Morning and welcome to the Jefferies 2025 Global Healthcare Conference. It is my pleasure to now introduce Jian Irish, CEO, and Pam Wapnick, CFO of Metagenomi. Just as a reminder, this will be a 25-minute presentation. Thank you.
Okay, good morning, everybody. Thank you very much for—very glad to be here. Jian Irish, I'm the CEO of Metagenomi. Pleasure to be here. Before we begin, please note this presentation—let me just try this. Okay. Please note that this presentation will include forward-looking statements. Please refer to our most recent Form 10-K and 10-Q on file with the SEC. Metagenomi is an in vivo genome editing company capitalizing on proprietary technologies to create curative genetic medicines for patients. We're founded on the science of metagenomics, the study of genetic materials recovered from the natural environment, leveraging machine learning and AI to discover and develop a suite of novel gene editing tools potentially capable of creating any type of genetic mutation found anywhere in the human genome. We spent our early years creating activities, creating capabilities.
Today, we are translating this vast discovery engine into a pipeline of in vivo therapy into the clinic. From our Metagenomi database, we generated over 20,000 signature gene editing systems, with which we improve editing precision, expanded genome targeting, and editing functionality. This is beyond CRISPR-Cas9 to effectively address genetically driven diseases. Our novel nuclease has demonstrated efficient and durable genetic editing, including gene knockdown, exon deletion, and exon insertion for multiple clinical programs. Our novel base editors have achieved seven-plex simultaneous editing with high efficiency and specificity in primary T cells and no adverse effects on cell health. In addition, our smart nuclease and compact editing systems are small enough to be packaged with AAV to broaden therapeutic targeting. Our RNA and DNA mediated integration systems leverage RNA and DNA templates to enable programmable gene correction and exon insertion.
Capitalizing our signature technologies, we're focusing on our most compelling programs with the highest probability of success, met medical needs, and potential for near-term value creation. We're prioritizing our capital allocation to focus on these programs. Our cash runway is anticipated into Q4 2027. Our lead program, MGX-001, with the approach of site-specific gene integration in the albumin for hemophilia A, is on track for pre-IND meeting with the FDA later this year and IND CTA filing in Q4 2026. In today's presentation, I'm excited to show you our latest data on this program. In addition, we leverage the gene insertion approach in MGX-001 to address unmet needs in other secreted protein deficiencies. In partnership with Ionis , we are progressing programs in cardiometabolic indications, including TTR and AGT. We're on track to announce additional targets and development candidates later this year.
To drive sustained growth and long-term value creation, we are also exploring opportunities to pursue neuromuscular disease targets, liver disease targets such as A180 and Wilson disease. We are also continuing our BD effort to expand therapeutic applications, and that would include the applications in cell therapy with our technologies. I will now turn to focusing on our lead program, MGX-001. I'm extremely excited to share the recent data from our dose range finding study in our hemophilia program. We believe this data clearly supports our plan to advance MGX-001 into clinical development. In this study, MGX-001 demonstrated curative factor VIII activity in non-human primates. The data also revealed clear dose-dependent efficacy across both the AAV and the LMP components of MGX-001, resulting in therapeutically relevant factor VIII activity in each animal treated in all but the lowest dose.
The study informs a clinical dose regimen strategy for therapy with best-in-class treatment potential. This demonstration of improved efficacy with reduced variability builds upon our previously announced program results. We previously demonstrated durable factor VIII activity over an approximately 19-month study in NHPs and an encouraged safety profile with minimal steroid use. Additionally, MGX-001 has also shown no identifiable off-target editing. Potential competitive advantages of our program include enabling endogenous production of factor VIII for hemostatic regulation and restoring the body's own ability to produce factor VIII that is in contrast to bispecific factor VIII mimetics rebalancing therapies. Because of its mechanism of action, MGX-001 has the potential to be an effective treatment for children as well as adults, with children and their caregivers having the most benefit from a lifelong therapy.
We believe that the totality of our preclinical data for MGX-001 is extremely encouraging and unique in the hemophilia space. This gives us confidence that our novel approach may provide a one-time potentially curative therapy, allowing patients a hemophilia-free mindset. I would like to give a brief overview of the disease and the market. Hemophilia A is the most common X-linked coagulation disorder that is caused by mutations in the factor VIII gene, leading to a loss of functional factor VIII protein. There are approximately 26,500 hemophilia patients in the United States and approximately 500,000 patients globally. In addition to spontaneous intracranial bleeding in 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 a degree of measurable factor VIII protein activity.
One current approach for hemophilia A treatment is factor VIII replacement therapy, which requires an in vivo infusion typically several times per week, depending on the product. The burden on patients of those therapies is very high, with time-consuming treatment preparation, issues of venous access, and challenging compliance with the regimen. A new class of drug is bispecific antibody mimetic, which mimics the function of a missing factor VIII clotting protein. This drug is effective at allowing patients to live in the mild hemophilia range, with an average 15% equivalent to human factor VIII activity, but with the ongoing risk of a breakthrough bleeding event. The gene therapy class emerged in the effort to cure hemophilia A, but it is well known that an improved gene therapy for hemophilia A has struggled with patient adoption.
We think this is due to multiple issues: a high variability resulting in lack of predictability of the efficacy, a high risk of prolonged cortisone steroid use, and the loss of durability observed in some patients who have no opportunity to redose. Finally, not only does hemophilia A create a treatment burden on patients and their families, but it also carries a substantial cost of care. It has been estimated that it costs between $565,000-$750,000 a year for current treatments, which would amount over a lifetime to an average cost of $18 million-$24 million. With a durable one-time treatment option that could also eliminate the burden of sporadic bleeding events and associated outcomes of that and the cost, MGX-001 could represent an important value proposition to both patients and the large healthcare system. Now let me tell you about our MGX-001.
The mechanism of action is that, as an investigational gene editing therapy, it is a two-component system comprised of an AAV and LMP drug product. The AAV delivers a promoteless factor VIII donor DNA template. The LMP delivers our novel gene editing cargo. The gene editing reagent 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 mechanism 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 preclinical program, we conducted two important studies: one, our recent dose range finding study, and our early durability study.
The primary aim of the dose range study in NHP was to identify potentially safe efficacious doses of both AAV and LMP components to guide GLP toxic study and future clinical studies. In this dose range finding study, an AAV encoding human factor VIII gene cassette was administered to six cohorts at doses from 5E11 to 4E13 VG per kilogram, followed by a single dose of our optimized LMP at either 0.2 mg, 0.6 mg, or 2 mg per kilogram. Each animal received only a single dose of cortisone steroid prior to the AAV and LMP doses. In our durability study, we used our pre-development candidate that is less optimized components of AAV and LMP and editing cargo that was completed early this year. We dosed three monkeys with 2E13 VG per kilogram AAV and 1.0 mg per kilogram LMP.
This study used the signal factor VIII gene to avoid immune response and enable durability to be evaluated. We are extremely pleased by the results of our dose range finding study, in which we not only see dose-dependent factor VIII activity, and we're also able to identify minimally efficacious dose and optimal dose in the NHPs. First of all, what is the efficacious range? There is a broad therapeutic window for treatment of hemophilia A, from 15%-150% of normal factor VIII activity. In general, 15% factor VIII activity is sufficient to reduce bleeding rates to less than one bleed per year in most, but not all the patients. It is generally accepted that the ideal range is 50%-150% because that is the level in our normal people.
Factor VIII levels above 150% increase the risk of thrombotic event, so it is essential not to go above that level. We will show you here two graphs. The graph on the left shows the AAV dose response with fixed LMP dose at 0.6 mg per kilogram. The graph on the right shows the LMP dose response from 0.2 mg to 2 mg at a fixed dose of AAV at 5E12 VG per kilogram. You can see from the graphs that factor VIII activity exhibited both AAV and LMP dose dependency. On the graph on the left, you can see the study identified 1.6E12-5E12 VG per kilogram as the optimal AAV dose range with main factor VIII activity right around 50%. That is where we want to be in both groups.
All animals in those groups had factor VIII activity above 15%, and five of eight of those animals had factor VIII activities of 50% or above. The LMP dose response also identified 0.2 mg per kilogram as the minimal efficacious dose that's on the graph on the right. In that group, all four animals had factor VIII levels right around 15%. We also identified 0.6 mg per kilogram as the optimal dose, achieving a mean factor VIII level of 49%. Important to mention, for potentially permanent therapy, no animal exceeded 150%, the maximum acceptable safety level in humans, even at the dose 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, therefore simplifying the clinical trial design.
In our early durability study, as I mentioned, we used an earlier, less optimized version of gene editing payload and AAV. The study demonstrated up to 19 months of stable factor VIII expression in the three treated animals. As shown in the bar graph in the middle, the mean factor VIII activities over months 12-19 were unchanged compared to months three to six, demonstrating the stability of factor VIII expression in each animal over the time. Importantly, factor VIII activity levels correlated with the gene integration frequency at a constant ratio, as shown on the bar chart on the right side. For gene editing therapy, genotoxicity is a unique safety aspect because editing at the 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, biochemical discovery, and in cell editing, were applied to identify potential target sites for the gene editing component of MGX-001. We evaluated all those potential target sites in relevant primary cell; in this case, it is hepatocytes. With saturating and supersaturating doses of our hemophilia A gene editing system, no validated target editing was observed, even at the highest supersaturating dose level. Additional assessments have also shown no evidence of translocations or of enrichment of AAV integration, except at the target site in albumin. Why do we choose to pursue hemophilia A as our lead indication? Because it fits with our strategy to pursue disease indications with well-understood biology and 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 factor VIII activity circulating in the blood. Additionally, there is a broad therapeutic window for treatment, as I explained earlier. Given the extensive history of drug development in hemophilia, there is a robust set of established preclinical models and regulatory familiarity in the design of clinical trials from IND through BLA. 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. Our MGX-001'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.
With the completion of these studies, provided the curative factor VIII activity and the durability data in NHP, we're on track for regulatory meetings later this year, with plans to file our IND and CTA in Q4 2026 and initiate the clinical trials thereafter in 2027. I want to reiterate my enthusiasm for our MGX-001 development candidate, which we believe has best-in-class treatment potential. As the MGX-001, we successfully integrated the factor VIII gene in the first intron of albumin that was expressed to achieve the desired level of factor VIII protein by native albumin promoter. If we switch the factor VIII gene to other therapeutic genes while keeping all the other components of a drug product, could we expand this approach into additional secreted protein deficiency therapies? In the mouse proof of concept study, we, in fact, achieved the normal circulating level of targeted protein with multiple constructed designs.
We plan to demonstrate proof of concept in non-human primates later this year and expand the applicability of this approach. We're also really pleased with the progress of our Ionis collaboration, where we provide our gene editing expertise and Ionis' deep disease knowledge, target validation, and expertise in cardiometabolic indications, where we're collaborating. Cardiometabolic market is a multi-billion dollar market. As a part of collaboration, our wave one includes four targets, and we are on track to announce additional collaboration targets later this year, add on to the TTR and AGT, as we already disclosed. We also remain on track to announce the first development candidate from our collaboration later this year. Overall, we remain pleased with our collaboration and the progress we're making on these targets. We're having a productive and exciting year in 2025 with significant progress across all our pipeline programs.
As I just shared, we have achieved the curative and clear dose-dependent factor VIII activities to inform our clinical dose regimen strategy for our lead program, MGX-001. We are also on track for several additional milestones by the end of this year, including conducting pre-IND regulatory meeting for the lead program, MGX-001, achieving non-human primate proof of concept to validate the broad applicability of site-specific larger gene integration for secreted protein deficiencies, and then naming additional target and declare development candidate from our collaboration with Ionis. Going forward, our company's priority will be in driving our lead program, MGX-001, and our other preclinical programs towards the clinic, with milestones ahead in 2026 and 2027 for regulatory submission and initiation clinical trial. Our efforts are enabled by a driven management team with a proven track record of drug development and the passion to create transformative medicines for the patients.
Thank you very much. Do we have time for one or two questions? Okay. Thank you very much.