Good morning, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the Metagenomi management team. We've got the CEO, Jian Irish, and the CFO, Pamela Wapnick, with us today. We're going to do hybrid format. Jian, I'll pass it over to you to give an intro to the company, and then we'll switch over to fireside chat after that. Thank you, Maury, for hosting us. It is pleasure to be here. I will start with our forward-looking statements. At the Jefferies in London just six months ago, we were talking about transitioning from a CRISPR platform company to a therapeutic company. Today, we're preparing IND submission for our program, MGX-001 in hemophilia A. The opportunity is especially relevant because the leading gene therapy in the field was withdrawn after durability and safety challenges become clear. Our program, MGX-001, is designed to specifically address the limitations through genomic integration with durable expression demonstrated in non-human primate study and an IND planned for Q4 this year. Our platform is not CRISPR-Cas9. It is entirely proprietary. With more than 20,000 signature gene editing systems, they're specifically designed to address the limitations of Cas9 approaches. They're including precise precision in editing, large integration, and broad genome access. What the previous gene therapy has experienced has clarified is that durability is as important as initial efficacy. The patients and the physicians are looking for is a normal level of factor VIII that remains stable over the time. That is the goal for a curative hemophilia treatment. MGX-001 is designed with that objective in day one. Over the decades, the conversation in hemophilia has been disease management, less bleeds, longer intervals between the treatments, and better outcome. Those advances matter, the burden has not gone away for the patients, the families, and healthcare system. The lifetime treatment cost runs from $18 million-$24 million per patient. Across 26,500 patients in the U.S. alone, that is a cost the system cannot sustain indefinitely. For the patients and the families, the question has been always much simpler than the economics. Can you cure it? To date, the answer has been no. MGX-001 is designed to answer that question. Genome editing is ideal for curative hemophilia treatment that is a monogenic disease with a clear biomarker and well-defined therapeutic window. The regulatory path is clear and the FDA knows deeply. Most importantly, unlike the previous gene therapy, MGX-001 is designed for patients of all ages, including children, that is the population has the most years ahead and the most benefit from a one-time curative treatment. The question of durability is the right one to ask. The answer is in the mechanism. Our approach is different from the previous attempts. Rather than episomal, the factor VIII is directly integrated in albumin locus, a stable chromosomal site. When the cell divides, the daughter cells carry the edits, so the genomic instruction is not lost. It is replicated. As you can see, the stable factor VIII expression has been achieved in our NHP durability study up to 19 months. No year-over-year loss was observed even in this early study with less optimized constructs. Our dose-range-finding study has confirmed the therapeutic window is achievable. As you can see on these charts, most animals in the targeted dose cohorts reached normalized effect 8 level, that is from 50 to 150 IU/dL with very clear dose dependency. No thrombosis was observed even at highest dose. The safety profile is favorable even only with one single dose prophylactically used steroid at the administration of the drug product. We applied orthogonal methods to assess the genome editing safety profile. No validated off-targets and translocation was observed. With these studies, we see clear dose dependency and to guide us for clinical study design. Our GLP study and the GMP manufacturing are progressing. Our path to the clinic is clear. Curative factor VIII activity, encouraging safety profile, well-established regulatory framework. We have completed our pre-IND meeting with the agency, so IND is on track for submission in Q4 this year. We will be in the clinic in 2027. Our goal is to enable a new standard of care for hemophilia A. Hemophilia A is just the beginning. Our broad and differentiate proprietary portfolio of gene-editing technologies represent a long-term value drive. We're advancing MGX-001 to the clinic, and the larger gene integration systems expands the potential to address additional protein deficiencies. We're advancing development with collaboration by pairing our technologies with complementary expertise. Our pre-IND meeting with the FDA was collaborative and productive, and we're on track for Q4 IND submission and first in human in 2027. For the patients that are waiting, for the physicians that have been asking, this is the next chapter for a curative hemophilia A treatment. We'll welcome your questions. Thanks, Jian. Thanks for the presentation and overview there. Yeah. You're definitely at a pivotal point now getting ready for the IND. I'm wondering just as you talk to the hemophilia community and patient advocacy groups, what feedback are you getting about this approach, and how is that informing your strategy? The community engagement is substantive, and it really shaped our thinking in specific ways. First of all, we have learned the need for curative therapy has not diminished from the previous gene therapy. If anything, that has been reinforced that the urgency. We'll see the medical communities at a conference and the publications encouraging the next generation development of gene therapy for a truly curative therapy for hemophilia A. I will share with you a direct feedback from the prominent pediatric hematologist as how he puts, "Despite my best effort with available therapies, there's still good chance a child in the adulthood is going to have some form of arthropathy because we just don't have a curative therapy yet, and we can't prevent all bleeding." That is how he advised the parents of child patients. It sums very well about the need for a true cure. Second, we learned a true cure has to meet the normal factor VIII level and with durable expression, that is what the community is looking for. As we shared our preclinical profile, they were encouraged first by the mechanism of approach, the direct integration of factor VIII in the albumin gene is structurally different from anything they have seen. They believe with this structure provides the ability to continue direct the genomic instruction as the liver cell device. Our data with durability, dose-dependency, and the safety profile is extremely encouraging, and they're excited about this new approach. They also encouraged us to treat the pediatric patients as soon as possible just because this unique ability to enable endogenous expression of factor VIII and even with the liver growing for the young patients. The third we also learned is development path is clear, built upon decades of clinical development precedence. The endpoint of this therapy is very clearly established as measurable factor VIII activity levels. We also learned most treatment centers have the infrastructure over the years of development. Most physicians participate in development of the programs, and they have the infrastructure to carry out the gene therapy and treatments. We will continue to publish our data over the medical conferences for the remaining of this year and continue our engagement with the patient advocacy and to share our progress. How we feel from the engagement, the community is ready, the buy is clear. We know what to measure and what they are looking for is a durable and stable expression of factor VIII. We're excited about the next generation of therapy. My colleague, Pam, has also been engaged in the KOL interactions. If there's anything to add, Pam, here. Yeah, no, Jian, I would just reiterate what you've already said, that there is ample enthusiasm around our mechanism of action, the distinctive nature of our program versus the prior gene therapies, such that we have a lot of community engagement, and we're going to continue to engage as well as to release additional data as we go through the remainder of the year regarding the preclinical program. Got it. Yeah. All makes sense. As you get ready for the IND or CTA, what are the gating factors to getting that submitted? Can you talk about what the clinical study design could look like, and could you potentially streamline development in any way? First, let me address the typical gating items for IND submission. We have had a productive collaborative meeting with the FDA for late last year in where we have aligned our approach for GLP studies and CMC strategy, as well as the genome editing safety profile. The data that the agency reviewed was satisfactory, and there was nothing more to ask us. We're focusing on executing those work streams and prepare for IND submission. We have also had discussions with the agency about clinical development plan to address your second point. FDA knows deeply what the primary endpoint they are looking for, the expectation, and we aligned with the approach for the initial study. There will be a global phase I/II study to establish safety profile as well as identify the targeted dose for optimally achieving our target factor VIII levels. The outcome of phase I/II study will inform the registrational study design. We will have ongoing discussions with the FDA as we initiate the studies. Got it. You could basically move from this study into your registrational study, potentially. Yes. The point here is the regulatory pathway is well established. Yeah. The clinical pathway is familiar to the agency as well as the KOLs, and we'll follow the path and engage in ongoing conversations with the FDA as we make progress. Got it. We'll talk more about just the dosing strategy, but just wondering for this program, where are you at on the CMC front at this point? Manufacturing has been always a parallel priority for us. It's not a downstream effort to us. Our CMC strategy leverages broadly the validated platform work accomplished in the field, and that includes mRNA, guide RNA, AAV, and LNP through both in-house and the CMC efforts. All components have been optimized for our gene-editing cargo and the transgene. Our GMP manufacturing is in progress. We are already at a scale that is sufficient for pivotal study, we feel really good about the CMC is in control. We're preparing for the IND submission in Q4. Got it. Okay. For dosing, are you planning on testing a single efficacious dose, or would it be a typical dose escalation setup? You've got NHP data where you've noted the AAV at 5e12 vg/kg and LNP at 0.6 mg/kg, where you saw an average factor VIII activity of about 49% within a range of 29.3%-59.5% in NHPs. I guess where will dosing be at relative to that in the NHP model? As I shown early, the dose-range-finding study was designed specifically to answer that question. The preclinical study data give us a very well-characterized dose-response relationship to work from. We do plan a phase I/II study including dose escalation regimen. As I mentioned, we have discussed with the agency on the dose escalation approach, if you look at our dose-range-finding study, the dose dependency is very clearly shown across both AAV and LNP components. Most animals in the targeted cohorts achieved normalized factor VIII activities. What is really encouraging is that such activity levels were achieved at a relatively low dose of both AAV and LNP, and we saw favorable safety profile with only a single dose of steroid used prophylactically. We feel good about the alignment with the agency on the dose escalation approach, and we're finalizing our clinical profile for the submission. Got it. For the single dose of prophy steroid, does that continue into the clinic? I guess with other gene editing, gene therapy approaches, we've seen safety issues come up. Do you have to do anything unique for risk mitigation strategies, and how will that work in the study? That's right. In the previous gene therapy, one of the feedback that come from the KOL is the cost on the patient. That's not about economic cost, it's about the patients that have to take up to eight months, most patients, majority of patients, of steroid treatment. In our profile, we see very lower AAV dose that we use in the preclinical study, that is significantly lower than the previous therapy. Lower AAV dose means lower innate immune burden. That is as a part of our design because it is directly integrated of the factor VIII. What noteworthy is our AAV delivering the factor VIII gene cassette has no synthetic promoter. It is promoterless gene that we delivered into the hepatocytes. Because of that underlines the lower dose of AAV and the effectiveness of that, the data validated the approach. Second, I want to mention is the genotoxicity assessment that's integral part of the gene editing. We used our proprietary gene editing cargo, and that has the strength in its specificity and applying the orthogonal methods in assessing the genotoxicity profile, both in silico and through biochemical and in cell, as well as evaluate the hepatocytes at a supersaturated dose. We saw no off-target site and translocations. FDA reviewed the package of our specificity data and had no additional requests. We will monitor closely through our phase I/II study, and we have aligned with the agency on the monitoring approach. With all that, a promoterless AAV delivery factor VIII, the lower AAV dose, and clean specificity profile, our risk mitigation strategy is built in the mechanism, and we're confident that we have thought thoroughly about this. Of course, we are going to monitor the safety through our early studies. Got it. Okay. Makes sense. Is there more you can say about the dose escalation and how that's going to work in the study, and how quickly are you going to be able to get to clinical data once you start dosing patients? Sure. Because the direct integration of factor VIII in the albumin gene, the kinetic of expressing of factor VIII in the NHP study looks very different, we see quick onset, reach the peak level of factor VIII within the weeks, that is relevant to the data timeline. How our dosing works, right? MGX-001 is a two-component drug product. AAV is dosed first to deliver the factor VIII gene cassette followed with LNP to deliver the gene editing cargo, then makes a precise cut in the albumin gene where the factor VIII integrates through the DNA natural repair process. Remember, the factor VIII expression is driven by the native albumin promoter. The therapeutic level factor VIII protein is achieved with very low integration frequency. That is what you see in our NHP study. The expression is durable up to 19 months, and most animals achieved normal factor VIII level. Our dosing speed, the kinetic matters. With the previous gene therapy, the peak expression arrives at six months. For us, we can see the factor VIII activity just in the first few weeks after dose. That gives us the opportunity to interpret the treatment efficacy early on after receiving the treatment. This is not a multiyear waiting for signal. The data cadence is going to be very fast. Got it. Okay. For your first clinical data readout, what benchmarks define a positive outcome for early biomarker or functional improvement, essentially? Yeah, the biomarker is very clear, factor VIII, as mentioned early, and it is measurable. The factor VIII activity is measured by chromogenic assay. It has been the primary endpoint across the prior hemophilia gene therapy programs. The FDA knows the endpoint deeply. The activity consistently above 50 IU per deciliter would represent a curative result, and that is the goal of our program. If you go down from that level, there are many papers published, studies published, as you reach about 25%-30% or even more, 30%-35% of some study indicating, and you will have a better chance to prevent a traumatic breakthrough. Still, the replacement therapy is required for surgery. The therapeutic window really is important to target. The severe hemophilia A is below 1% of IU per deciliter, and normally once you exceed 5%, the patients start to shift into the moderate level of hemophilia. Again, for a true cure, we do see a normal factor VIII level is our target, and our preclinical study profile has been supportive of that goal, and we'll take that into our clinical study. What's really important is the endpoint is clear and it is measurable, and we'll see the activity within the first few weeks early on after treatment. Got it. Greater than 50 IU per deciliter is the goal. Whether you show that in the initial dose cohort, I don't know how much that matters. You could probably extrapolate based on that, based on prior hemophilia studies that I've looked at, and get there with higher doses. That's the right way to think about it. Can you repeat the question one more time? Just for the getting to greater than 50 IU per deciliter, you wouldn't necessarily need that with the initial dose, because whatever you see with the initial dose, you can probably extrapolate based on the next higher dose that you're using. Yes. You're talking about is a dose escalation strategy here. Yeah. That's great. We did discuss the dose escalation approach with the FDA at the pre-IND meeting. It is a single arm study, so the patient arm is the comparator for the study. We will start with efficacious dose and escalated dose to the optimal dose for the targeted factor VIII level. Got it. Okay. Makes sense. To get to target levels, you mentioned you're going to the albumin locus, so you don't need a lot of editing there. What editing efficiency do you think you need to get to a durable treatment benefit? This is really a mechanism question we thought deeply, and answer does connect the mechanism to the clinical outcome. The target is not just the gene editing, it is the result of both editing and factor VIII integration. The early data you have seen is at a very low integration frequency. We are able to reach a therapeutic level. Again, this matters for not only therapeutic level. We also see the sustained expression. This matters as the cell divides, the instruction carries on, and that's why we see the durability. To answer your question, yes, the mechanism matters. It is efficient, and it requires a very low integration factor VIII rate for us to achieve the therapeutic window as that has been shown in the NHP study. Got it. Makes sense. We're pretty much out of time, but maybe in closing, if you want to talk about the Ionis partnership, just the strategy with selecting targets and the go forward strategy there, and talk about cash runway and just how we should think about updates for the rest of this year. Fantastic. Sure. I would like to ask Pam to chime in here. Yeah. I'll take those last couple of questions. Relative to Ionis, our partnership is progressing. There were four targets that they chose in wave one, TTR, AGT, APOC3, and one which is not disclosed. We do have 50/50 co-development, co-promote options, which will come at the point where Ionis declares a development candidate. Relative to runway, as of the end of Q1, we talked about that we had $140 million of cash, and that gave us runway through the fourth quarter of 2027. There are some key milestones that we achieve over that horizon. That includes first, for the rest of this year, we're going to be continuing our KOL engagements, and attending medical conferences. The IND filing will come in the fourth quarter. Then in 2027, we expect to be in the clinic. As Jian mentioned earlier, it doesn't take us long once we begin dosing patients to see those early clinical results. We get to our target level of efficacy, or we get to efficacy levels that are stable very, very quickly. It's only a few weeks after dosing where we expect to see the levels that we will achieve, and then those carry out stably. It's a very quick time to read out once we begin dosing patients, at least for those early readouts, which we think are tremendously de-risking. Got it. Jian, Pamela, thanks so much for joining us today. Thank you, Maury.