Metagenomi Therapeutics, Inc.

Good day and thank you for standing by. Welcome to the MGX-001 program and business update conference call. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. After the speaker's presentation, there will be a question and answer session. To ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. I would now like to hand the conference over to your speaker today. Steven Jasper, Managing Director at Gilmartin Group.

Ladies and gentlemen, welcome to the Metagenomic Conference Call to discuss the company's MGX-001 program and business updates. Before we begin, please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please refer to our most recent Form 10-K and 10-Q on file with the SEC for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. Joining us on the call today with prepared remarks are the company's newly appointed Chief Executive Officer, Giann Irish, and the company's Senior Vice President of Research, Alan Brooks. Also joining on the call today is Dr. Glenn Pierce. an internationally recognized hemophilia physician-scientist. After the company's prepared remarks, we will open the line for a live Q&A session. I would now like to hand the call over to John Irish. John, please go ahead.

Welcome to today's update, our wholly-owned MGX-001 Hemophilia A program, and thank you for joining us. I'm extremely excited to share new data today from the recent dose range finding study in our hemophilia program. We believe the data presented to you today clearly supports our plan to advance MGX001 into clinical development. In this study, MGX001 demonstrated curative factor VIII activity in non-human primates. The data also revealed a clear dose-dependent efficacy across both the AAV and LMP components of MGX001, resulting in therapeutically relevant fact data activity in each animal treated in all but the lowest dose. The study informs the clinical dose regimen strategy for a therapy with best-in-class treatment potential. This demonstration of improved efficacy with reduced variability builds upon our previously announced MGX001 results. We previously demonstrated durable FACT-8 activity over an approximately 19-month study in NHPs and an encouraged safety profile with minimal steroid use. Additionally, MGX001 has also shown no identifiable off-target editing. Potential competitive advantages of MGX001 include enabling endogenous production of FACT8 for hemostatic regulation and restoring the body's own ability to produce FACT8 in contrast to bispecific FACT8 memetics and rebalancing therapies. And because of its mechanism of action, MCX001 has the potential to be an effective treatment for children as well as adults, with children and their caregivers having the most to benefit from a lifelong therapy. We believe the totality of our preclinical data for MGX001 is extremely encouraging and unique in the hemophilia A space. This gives us confidence that our novel approach may provide a one-time potentially curative therapy, allowing patients a hemophilia-free mindset. In light of the encouraging preclinical MGX001 hemophilia results, we reported today. We made a strategic decision to focus on our most compelling preclinical programs that have the highest probability of success and the potential to address unmet medical needs and create near-term value. This included the MGX001 program in hemophilia A, secreted protein disorders, leveraging the MGX001 approach, and cardiometabolic indications in collaboration with IMIS. In line with the strategic focus, we prioritized early discovery and platform research and reduced our workforce by 25%. As a result of these actions and our revised capital allocation strategy, we expected to extend our cash runway into the fourth quarter of 2027. I want to express my deepest gratitude to every member of the metagenomic team, including those who were impacted by the workforce reduction, for their invaluable contributions towards advancing our mission. Before I turn this presentation to Dr. Glenn Pierce, I would like to say a bit about Dr. Pierce's background. Dr. Pierce is an internationally recognized hemophilia physician scientist who has spent more than three decades in drug development, as well as patient advocacy. He has been actively involved in the approval of six hemophilia therapies. In addition to his previous leadership roles at various biopharma organizations, he also services as the vice president of medical for the World Federation of Hemophilia. He is currently our independent advisor. Importantly, Dr. Pierce was historically a hemophilia A patient and lived with the disease until being cured by a liver transplant. He can speak firsthand about the burden of the treatment for patients with hemophilia A. Glenn?

Thank you, Jian. I'd like to start with just a quick reminder on the hemophilia A disorder and the market. Hemophilia A is the most common X-linked coagulation disorder that's caused by one of a number of different mutations in the factor VIII gene, leading to a loss of functional factor VIII protein. There are approximately 26,500 hemophilia A patients in the U.S. and approximately 500,000 globally. 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 and muscles, leading to cumulative joint damage. Importantly, the risk of bleeding has been shown to be highly correlated with the degree of measurable factor VIII protein activity. Our current approach in the landscape for hemophilia A treatment in the developed world includes factor VIII replacement therapies. There are several of these therapies which require an intravenous infusion, typically one to three times a week, depending on the product. The burden on patients for these therapies is high, with time-consuming treatment preparation, issues of venous access, and challenging compliance with the regimens. A newer class of drug used to treat hemophilia A is a bispecific antibody mimetic, which mimics the function of the missing factor E clotting protein. A currently approved drug in this class bridges factor IX and factor X to restore the coagulation cascade and prevent bleeding. This drug is effective at allowing patients to live in the mild hemophilia range, which an average of about 15% equivalence factor VIII activity, but with the ongoing risk of breakthrough bleeding events, which even if occurring as little as once a year, can lead to significant risks. This therapy can also require administered supplemental factor VIII treatment during surgery or significant injury. Treatment requires subcutaneous injection typically every one to four weeks. Several mimetics are currently in development and seek to achieve higher levels of factor VIII, but these are not yet approved products. The ultimate goal in hemophilia is to cure the disease, and that's been the goal for many, many decades since the first treatments emerged. The gene therapy class emerged in an effort to cure hemophilia A, but it's well known that an approved gene therapy for hemophilia A has struggled with patient adoption. I believe this is a multifactorial problem. First, in clinical trials, the therapy had high variability in responses, resulting in a lack of predictability as to who would achieve a suboptimal versus a curative or a super high factor VIII level. Second, there was a high risk of prolonged corticosteroid use, which carries its own inherent risks. Third, a loss of durability has been observed in some patients with no opportunity to redose due to the generation of high titers of anti-AAV antibodies. And fourth, reimbursement schedules, which take into account the above variables in responses, have been challenging to negotiate with payers. The MGX001 gene editing approach represents a potential paradigm shift for the treatment of hemophilia A patients. It has the potential to be a one-and-done curative treatment enabling a new standard of life for patients whose goal is a hemophilia-free mind. Unlike gene therapy, gene editing has the potential to be a treatment for very young children, which may give them an opportunity to grow up with a completely normalized life. which currently does not exist because of the lingering risk of breakthrough bleeding. Currently, patients need to remember every Sunday morning or every two weeks or every four weeks that they are tied to their medication. And not to mention, when they travel, they need to carry a dose or two of Factor VIII for emergencies. For children and their parents, it may inhibit their activities. Finally, not only does hemophilia A create a treatment burden on patients and their family, but it also carries substantial cost of care. It's been estimated that it costs between $565,000 to $750,000 a year for current treatments, which over a lifetime can amount to an average cost of $18 to $24 million. With a durable one-time treatment option that could eliminate the burden of sporadic bleeding events and associated outcomes and costs, MGX-001 could represent important value proposition to both patients and the larger healthcare system. I will now turn this call to Alan Brooks, who will walk through the exciting recent results for the company's MGX-001 program. Alan?

Great. Thank you, Glenn, for that introduction. Our investigational gene editing therapy for hemophilia A, MGX001, is a two-component system composed of an AAV and LNP drug product. The AAV delivers a promoterless factor-rate donor DNA template. The LNP delivers our novel proprietary gene editing cargo, comprised of mRNA encoding our novel CRISPR nuclease and targeting guide RNA. The nuclease makes an efficient and specific cut in the first intron of the albumin gene, and the factor VIII donor DNA is inserted at the cut site by natural repair mechanisms present in liver cells. The integrated factor VIII gene is expressed from the native albumin promoter, resulting in therapeutically relevant levels of factor VIII expression at low integration rates. For our MGX001 preclinical program, we conducted two important studies, our recent dose range finding study and our early durability study. The primary aim of the dose range finding study in NHPs was to identify potentially safe and efficacious doses of both the AAV and LMP components for our upcoming GLP-TOX study and future clinical studies. In this study, an AAV encoding our optimized human factor VIII gene cassette was administered to six cohorts, with four animals per cohort at doses from 5E11 vector genomes per kilogram to 4E13 vector genomes per kilogram, followed by a single dose of our optimized LMP at either 0.2, 0.6, or 2 milligrams per kilogram. Each animal received only a single dose of corticosteroids prior to the AAV and LMP doses. Plasma was collected and assayed for safety parameters and factor VIII activity from day three to day 22 post-LMP. This is a relatively short study because peak human factor VIII levels are achieved within one week of LMP administration, and NHPs develop antibodies against the human factor VIII protein within the first two to three weeks that interfere with the detection of factor VIII. It is important to note that MGX001 uses a B domain deleted human factor VIII gene with biological characteristics comparable to the native gene. MGX001 therefore provides natural factor VIII activity, which is expected to reestablish physiologic hemostasis. In our durability study with our pre-development candidate that was completed earlier this year, We dosed three monkeys with 2E13 VG per kilogram and 1 milligram per kilogram LMP. This study used the NHP factor V8 gene to avoid the immune response and enable durability to be evaluated. We are extremely pleased by the results of our dose range finding study in which we saw dose-dependent factor V8 activity And we're also able to identify minimally efficacious and optimal doses in NHPs. The graph on the left shows the AAV dose response from 5E11 to 4E13 with a fixed LMP dose of 0.6 milligrams per kilogram. The graph on the right shows the LMP dose response from 0.2 milligram per kilogram to 2 milligram per kilogram at a fixed AAV dose of 5E12 vector genomes per kilogram. There is a broad therapeutic window for treatment of hemophilia A from 15% to 150% of normal factor VIII activity. As you heard from Dr. Pierce, 15% factor VIII activity is sufficient to reduce bleeding rates to less than one bleed per year in most but not all patients. It is generally accepted that the ideal range is 50% to 150% because this is the range of factor VIII levels in normal people. Factor VIII levels above 150% increase the risk of thrombotic events, and so it is essential to not go above that level, especially with a gene editing therapy designed to last a lifetime. You can see from the graphs that the factor VIII activity exhibited both AAV and LMP dose dependency. The study identified 1.6E12 to 5E12 vector genomes per kilogram as the optimal AAV dose range. with the mean factor rate activity right around 50% in these two groups. All animals in these two groups had factor rate activity above 15%, and five of eight animals had factor rate of 50% or above. The LMP dose response identified 0.2 milligram per kilogram as the minimally efficacious dose, in which all four animals had factor rate levels right around the 15% level. We identified 0.6 milligram per kilogram as the optimal dose, achieving a mean factor VIII level of 49%. Taken together, these data identified an AAV dose of 5E12 vector genomes per kilogram and a LMP dose of 0.6 milligram per kilogram as the optimal dose with mean factor VIII activity of 49 IU per deciliter, which is 49% of normal human levels. and a range of 29% to 60%. Importantly, for a potentially permanent therapy, no animal exceeded 150 IU per deciliter, the maximum acceptable safe level in humans, even at doses of AAV and LMP significantly above the optimal doses. We believe this provides a robust safety margin. These data support our intent to enter the clinic with a fixed AAV dose and LMP dose escalation thereby simplifying the clinical trial design. For the sake of simplicity, we are showing here the safety data for only group two, the optimal dose group in terms of factor VIII levels. As shown in the graphs, the four NHPs that received the optimal dose of AAV and LMP, which is 5E12, VG per kilogram AAV, and 0.6 milligram per kilogram LMP, experienced mild transient elevations of liver transaminases that peaked at less than twofold above baseline, with no change in bilirubin. There were no significant changes in serum albumin, and body weights were stable through the end of the study. With regard to the other five cohorts in this study, we saw that the treatment was well tolerated in all animals. There were no safety findings related to the AAV component, even at the highest dose of AAV. The only finding of note was a moderate but transient elevation of liver transaminases post-LMP dosing at the highest LMP dose of two milligram per kilogram that returned to baseline within two weeks. No significant changes in bilirubin or other clinical chemistries were seen. In our earlier durability study, which we have shared previously, we used a surrogate factor VIII construct containing the cinnamologous factor VIII sequence so that the NHPs would not mount an immune response against the human protein. This study also used earlier less optimized versions of the AAV gene editing payload and AAV. This study demonstrated up to 19 months of stable factor VIII expression in the three treated NHPs. As shown in the bar graph in the middle, mean factor VIII activity over months 12 to 19 was unchanged compared to months 3 to 6, demonstrating the stability of factor VIII expression in each NHP over time. Importantly, factor VIII activity levels correlated with the gene integration frequency in the liver, as illustrated by the consistent ratio of factor VIII activity to gene integration at low integration rates of 0.9 to 5.3%. With regard to safety in the durability study, we also observed transient transaminase elevations immediately after LMP administration that did not reoccur during the 19 months of the study. There were no elevations of total bilirubin and no significant changes to albumin levels. The animals gained weight normally over the course of the study, and there were no histopathology findings at study termination. This study provided preliminary evidence for the long-term safety of our gene editing approach that complements the short-term safety data collected in the DRF study. Genotoxicity is a unique safety aspect for a genome editing therapy because editing at sites in the genome other than the desired site has the potential to be a safety risk. We used an industry standard approach in which three orthogonal methods, including in silico prediction, in vitro editing, and in-cell editing, were applied to identify potential off-target sites for the gene editing component of MGX001. We evaluated all of these potential off-target sites in primary human hepatocytes, the cell type in the liver that is edited in vivo. After editing these primary cells with saturating or supersaturating doses of our Haemophilia A gene editing system, we quantified editing at the potential off-target sites using Amplicon sequencing, which can detect editing frequencies as low as 0.1%. The graph on the right is a plot of editing of these potential off-target sites in treated versus untreated hepatocytes. such that a signal above the background will appear above the diagonal line on the graph. The only signal observed is at the on-target site in albumin, with editing close to 100%. No validated off-target editing was observed in hepatocytes from three different human donors, even at doses 32-fold higher than the dose that resulted in saturating on-target editing. Additional assessments have shown no evidence of translocations or of enrichment in AAV integration except at the target site in albumin. To summarize our hemophilia program, we have generated a robust preclinical data set demonstrating all of the characteristics we believe are required for a competitive product. Normalization of factor VIII activity with demonstrated durability, good tolerability with limited steroid exposure and no genotoxicity concerns, and with our successful DRS study, the identification of potentially efficacious doses supportive of a first-in-human study at dose levels of AAV and LMP with acceptable safety margins. I will now turn the presentation back to our CEO, Jeanne Irish, to review our plans for the HEMA program and provide closing remarks.

Thank you, Alan. Metagenomics choose to pursue hemophilia A as our lead indication because it fits with our strategy. To pursue disease indications with well-understood biology and a clearly defined clinical development and regulatory pathways. Hemophilia A is a monogenic disease with well-characterized disease biology. It also has a clear biomarker. the level of fact aid activity in the blood. Additionally, there is a broad therapeutic window for treatment. Given the extensive history of drug development in hemophilia, they are a robust set of established preclinical models and regulatory familiarity in the design of clinical trials from pre-IND through BLA. And very importantly, there is a strong and informed patient advocacy network, which is critical for education, clinical trial enrollment, and ultimately for adoption of a novel therapy. MGX001's mechanism of action is designed to provide a durable, curative approach for patients of all ages. especially children who have the most to gain. As you heard from Alan, we demonstrated the curative factor 8 activity in NHPs and built upon our 19-month durability study data. With the completion of these studies, we anticipate regulatory meetings in Q4 2025. with plans to file our IND and CTA submissions in Q4 2026 and initiate clinical trials in 2027. I want to reiterate my enthusiasm for our MGX001 development candidate, which we believe has the best in-class treatment potential. Going forward, Our company priority will be in driving MGX-001 and our other preclinical programs toward the clinic. Our efforts will be enabled by a driven management team with a proven track record of drug development and a strong cash position with anticipated runway into Q4, 2027. As we transition to the Q&A portion, I would like to remind everyone that in addition to our leadership team, we have the honor of having Dr. Glenn Pierce online with us. We will also now be joined by our chief financial officer, Pamela Webnick. And with that, operator, please proceed to take questions.

Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star one, one again. One moment for questions.

Our first question comes from Yanen Zhu with Wells Fargo Securities.

You may proceed.

Great. Thanks for taking our questions and congrats on the new NHP data. Perhaps a question for Dr. Pierce and a question for the company. For Dr. Pierce, Obviously, we have the long-term durability from NHPs, but still wanted to hear your thoughts on, in humans, do you think this gene insertion approach could overcome the durability issue with an AAV-mediated gene addition approach like Roktavian? any underlying biological mechanisms that gives you confidence that this approach wouldn't have the same durability issue. For the company, recently there has been a safety event with a gene editing peer company. I was just wondering any thoughts on how you assure the safety of this program, or perhaps any differentiation that you think could assure the safety of this program. Thank you.

Hi, Yanen. This is Glenn. To answer your first question, there are significant differences between the AAV gene therapy, such as Ractavian, and a gene editing approach, as you're probably aware. And the biggest difference is that we're inserting the gene into the chromosomes, into the genome. And we're not only doing that, but the company has selected a safe harbor in the albumin gene for the insertion. And albumin is one of the, well, it actually is the largest plasma circulating plasma protein, the highest concentration circulating plasma protein in the body. And as such, it has an exceptionally strong promoter. So putting that promoter in front of the factor VIII gene allows the company to use a derivative of the native factor VIII gene, the domain-convenient gene, and get very high levels, get therapeutic levels in the non-human primates. There's really no reason to think that something different would occur between the non-human primate experiments, of which there has really been a pretty exhaustive dose response curve, as Alan described, and what would appear in a first in human clinical trial. Does that answer your question?

That's very helpful. Thank you, Dr. Pierce.

Yes, so this is Alan. I can address the second question. I think, you know, we can say that we only have access to publicly available information on intelligent situations, so we're not really able to comment on that. What we can say, however, is that, you know, while we have to wait for our own clinical data on the HEMA program, that really are significant differences between MGX001 and Intelia's program, such as the drug product components, including the LMP. It's a different LMP. It's a different . It's obviously a different guide. It's targeting a different site in the genome. I would say also that the patient population is very different. You know, the Intelia patient population is, you know, cardiovascular risk patient population, whereas ours is hemophilia. So, you know, underlying medical conditions are very, very different. And, you know, I would just point you back to the preclinical safety profile of MGX001, including the fact that we have no identifiable off-target sites, good safety margins in the DRF study, enabling us to identify a safe and efficacious dose range to go into the clinic with.

Great, great. If I may just maybe a quick follow-up. In the ALT graph at the last time point, there seems to be an increase. Can you characterize that and what might be the underlying reason? Thank you.

Yes, I have to answer that question. There are four animals per group, as you're aware, and that ALT, the parent ALT increase you see is driven by a single animal The other three animals of the group did not show that increase at the last time point. We don't have an explanation as to why that animal had a sudden elevation of ALT at that late time point. Talking to our CRO that runs the study, they do see this sometimes in monkeys when they're under stress. So sometimes stress alone can cause that ALT to go up. I think if you look at the durability study, there you see very consistent, no reoccurrence of ALT elevation in that long-term study.

Very helpful. Thank you.

Thank you. Our next question comes from Joseph Thome with TD Cowan. You may proceed.

Heather, good evening, and thank you for taking my questions. I was hoping if you could go into maybe just a little bit more detail on how you decided to choose the group two dose versus the group four dose. I guess, were you seeing any DLTs at the group four level or any concerns around thrombosis when you get to those levels? And it would be great if Dr. Pierce could maybe weigh in on that in terms of when you start getting concerned on thrombosis risk, if it's even below that 150 level. And then when you think about the proposed next human clinical study, is there an option to add additional dose finding work, I guess, once you're in the clinic? Or are you going to move forward with just a single dose of AAV and LNP? Any color around that would be great. Thank you.

Yeah, I can take that a little bit and then hand over to Glenn. With regards to why we chose group two as our optimal dose versus group four. So group two is the 5E12 AAV and then the group four is the 4E13. You do see a trend to obviously increasing factor A levels at the high AAV dose. But we want to be able to go in at a lower starting dose in the clinic And we feel like 5E12 is already giving us mean factor rate levels of around 50%, which really is our target. And so going to 4E13 really doesn't buy you a lot in terms of increased factor rate levels based upon the preclinical data. I would say that in our phase one design, which we haven't discussed yet, we're not ready to announce that yet, obviously. we would include probably an option to dose escalate AAV in the event that we felt like that was necessary. But right now, we feel very confident that with that 5E12 dose, which, you know, is going to put us in a relatively low dose range of AAV, but that is the best option going into the first human study.

Great. And then can you just remind us, I guess, what needs to happen between your pre-IND meeting later this year and actually filing the IND in Q4-26, just highlighting any sort of specific components on the critical path there would be great. Thank you.

Yeah, it basically comes down to completing the GLP-TOPS study, which we are, you know, we're about to start early next year. We don't see any hurdles there. We don't expect any unexpected findings from that study, having treated many, many monkeys now with this approach. So that really is all we need to do to get to our IND filing. Great. Thank you.

And I can cover the thrombosis risk. One of the crucial things to remember is that the normal range is 50% to 150%. or 50 IU per deciliter to 150 IU per deciliter. So that's the range that is in most clinical labs. And what that indicates is that there really is no thrombosis risk in individuals within that range. Thrombosis risk begins with factor VIII levels 250 to 300, 350, 400%. And that risk is still relatively minimal unless the patient has other risk factors, effectively the equivalent of having a factor V Leiden mutation. So with the metagenome MGX011, getting into the normal range really is the goal. The goal is zero bleeds. and a hemophilia-free mind. And so getting close to the normal range or into the normal range is required in order to achieve those kinds of goals for individuals with hemophilia A, and there is no risk of thrombosis at those levels. Does that answer your question?

Yep, that's very helpful. Thank you very much. Thank you, and as a reminder, to ask a question, please press star 1-1 on your telephone. Our next question comes from Maury Raycroft with Jefferies. He may proceed.

Hi, congrats on the progress, and thanks for taking my questions. I'm wondering if you can remind me what optimizations you made to the new development candidate versus your pre-development candidate, and is that the driver of the better efficacy you're seeing, or is it more related to the fine-tuned dosing in respect to AAV and LMP doses?

Yeah, thank you. That's a really good question.

I think to answer a very high level, I think it is a combination of both the optimization and optimizing the doses that we selected. So, remind you that that durability study was started way back in, like, 2022. And at that time, we had never dosed a monkey with this approach. And so, you know, we basically had to guess all the doses, so that's one thing. The second, you know, in terms of what we did to optimize the development candidate, it was mostly around the potency of the LMP, so improving the mRNA, improving the guide chemistry and so on to allow us to get higher levels of editing at lower LMP doses. The AAV construct underwent minor improvements. But we have certainly improved our AEV manufacturing process. And, you know, the AEV used in this DRS study uses that manufacturing process.

Got it. Okay. Okay, that's all helpful. And then we see in your slides the new indication disclosed for SHTG under the IONIS collaboration. Wondering if you could talk more about that program. Will that be prioritized? Or which of the four programs are going to be prioritized, and which two are you leaning toward for co-development?

I'm happy to answer that question.

So first of all, we're very pleased by the progress we're making together with our partner, INS. As a reminder, we have previously announced the collaboration targets in the Wave 1 collaboration. Those are TTR and ADT. We are on track to announce the third target later this year and declare a DC nomination. And we will continue to make progress to announce additional DCs next year.

That is our plan.

Got it. Okay. Thanks for taking my questions.

Thank you. Our next question comes from Brian Chang with JPMorgan. You may proceed.

Hey, guys. Thanks for taking our questions. If you're just heading into your pre-IND meeting with the regulators, I'm curious what are some of the major components that you want to sort through with the regulators? What key questions do you want to, you know, resolve or do you have in mind? to ask at the pre-IND meeting.

Thank you for the question.

Yeah, we are on track to nominate for the IND and CTA submissions in Q4, 2026. We're currently in discussions with the regulatory agencies in the U.S. and ex-U.S. for pre-IND meetings. to seek their feedback on our preclinical data, our CNC development, most importantly, to discuss the clinical development plan, including initial first human study design.

And then just on the liver transaminase excursion that you're seeing around day 20, I'm curious if you have any rationale behind that. Is that driven partly, you know, by some baseline risk factor of these NHPs that you're using? Because it seems that the error bar in, you know, on slide 10 around day 20 for ALT is pretty tight. So I'm curious if you have any insights on that.

Yeah, so happy to address that. Yeah, I should have made it clear during the presentation that, The time course you see for safety starts at day zero, which is the time when the AAV is dosed, and the LMP was dosed on day 21. So that little uptick you see in ALT right around day 21 happens right after dosing. It peaks basically about 8 to 12 hours post-dose, then declines. So this is a response to the LMP. But at these doses that we are taking forward into the clinic, the fold elevation is probably less than twofold above baseline.

Got it. Thank you so much for the clarification.

Thank you. Our next question comes from Gula Lipschitz with Chardon. You may proceed.

Thanks for taking the questions, and yeah, congrats on the data here as well. I'm just wondering, in terms of the reduced variability that you're showing here, again, the error bars for group two look comparatively tight, but in group three, it looks like there's one non-human primate with considerably higher factor VIII levels. So just wondering if there's anything specific that drove that that could point to any factors that might be relevant for the clinic. And then as you think about the potential to eventually dose pediatric patients, As we said, the advantage here is to be able to leverage that durable integration here. But can you discuss what gives you confidence that you'll be able to hit this same window of factor VIII within that 50 to 150 range? Thanks.

Yeah, thank you for the question. It's several things you're asking there. I think maybe I start with the variability. I believe you're talking about the group four, where there's one animal at about 125, 125 percent of normal, that is the highest animal in the DRS study. We don't have a definitive answer as to why that particular animal has high levels, but if you look at the variability in that group, it's between 50 and 125. with, you know, all four animals right in the, you know, the normal range of factor A. So, from a, you know, if we would achieve that in the clinic, it would be great. So, I don't see that that variability is actually an issue. I think your other question was about what is our confidence that we can achieve these levels in the clinic. I mean, obviously, we have to get the clinical data to prove it. But we know from other gene editing studies that the LMP efficacy translates reasonably well one-to-one from monkeys to humans. And the other component with AAV, I think there's not a lot of data there, but we do have confidence based upon our data in mice going to monkeys. that we should see a reasonable translation from monkey to human.

Yeah, I guess I'm asking longer about the pediatric population and to what extent there could be breakthrough there in terms of the numbers. Yes.

Yes, I think for us this is a very exciting prospect because, you know, a gene edit has this unique property versus a gene therapy of being able to treat pediatric patients, at least theoretically. The reason being because the gene is integrated into the genome of the cells in the liver. So even in young kids whose liver is still growing, as those liver cells divide, the gene is maintained. It's not lost. And, you know, there's a lot of preclinical data already out there to show with gene editing that you can edit, you know, very young mice and show that is maintained as the liver grows and so on. So I think, you know, there's no theoretical barrier to why this couldn't be applied to kids. And, you know, from a clinical perspective, it's the best situation because you want to treat them before they've accumulated joint damage, which, as Glenn pointed out, even on the best therapy today can still happen. So even, you know, one bleed a year or one bleed every couple of years leads to cumulative damage to the tissues and the joints.

Alan, if I could point out also that the normal range for factor VIII, 50 to 150%, means that there's a threefold variation among all individuals at a minimum, and that's contributed to by many things. And so to see a little variation in the primates would be expected, but it's not at the level of some of the extreme variations that we have seen with gene therapy. So the mechanisms here are quite different for MGX001 than they are for the episomal mediated factor VIII transcription translation that's seen with gene therapy.

Thank you, Glenn. I just want to add that we are committed to advance MGX001 program to the clinic as fast as we can. We plan to start a clinical trial with adults and then fast follow-up with the pediatric patient study as soon as we have sufficient safety and initial efficacy data.

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect