity, I think is also not well understood. But moving down on dose is an important component. Getting a permanent location within the genome, as Alan has described, is also an important component, especially in livers that do have a significant rate of cell turnover year over year. So the commercial. So coming to the commercial appetite, we're not there yet with Factor VIII.
And while we may be there with a 1st generation Factor IX for a long-term effect, we're not there at all with Factor VIII. And for Factor VIII, while we've got some increasingly improved therapies that have come along, the field has changed remarkably in the last sixty years, we still do have occasional breakthrough bleeding. We have occasional progression to joint damage and long-term sequelae from hemophilia, from unexpected bleeding episodes. And so we're not there with a cure, and the concept of being curative, being able to treat one time and get a long-term effect, is not with us yet for Factor VIII, and is going to be an important improvement for the quality of life as well as the economic viability for people with hemophilia.
Does that answer your question?
Yep, that's very helpful. Thank you very much.
The next question is from Kostas Biliouris of BMO Capital Markets. Please proceed with your question.
Thanks for taking our question, and, congrats on the progress here. Two questions from us. The first one is, can you discuss a little bit the levels of improvement you observe from the optimization of the different components you mentioned, such as the timing between AAV and LNP administration? And is the improvement on the peak Factor VIII levels, or also those optimization processes also affect the durability as well? And I have a follow-up.
Those components are designed to improve Factor VIII expression, and, you know, this is the study with this construct is the only one to date that we've looked at durability. So we believe that the enhanced components that we plan to take into the clinic are going to build on this durability data that we're showing here, but allow us to use lower doses of AAV as well as lower doses of LNP, you know, both of which, as Dr. Pierce mentioned, are important factors for safety. But we don't believe any of those optimizations will impact durability that we've been able to demonstrate.
Thank you. Very helpful. And maybe a follow-up on pipeline. Can you talk a little bit about potential pipeline programs whose development could be accelerated by leveraging MGX-001 safety and efficacy data. Can you remind us which programs potentially could use the same approach? And, given regulatory advancements recently, which programs can really be benefited by your hemophilia program? Thank you.
So, I mean, theoretically, any disease that's caused by secreted protein in the liver that's, you know, deficient, can be addressed with this platform. So in other words, we use the same guide, the same mRNA, the same LNP, and the same viral vector. The only thing which changes is the gene for the protein that we want to put back into the liver, and so that opens up a much bigger space of potential diseases. Currently not disclosing what those are that we're working on, but we have a number of early programs.
The next question is from Jeff [Stiff] of Wells Fargo. Please proceed with your question.
Hi, this is Jeff on for Yanan. Congrats on the data, and thanks for taking our questions. First, a question for Dr. Pierce. Given the data you've seen so far from this NHP study, do you expect the durability to translate to humans? And then a question for the company. From the day 70 biopsy, did you see any change in integration rate compared to the day seven biopsy?
With regard to your first question, looking at durability, I think that it is still somewhat early to be able to make a full judgment on durability with gene editing. But if we look at the whole field holistically from the very first gene therapies that have been done for Factor VIII, beginning in the late nineteen nineties, all the way through today with the latest AAV gene therapies, it's pretty clear that there are two factors that are missing that need to be either fixed or corrected or addressed. And one is the durability question, and the other is the ability to be able to get significant levels of clinical expression.
And so, the approaches that are being taken really require consideration of a variant, a Factor VIII variant that has increased biological properties that would allow for improved activity or secretion, and the ability to get full integration. And so both of those parameters need to be addressed at this point in time if we look at all of the work that has led up to this point. And so this approach is addressing both of those, and that's important.
And the other question you had was about day seven versus day seventy, and unfortunately, you get very little material from these liver biopsies, and so we are unable to measure integration at day seventy. We're only able to measure mRNA. We chose to look at that endpoint instead.
Okay, thank you very much.
The next question comes from Geulah Livshits of Chardan. Please proceed with your question.
Good morning, and congrats on the day, and thanks for taking the questions. Maybe to follow up on the range that you're seeing in this experiment. You talked about the various optimizations of the construct that were made to the study. To what extent do you expect those levers to narrow that range? For Dr. Pierce, is that 10% Factor VIII levels often cited as a threshold for joint bleed? To what extent would a durable gene replacement at that level, rather than going above it, as we see for two of the three animals here, but to what extent would that lower bound be attractive for patients?
Um, that's-
I think you're asking about the-
Go on, Alan. I didn't catch everything.
Yeah, I think the question is about the variation in the Factor VIII levels that we saw in the NHP study we presented today.
Yeah.
You know, the lower expression being around 8%,9% , 10%, that range, and whether that would actually be something that was attractive for patients. So I'll let Glenn answer that.
Yeah, so I think that the overall answer is not very attractive if 10% is the target. And that's because, as you all know, of the progress that has been made in the development of other therapeutics. And so other therapeutics are giving us a 15% equivalent over a long period of time, such as the bispecific antibody, the Factor VIII mimetic. A new ultra-long half-life product is giving us 40% expression for up to four days, and then dropping down to 10% or 15% at a week. And so it's important to recognize those are offering a very high level of protection, but they also require repeated dosing, and there is occasional breakthrough bleeding with those.
Hemophilia is ever present in the mind of a person with the disease because of concern for the risk of bleeding. And so as we start moving toward more normalization of Factor VIII levels, getting into the high-mild range and the low-normal range, that is going to be an important target for gene editing therapies as well, getting into a protective range. And protective range, you know, everybody will give you a different number for what that should be. But generally, people that are at 20%- 30 %, a number of them aren't even diagnosed unless they have come into some sort of major trauma or require surgery. So they could go through life without a diagnosis at 20 % or 30% .
And so we recognize then that that's a good protective level, but moving it a bit higher really frees an individual from any need for considering Factor VIII replacement therapy.
And if, if I may add to that as well, you know, I think, be careful to interpret this study in the format that it was designed. So it was designed as a durability study. We had to guess on the dose of AAV and LNP to give in this study, so it wasn't designed as a way to evaluate variability or to find an optimal dose. So the fact that we have one animal at 10% or 8%, whatever you wanna call it, it is not really indicative of what our final target is. So clearly, our target is to get patients into the normal range so that they would never have to worry about a bleed ever again.
The way I would look at this is that this is a very successful first effort.
Great, and just as a quick follow-up, do you think redosing with the lipid nanoparticle, while the AAV is still present, could, in theory, bolster the insertions of the animals, let's say, or eventually individuals with lower Factor VIII levels after the initial round?
It potentially may be, but it's not something we're pursuing because we really think that this is a one-and-done treatment where the patient would not have to come back for a second dose, so that's not our goal.
Great, thank you.
The next question is from Mitchell Kapoor of H.C. Wainwright. Please proceed with your question.
Good morning. Congrats on the data, and thanks for taking the questions. I wanted to ask about the... If there's any work to be done still on the optimization of time of administration of AAV and LNP, and if you could just talk about the work done so far there, and how you've got to this point and this, this spacing between the two. And then could you talk about, you know, the next time point where we could see more of this durability data in this NHP study, when we could just expect more, more follow-up here?
Sure. Yeah, happy to answer that. So, the timing of dosing was looked at only in mice so far. So we have not done a rodent, I mean, we have not done a monkey study to look at dose timing. What we found in the mice was that there's quite a wide range over which you can space the AAV and LNP and still achieve, you know, similar levels of Factor VIII. One cannot dose too soon after the AAV. That's really the big limitation. But going out, you know, multiple weeks between AAV and LNP seems to be fine. And so we think that's actually quite an advantage because that allows you to give the patient some time to recover from the AAV administration before they get the LNP. Your second question was around new data release?
Yes, we're continuing to follow these monkeys, and we expect to give a further update at scientific conferences. But we expect to follow for up to two years, so we will follow durability as well as safety.
Great, thank you. And then, could you just talk about the potential phase I design that you could potentially explore? Would you explore adults only or pediatrics as well? And what durability might support a move towards a pivotal development?
Yeah, I think in phase I, we would start with adults to ensure that we understood dose and safety before moving into children. I think, you know, for a permanent gene editing approach and to advance on the standard of care, we expect to be durable over the lifetime of a patient. Obviously, you can't prove lifetime over a clinical study, but we expect to see no change or no loss of expression over time, and that's the bar that we're setting for ourselves, and that's why we believe that this data is so critical.
Great, thank you.
The next question is from Brian Cheng of J.P. Morgan. Please proceed with your question.
Good morning. Thanks for taking our question. This is Sean, on for Brian. I had a question for Dr. Pierce. Considering the current treatment landscape and the pipeline, how would you best design a study to really showcase MGX-001's differentiation to the other players in this space?
Well, the other players in the space are that are successful are largely the protein replacement therapies. And so, the field has evolved to show that tracking a patient for 6-1 2 months on their previous therapy, and then moving them to whatever the new experimental therapy is, and then doing an intra-patient comparison, has been an effective way to show either superiority or non-inferiority or equivalence of the product.
I think that if one looks at a number of new quality-of-life measures that have been developed over these past 10 years to take into account the benefits that one gets from these newer products, including the potential benefits from gene therapy, one can also tease out the improved quality of life, ranging from increased school attendance, to increased ability to become a productive citizen, to just taking care of the activities of daily life.
A number of individuals with severe hemophilia, as they age into their 40s, 50s, 60s, 70s , have not had the benefit of lifelong treatment with some of the newer products and have significant joint damage that not only causes them difficulty with the activities of daily life, but also progresses and is predisposed to bleeding, and so being able to maintain factor levels that are relatively constant and high becomes an important contributor, and all of these are outcome measures that have been developed, so I don't know that any new particular outcome measures are required. I think we have a series of outcome measures that have been able to demonstrate the improvements that we've seen over these past 10 years.
And when one looks at gene editing, and the ability to maintain a constant level, the Factor VIII is a great surrogate to really allow patients to, and their families, as well as their physicians, to predict what the phenotypic response is going to be to that kind of a Factor VIII level, a Factor VIII level in the high, mild, or low normal range. Did that answer your question?
Yes. Great. Thanks for taking our question.
There are no additional questions at this time. I'd like to turn the call back to management for closing remarks.
This is Brian Thomas. I'm the CEO. Very happy to have the analysts with wonderful questions this morning. We're really excited about the data we've presented today, and I'd also just like to take the opportunity to say Metagenomi is a really unique company in the gene editing space. We're leveraging a toolbox of gene editing systems that I think is unparalleled, and I think the execution that we've been showing with especially our lead program in heme is something that I'm really proud of, and we are excited to in the future be able to give you further updates on our programs, both with heme as well as our partnered programs with Ionis. Thank you.
This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.