Metagenomi Therapeutics, Inc. (MGX) September 10, 2026 Conference Transcript

Thanks, everyone, for being here. My name is Yanen Zhu.

I'm one of the biotech analysts here at Wells Fargo.

I'm very pleased to be joined by the management team of MetaGenome. Here with me are CEO of the company, Jan Irish, and also CFO of the company, Pam Wapnick. Thanks, Jan and Pam, for joining us. I think Jan will do a short presentation, so Jan, please take it away.

Wonderful. Thank you, Yan, for having us here. So I will start with our forward-looking statements. So Metagenomy is an in vivo CRISPR gene editing company capitalizing on its proprietary technologies to create curative genetic medicines. And our leader program, MGX0014 Haemophilia A, is advancing into the clinic with well-defined development paths and clear endpoints. We are also expanding our pipeline with our differentiated site-specific gene integration platform and our partner assets in cardiometabolic indications. Our cash on hand at the end of Q2 was $120.7 million, which we expect will fund our operations through Q4-2027. From our unique metagenomic database, we have discovered more than 20,000 signature gene editing systems capable of effective and durable gene editing, including genock-out, correction, deletion, and insertion, as well as multiplex editing with excellent specificity. We have published extensively on editing efficiencies, specificity, and functionality. Beyond that, we have been expanding genome targeting exceeding SP-CAS9. Applying these technologies, we're focusing on our most compelling therapeutic programs that has a high probability success and the near-term value creation. Genome editing is well-suited for a potentially curative hemophilia therapy. MGX001 uses site-specific gene integration in the albumin locus. And this program is advancing and into the clinic on track for IMD submission in Q4. Beyond hemophilia A, this approach has the platform potential across other protein deficiency diseases. In collaboration with our partner INIS, we're advancing metabolic indications. We are also pursuing neuromuscular indications with our compact gene-editing technologies and the pursuing business development to expand the therapeutic applications, including in cell therapy. Now I'm going to turn to MGX001. It is designed to potentially provide a lifelong benefit for patients of all ages, especially children who have the most to gain from a lifelong therapy. Now, our approach is structurally different from the previous AAV gene therapy attempts. Rather than remaining epizomal, FACT8 is directly integrated into the albumin locus that is a stable and active chromosomal site. We achieve that by first delivering an AAV, a promoterless AAV cassette that contains the FACT8 DNA template. And that is followed by the LNP, encapsulated of our novel CRISPR gene editing payload, which will create a targeted specific DNA cut to enable the Factor VIII integration into their specific site. The integrated Factor VIII Then it is promoted, is expressed, driven by the native albumin promoter to reach the therapeutic levels at very low integration frequency. So we have done two important studies in non-human primates to evaluate this approach. Both the studies have delivered a desirable factor eight activities. So let me show you some of those key data. The first study was a dose-range finding study, and we're extremely pleased by the outcome of that study. The study demonstrated not only dose-dependent response to both drug product components, AAV and LNP, but most animals in our target dose cohorts achieved the normal level of factor VIII. The patients with severe hemophilia has very low Factor VIII activity that is typically below 1%. We are targeting 50 to 150% that is broadly represented as normal Factor VIII level. What's really important I want to point out is that the AAV dose level that achieved the normal Factor VIII activities is significantly lower, more than tenfold lower than the doses used in the previous AAV gene therapy for hemophilia A. We believe that is an important safety advantage of our approach. The other study is also important that was to evaluate to the durability of the expression. In this study we conducted the early with the less optimal drug product components regardless achieved the durable expression up to 90 months in the three animals treated. I want to bring your attention to the The graph, the durability graph, where you can see the Factor 8 activity reached the peak within two weeks and then remain stable through the end of the study. Also importantly, the activity level is correlated closely to the integration, which is the result of the mechanism of our approach. This was exactly as we expected our mechanism to do. So in conclusion, I want to say that the totality of the data we have achieved is extremely encouraging and supports a highly differentiated profile in the hemophilia space. And we have conducted a pre-IND meeting with the agency at the end of the last year. We, the meeting was productive, was favorable outcome. We confirmed the regulatory pathway. We have been executing driving for our IND submission. Remember, our IND submission is Q4 this year. We're planning to enter the clinical study in 2027. With that, I welcome your questions.

Great. Thanks, Jian, for the overview. Perhaps maybe a bigger, a big-picture question. One differentiation of metagenomy from other gene editing companies is that you have, you know, through your metagenomic You have access to a very large number of gene-editing systems. I think you might have said 20,000-plus different systems. What advantage does that provide in terms of product design? Can you give us specific examples?

Happy to. So we have built a broad and differentiated library of proprietary gene editing technologies. And we believe that represents a long-term value driver. We can apply our technologies based upon the therapeutic target and to deliver the efficacy and the safety profile as we desire. For example, the first result of our platform was applied in our leader asset, MGX001, where we use the editing system that's called MG291, not only exhibited high efficient editing efficiency, but in our examining of gene editing safety profile for the purpose of ID submission, We discovered no detectable off-target editing and then no translocation, and it's really uniquely clean safety profile. And one additional practical benefit of MG291 is that the guide RNA that we use in this system is substantially shorter than the average guide RNA using SP-Cas9, Which really provides the ease of manufacturing and control of impurity, for instance. Now the broader profile, we believe, also gives us the potential for partnering collaboration, maximize the application in the therapeutics. For instance, our base editor has demonstrated more than seven-plex editing with high efficiency and specificity, which can be used exclusively for cell therapy. As well, early this year, we published on our compact system, which has a much shorter sequence structure, rather than SP-Cas9 has to break them into, you know, two sequences delivered with different AAV vector for ex-hepotica, and our compact system can be packaged into a single AAV, such as for neuromuscular application. So we're very happy with that. The publication was on Nature and was recognized by the field.

Great. Thanks for walking us through those great points. Then the lead program, MGX001, I want to ask a question about the indication. Hemophilia, it does have multiple products on the market. There was one gene therapy product, but the performance is not great. So, in that setting, can you elaborate on what problems are you trying to solve with MGX-001?

Excellent question, Yan, and we have given a lot of thoughts to that. There are current therapies. Current therapies are to control the disease, chronically manage the disease, but not permanently correcting the underlying genetic cause for hemophilia. Hemophilia is a genetic disease, so there is a genetic cause. Patients on the current treatments are still experiencing breakthrough bleedings, even though the annual bleeding events have decreased, but they're still bleeding. We heard if a patient is only bleeding once a year, over 10 years, that means 10 bleeds. The lifestyle is very restricted, and they always worry about the injury, surgery cases, so the disease is always on the mind of them. And also there's this thing about undetectable microbleeds. Where the patients are, say, one of the key category, Factor VIII replacement, if you don't have Factor VIII, we'll give you a replacement. Patients, despite frequent multiple times per week IV infusion, they still have to deal with the peaks, the truffles, you know, over the lifetime, the joint damage would accumulate, so doctors always worry about eventual arthropsy in the late life. Mimetics, another category, does not provide a factor VIII. So the ongoing risks of microbleeds in the later in the life is unclear. So beyond that, the cost burden on patients in the healthcare system is enormous. Any treatment cost The cost alone per patient is more than half a million dollars. It's one of the most expensive chronic treatment for inhibited patient that goes to one million dollars per year. Over the lifetime, it amounts more than 20 million dollars. So our thought is even an expensive one-time treatment would be just a very small fraction of that cost. So our goal is to provide a curative treatment to provide normalized effect at a level for the patients.

Got it, got it. And regarding the below-expectation performance of the one-and-down therapy in the past, any lessons learned?

Absolutely. So we have the advantage to have the ability to learn from the previous challenges early on as a new entry company into this space. So the lack of success was frequently attributed to unpredictable or declining Factor VIII expression. So our approach, as you heard, is structurally different, and we integrate the fact that it directly into the absomal site, and the genetic instruction will preserve it even as the cell divides. The study you see that shows the durability up to 19 months, actually we use a juvenile Monk, non-human primates, monkeys, so their liver volume doubled over the course of 19 months as you saw the expression remained stable to the end of the study. So with that clinical, preclinical data, we believe our approach will absolutely provide different performance unlike than the previous approach.

Great, great. Very helpful. Let's talk about this treatment will involve both an AAV component and the LNP mRNA component. So when people think about these, I think, obviously, safety is very important for gene therapy, gene editing. I think you touched upon the AAV part, which is quite convincing. If it's only one-tenth of the dose of prior AAV gene therapy dose, then it should be very, very safe. I guess that's the, you know, the message.

That's our thought, yes. And also, I want to add to this is the DNA template we deliver is with a promoterless AAV cassette, so we believe that's additional safety factor built in. Yes, so the combination of those two gave us a very comfortable level. In fact, we saw in the preclinical animal study, the safety profile was absolutely favorable as we expected. Right, right.

Okay, that's a great point about the construct. It doesn't have a promoter, so supposedly it's very inert unless it's inserted into the right place.

Exactly.

Yeah. Okay, but now let's talk about the, you know, LMP component of it, right? So you licensed it from Acutus. Can you give us some sense of what this LMP is? Has any of its component been studied in humans? What's the expected safety profile?

Yes. So LMP, in fact, is a complex of multiple components, right? So it has to be optimized for the gene-editing payload. And in our case, the 29-1, and it's a company, a guided RNA. So our LMP was optimized specifically for our program. That's number one. Secondly is the performance of LMP in the effectiveness as well as the, you know, specificity and the profile we have achieved, as I shared with you, as well as the safety profile in the animal study was It was favorable in our view. So we are confident this is going to, you know, translate into the trial, human trial.

Okay, great. So IND-enabling activities are expected to be completed this quarter with IND next quarter. Can you give us an update on where things stand today and what remains between now and the IND submission?

Yes. So we have the advantage of working in a space, the regulatory path and the clinical development path is very clear. In fact, the World Federation of Hemophilia published a guideline for AAV gene therapy in hemophilia in 2025. So with that clearly defined past, as was the meeting with the agency last year, our IND preparation was very clear, and to date, we have completed all the IND enabling studies in life studies and GMP manufacturing. We're in the data analysis and reporting phase and the draft of the dossier, so we feel really good about being on track for the IND submission. At the same time, this is the time for us to identify the treatment centers for the eventual clinical study, so we have actually put a lot of effort in engaging the lead hemophilia treatment centers. In the U.S., it's going to be a multi-center study as well as an international study. What we have learned is that there are a number of, more than I thought, a number of treatment centers, they have had a gene therapy experience and infrastructure to conduct the studies, and so those will be the sites we plan to work with. And most importantly, the interest in working in our study is very strong from the potential investigators, the KLL community, because the preclinical profile is uniquely strong as they see.

And I'll just add, in fact, we can't accommodate all of the investigators that have expressed interest in the study, So we'll be picking a subset for the Phase I, too.

Great. That's great to hear. So perhaps let's talk about the design of the Phase I study. So maybe before that, maybe the question I should have asked is, after the IND clearance, how much time do you think will it take before you dose the first patient?

Yeah, so we are, as I said, it's going to be a multi-center study, and we plan to conduct the study both in the U.S. and neither countries outside of the U.S. with the top hemophilia treatment centers. We are pursuing IND submission. Upon the clearance of IND, we'll follow with the clinical trial applications in those countries. In parallel, we are engaged with the potential investigators to prepare for the startup activities at the treatment centers. So that will be a process to take us through. And upon our IND clearance, we will plan to provide further guidance on the study plan and the patient enrollment.

Okay, got it, got it. Now let's touch on the design, you know, including patient population, age range, size of cohorts, and then I do plan on also asking a question about starting those, but, you know.

Yeah, wonderful. So at our pre-IND meeting, this is the discussion that we carried with the FDA. We plan to conduct a phase one, two study, agree with the agency in severe and moderately severe hemophilia patients. And we started with adult patients and then move into younger age patients. And phase In this 1-2 study, the objective is establishing safety and identify optimal doses and then expand the patient cohorts. As I said, we plan to do a global study. It's a single-arm, open-label study. As we said earlier, we have learned from the past practices in this space. So the escalation cohort structure is very clear, and we do expect to start our study at a lower dose, nevertheless at a dose that has biological activities for the patients who participate in the study. That is a very important element. But we expect, if we reference other studies ahead of us, we will go through those escalation rather relatively quickly and to reach the optimal dose.

How many patients at each dose?

We are not ready to disclose exactly study design. But again, as we look at the guidelines as well as the previous studies, we expect it's going to be a very small number of patients for us to see activities and safety and get to the optimal dose.

Right.

And so you remember that the fact that the activities peaks in two weeks in the animal study, we hope that's going to be replicated. Right.

I was wondering, do you have a safety stagger after each patient wait until a certain amount of time before you dose the next patient?

Right. So safety is important. Although the agency did not mandate the staggering schedule, we will be carefully monitoring each patient at the beginning of the study. Okay, right, right.

Because there are two components, I was wondering, how do you, are you increasing the AAV and LLV together, or keep one fixed?

Excellent question. That's why the dose range finding study was so pleasing to us, because we have seen the escalating AAV, I mean, we've seen achieving the normal level for factor 8 level while we're at the, let me ask you a question. In the dose range of finding study, first we identified the lower AAV dose to achieve the normal factor 8 level, and that gives us the ability to escalate the other arm with the lower AAV dose. So that's our plan, and we also had, that was also part of the discussion, you know, in our pre-IND meeting.

Got it.

Great. But we plan to provide more details once we have IND clearance.

Yes. Yeah, definitely looking forward to that. Can we talk about the bar for success here? You mentioned factor VIII levels can be readily measured very quickly after treatment, so how do we think about what would be a level that you as a team would be happy with?

Absolutely. For one-time treatment, it's tremendously important to provide a product that is safe and with predictable efficacy and durability. So as you see in the pre-clinical studies, normal level factor VIII is achievable. So, we believe, you know, we're aiming to translate that into the clinical study, but it's still early, and we'll, you know, look forward to see how that plays out in the clinical study. Our goal is to target the normal level, 50 to 150 percent.

Got it. Right. In terms of data disclosure, do you think it would be more like disclosing when you see promising signal, you can disclose, or would you have to hold until a certain number of patients and certain lengths of duration have been reached?

Yeah, given it is an open-label study, we will see the safety signals as well as the activities, and we hope to provide more guidance once we have IND clearance.

Okay, got it, got it. Is it fair to think next year we should see data at some point?

I think we should provide more guidance once we have I need clearance. But one thing, you know, we're actively working on is, you know, with the treatment centers and the clinicians, what's encouraging to me is the physicians, the hematologists, the treating hemophilia patients, they are just very knowledgeable about the gene therapy. And in fact, for me, myself, I have learned a lot by speaking directly with the hematologists in this space. And the depth of experience and learning from previous gene therapy has been tremendously helpful.

Got it. Yeah, yeah. So maybe also a question on enrollment. So I heard you very clearly that there are strong interests from the PIs, the scientists, physician scientists, right? Do you have a sense of whether patients are excited or enthusiastic about potentially participating in a study?

That is a reasonable question to ask after the previous AAV gene therapy, right? We're asking ourselves about that. I can share with you as we engage with the hemophilia community. The hemophilia community, first of all, is a very educated community because patients are living with diseases through their life. They're very knowledgeable. Through the last AAV gene therapy attempt, the community actually learned a lot and have a lot more awareness of actually this approach for lifelong treatment. Even though the withdrawal of Ractavian from The market was quite an event in this space, but the desire, we did not see the desire diminished. More so, we feel more awareness of a lifelong treatment and more desire for such. With the patients treated by gene therapy, and they just share with us the relief. If they don't have to think about disease all the time, the ones that worked, right, because it was unpredictable. But the patients that worked for them, it was just such a relief and a quality of life change for them. Yeah, we do. We are reminded by patients, by the physicians, by the caregivers, and one-time treatment is going to be a life change, and that's what they want.

Got it. Yeah, thank you for that, Carla. Let's talk about, I think, on your pipeline chart, there is the undisclosed program for this platform of protein replacement gene insertion approach. What are your considerations? I know you can't tell us what it is now. Can you tell us, when you selected the program, what were the criteria?

Yeah, the pipeline is going to be based upon our site-specific gene integration approach. Since you've heard a lot from me, now I'm going to ask my colleague, Pam, to talk about that.

Absolutely. So we are really pleased by the data that we have been able to generate preclinically with our MGX001 system. And what we've seen is the ability to substitute the transgene that is encapsulated in the AAV with a different transgene, deliver that using the LNP, and express in a secreted protein disorder, we were able to express at the levels, the activity levels, that we were looking to see in that disorder. So what we are thinking about with MGX002 is leveraging the MGX001 system, and we're trying to work to identify the optimal indication. And stay tuned there. We will have more for you at a later date.

Great, great. Then turning to the IONIS collaboration, could you talk about any upcoming milestones and other catalysts from that collaboration?

Sure. So as you know, Mian, and the background of our IONIS collaboration is we received $80 million up front, and IONIS selected four targets in the cardiometabolic space. Three of those were disclosed. Those were TTR, AGT, and APOC3. The fourth one they selected but has not been disclosed. We look at that Ionis partnership as a good partnership for us from the perspective that Ionis brings tremendous disease knowledge, really understands the space, the cardiometabolic space, and we benefit from that. And, of course, we bring our gene editing technology. In terms of those upcoming milestones, really, Ionis has the control over any data releases, so we need to look to Ionis for that.

Great, great. I was wondering if you can touch on cash position and cash runway, and what kind of clinical data milestones could come within that runway?

Yeah, sure. So I'll just, really, this is a good way of summarizing everything that you've heard today. So we are on track to file our IND in the fourth quarter. We've completed all our in-life studies, including our tox study. As Jan said, we've got our GMP manufacturing in hand. We are ready for that IND submission. We are very pleased by the totality of all the data that we have produced, and we plan to present additional preclinical data later this year. So the next step then, of course, the big milestone is getting ready to be in the clinic and being in the clinic in 2027. And as we've highlighted here, our time to seeing the effectiveness of our therapy, the activity of factor VIII, we expect to be sure based on those preclinical studies.

Got it. Great. With that, I think we are out of time. Thank you, Jan and Pam, for a very, very helpful session.

Thank you.

Thanks, everyone, for your time.