Hi, everyone. Thank you for joining us in the room and online for the third day of TD Cowen's 45th Annual Healthcare Conference. I'm Joe Thome, one of the Senior Biotech Analysts here on the team at Cowen. It's a pleasure to have with us today the team from Metagenomi. To kick things off, CEO Brian Thomas is going to do a few slides, and then we'll jump into Q&A.
Thank you, Joe. I appreciate the invitation and appreciate everybody sticking with us till the end of the conference here. Another fantastic conference, and really happy to have been invited. Metagenomi is a genetic medicines company. We are leveraging 4 billion years of microbial evolution to tackle curative genetic medicines. Today's presentation will include some forward-looking statements. Our vision is really to leverage the natural world around us and the ecosystems that we see on the planet to become a source for novel gene editing capabilities. We developed these tools into programmable genome editing tools that allow us to precisely edit the human genome in a variety of ways. The goal is curative genetic medicines, and underlying it all is a discovery platform that is powered by metagenomics.
Metagenomics is the ability to go into the natural world, and instead of isolating and characterizing individual organisms, you actually sequence everything that's present in the environment. This tells you a lot about the world around us. It tells us that there's a lot of life on this planet we didn't know existed. It also tells us that even though we've never studied these organisms, that there is a lot of diversity in their genetic machinery that we now have access to. We've built a proprietary database that is massive. It's one of the largest databases of its kind that includes the reconstructed genomes from these unknown life forms. Many of these organisms are extremely rare, and as a result, the genomes are incomplete. We actually leverage AI in a couple of different areas throughout our discovery process. The first is through our screening ability.
This is our ability to go out and to identify these novel systems and, more specifically, novel genes on these unknown genomes. We also leverage AI in our engineering efforts. Once we find one of these novel enzymes, oftentimes they're inactive in a human cell backdrop. This is where we really bring artificial intelligence to help us guide through the process of taking an enzyme that shows no activity in a human cell through one that is highly active and designed for the task that we have in mind. This has allowed us to build a comprehensive set of genome editing capabilities that allow us to edit anywhere in the human genome. That Toolbox is seen here. It is comprised of many different modalities. The primary modality, however, is our nuclease components. These are very novel.
They are in a variety of sizes, everything from 30% to 50% of the size of Cas9 all the way to larger sizes. They're very specific. They can edit where they're supposed to edit and don't show any off-target activities. They're very efficient, so we can actually find systems that will edit in specific cell types at very high levels. Furthermore, when you take this collection of enzymes as a whole, it allows us to target throughout the human genome. This is really important. When you have a single tool, getting it to target at a specific location in the genome can become quite a challenge.
We have shown over and over again that this capability really allows us to look at the gene space across a genetic disease and focus exactly where we need to be in order to achieve whatever the desired effect is on the genome. A good example of this is with our base editor, where we have been able to use the chassis of some of our nucleases to give us that programmability, but also focus on enzymes that have a very small size. This small size then allows us to tether on other enzymatic activities, such as deaminases, and create base editors that, again, benefit from this very small size. Thus, we can package them into AAVs and get them outside of the liver into other organs.
Similarly, when we think about the nucleases as a chassis, we can go back into our metagenomic database and find novel reverse transcriptases. That allows us to build what we call our RIGS, which is our RNA-mediated integration systems. With RIGS, we're able to do small and large insertions and deletions. Finally, we have a system called a CAST, which is kind of a combination between a programmable CRISPR nuclease, which is naturally defective, and a transposase system, which does an active integration of a much larger molecule. What you see as you transition from the left to the right on this slide is everything from the ability to do cuts, knock-ins, knock-downs, and other effects on the genome to single base changes to then, as you move to the right, very large changes to the genome.
We have leveraged this Toolbox to build out our pipeline, which you can see here. I am just going to go over this briefly and then give you a quick update on our lead program in hemophilia. What you can see, first of all, is that we are really following a strategy that we adopted about four years ago now, which is, as we started to develop this diverse set of tools, we knew that some of them were extremely powerful. They showed these optimum characteristics, such as high efficiency and specificity and targetability. We really did not want to wait around to develop other tools when we knew that these were capable of moving towards the clinic now. That was our strategy early on, to drive those early technologies towards the clinic. As a result, you see that those are supporting our lead programs.
These are all targeting in the liver. This is, again, taking advantage of the fact that we can use lipid nanoparticles in order to target the liver quite readily. Our lead program is in hemophilia A, and that is in lead optimization. I'll be giving you a quick update there. We also have a partnership with Ionis that is really focused around knockdown of specific genes in the cardiometabolic area. We have four programs in the first stage of that partnership, and they are all neck and neck. Two of them have been disclosed. We'll likely be disclosing the other two later in the year. We're anticipating one to two development candidates announced with that partnership this year as well. With that, I'll give you a quick update about our hemophilia A program.
Just to acquaint you with the focus here is it's really about going after a replacement factor VIII gene for hemophilia A patients. This is a two-vector system. We have an AAV that carries the donor factor VIII gene. Importantly, this is not a gene therapy. This is a gene editing system. As a result, this AAV does not include the promoter that you would typically see with a gene therapy. As it infects the cell, it just creates an episomal piece of DNA that is sitting extra chromosomally. This is followed by one of our lead nucleases, MG29-1, and that's delivered by an LNP at a point later in time. That enzyme is loaded with a guide that targets intron 1 of the albumin locus.
Importantly, it's an intron, so it's a safe location where we can make cuts without interfering with the albumin gene. Importantly, also, we're taking advantage of exon 1, which is the signal peptide that causes secretion of that protein into the bloodstream. The final part that we're co-opting is the actual promoter of the albumin gene, which is a constitutively on, highly expressed promoter. We get very high levels of protein, even though we're only achieving very low levels of integration. This, as a side note, we're going to show some data here on our lead program. We're very pleased with the outcome.
On a side note, we also realized that it would be very easy for us to swap out the payload of the AAV and turn this into a platform that could also integrate at that exact same location with the same guide nuclease, the same off-target characterization, et cetera, so that we could very quickly leverage the work that we put into the hemophilia A program in order to move other indications forward. Recently at ASH, we had an oral presentation where we gave an update on our ongoing durability study. This is a non-human primate study that we started about a year and a half ago. We really did this study first, this durability study first, because we wanted to address one of the primary concerns with hemophilia A, which is the gene therapy-based treatments for that disease. They do not show a long-lasting durability.
That is a big concern. We really wanted to hit this head-on, and that is why we chose to do this study initially. This is a study that is using a monkey factor VIII so that we could actually extend this study for the full 18 months. Originally, it was only planned to be a six-month study, but given the readout after the first six months, we were encouraged enough that we decided to extend it for an additional year. That is the graph that you can see on the left of this slide. You can see that even after this is a readout of 16 and a half months, even after 16 and a half months, you still see stable levels of expression. These are three different monkeys. Each of the different colors is a different animal.
One thing you'll notice is that there's difference in variability here. We were targeting a 10%-150% range for factor VIII activity. On all three monkeys, we hit that range. We were very pleased with this, given that this was our very first NHP study with this system. Subsequently, and while this study was ongoing, we've made many changes and improvements to many different aspects of that multi-component system. One of them includes the adoption of a bioengineered factor VIII variant. This gives us a much higher level of factor VIII activity, as you can see in the graph on the right compared to our original construct. This is, again, another tool that we will be able to use in order to hopefully control that variability as we go forward. Again, the variability between 10% and 150% is effectively a cure for NHP. That is something that we've really targeted out of the gate. With that introduction to the company, I think we can move to questions.
Perfect. I think Dr. Sarah Noonberg is also going to join, CMO of Metagenomi, for the discussion. Maybe to start, maybe where you just left off on that slide, can you talk a little bit more about how you arrived at your development candidate for hemophilia A based on the initial data that you were seeing there? Maybe what changes did you make?
Sure. I'll summarize what Brian just covered, which is when we went to select our DC, we really wanted to learn what we could from Roctavian. In talking with advisors and the advocacy community, recognizing that commercial uptake has been a little bit disappointing, the two main limitations of Roctavian were really the lack of durability and the AAV dose that requires a substantial amount of steroids to control liver function test abnormalities. Those were two areas that we really focused on to make sure that we had a development candidate that was truly differentiated. The first thing we did was ensure durability. That's the graph that you've seen. We've taken it out to a year and a half. Not only does it give us really de-risking data, but it makes sense because you're integrated as opposed to episomal.
You're not invoking any of the cellular mechanisms that might cause transcriptional silencing from being an extra chromosomal element with an exogenous promoter. We were not surprised by the durability, but this had not been a study that BioMarin ever ran with Roctavian. This was very reassuring. The next thing we did, as Brian mentioned, was really look at how we can reduce the dose of AAV. As we've known, AAV can have a number of acute as well as longer-term side effects, primarily in the liver. Those are very dose-dependent. The bioengineered variant that we constructed with five- to eight-fold higher activity really will allow us to reduce that dose. In our initial experiment, we were 2E to the 13 using a wild-type construct. By going to this bioengineered variant, we think we'll be in the low 2E-12 range, viral genomes per kilo, which, again, takes us out of that range where we expect to require long-term steroids.
Additionally, we've done extensive off-target characterization to ensure that in a gene editing approach, we're not introducing any off-targets. To date, we've seen no validated off-targets throughout a whole slew of assays that have been put forward by the FDA. Lastly, we've done some work with the mRNA of MG29-1 to increase potency. That'll allow us to reduce the dose of LNP, which also should have some safety effects. We've taken this multi-component system, and each of those components, we've really looked to optimize. Hemophilia A is a mature area to go into. We want to make sure that we are going in with a candidate and a product that's going to make a meaningful change for patients.
Can you talk a little bit about the required factor VIII expression that's needed or desired for a therapy? I feel like if we look back 10 years, people were initially excited by 3%. Then it seemed to jump to 12% and then 30%. What do we need to see with effective therapy?
Yeah. I think you can look at graphs of factor VIII level and number of joint bleeds that can tell you that once you're above 10%, your risk of spontaneous joint bleeding goes markedly down. 10% represents a real floor. Now, when you're dealing with actual recombinant protein factor, the amount of factor that you're going to need to make may be less than when you're dealing, let's say, with a mimetic such as Hemlibra, which is not actual factor, but trying to recreate the activity of a factor. We believe that 10%-150% range represents a true functional cure. Those are our goalposts. When we're in the clinic, we're really going to be pushing toward getting patients in that middle 40%-80% range.
We believe that with hemophilia A, and it is one of the reasons why we chose it as one of our first programs, the goalpost is wide. Even if we have patients that are in that outer 10%-150% range, we see that as a long-term success, as do our advisors. Clinically, there is not a lot of difference that you would see day to day between a patient that is stable at 10% versus 150%.
Maybe in that range, because it is a reasonable range, even going back to the initial gene therapy interventions, you did see a lot of spread between those that had a great response, maybe those that did not see as much of a response. Even in your preclinical data, there is a little bit of a spread, even though having the lowest responder, it is still a good response. Is there any risk in that level of variability, or is there a level of spread that you think is concerning at all or no?
We'd like to focus in that 10%-150% range, and that is a pretty wide window. Obviously, we don't want to overshoot. One of the things we've done by using an optimized both guide and mRNA for very potent editing as well as a bioengineered variant, we can reduce the doses of our components. We also believe that that's going to have an important lever that we can use for variability. Now, with this first study, I'll also point out it was our very first study that we ran. It's with research-grade materials, which don't have the quality attributes of GLP and GMP-grade materials. We also believe that improvements in manufacturing are going to help control variability.
I'll just add something. I've asked Glenn Pierce, who's one of our advisors, and he's the head of the World Federation of Hemophilia, about on some of our graphs, you'll see them go up and down over time. I've asked him, what is the normal fluctuation for factor VIII? Interestingly, we don't actually know. There haven't been any studies for the sort of day-to-day, month-to-month fluctuation that happens with factor VIII. That's why we think having a buffer is reasonable.
Maybe can you walk through what's necessary to file the formal IND? Kind of where do you sit right now with the candidate? I guess, what do you need to do internally? What will we see externally in terms of data?
Sure. We are really pleased with our progress. We have declared a development candidate. We have interacted with the FDA, very successful interaction with a high degree of engagement. It gave us a real roadmap as to what they are looking for. In addition to the increasing transparency and guidances that are coming out for gene editing, we really got a lot of great feedback as to what they are specifically looking for in hemophilia, not just in the non-clinical and specificity, but also we were able to talk a little bit about what an initial clinical protocol might look like. In terms of where we are now, we are well underway in initiating GMP manufacturing. We will be completing our GLP studies. We have done extensive off-target characterization. There are still some more FDA-required assays that we will be doing, but we feel very confident. That should take us into 2026 for an IND and CTA filings.
Maybe Sarah mentioned that we'll be concluding this durability study.
Right. This has been a great study. We've learned a lot from it. Now that we've convinced ourselves and others with durability, we're going to be taking down this study and we'll do a fulsome analysis, not just of factor VIII levels, but histology, integration, and looking at different organs there and safety. That's data. We have a number of non-human primate studies that we'll be running as part of our IND enabling package.
With our other programs, with our partner with Ionis, we are, as I mentioned, we're expecting one to two DCs this year on those lead programs as well. Those will be announced later too.
One way we have a good idea of the phase I/II development program, if we were to look, obviously, the gene editing has shown more substantial levels of maintenance of factor VIII. If we look at sort of the initial BioMarin-Roctavian phase I/II , should that be a good guide? Is there anything that you would like to do differently when you look at that trial design, or how do you think about that?
While it's premature to talk a little bit about the trial design before we have agreement with the FDA in a pre-IND meeting, I think the Roctavian clinical development program is a good example of how to do it efficiently. There was very limited dose escalation. Once you found a dose that you were happy with, some dose expansion, getting comfortable with that dose, understanding variability, and then moving quickly into phase III. I think that's a good guide to follow.
Can you talk a little bit about manufacturing and maybe what are the pros when it comes to manufacturing? Obviously, you've touched on a little bit of the vector strategy, but obviously, BioMarin had to change their manufacturing between phase I/II and phase III and made some edits to their protocol. Will you be able to kind of seamlessly go through your development program with your manufacturing as it is right now, or how are you thinking about that?
Sure. This is a multi-component system, whereas BioMarin had all in-house manufacturing. We'll have a hybrid. We have a GMP facility in Emeryville where we manufacture the mRNA that encodes our nuclease. We have a number of CDMOs that we'll be working with. While we won't necessarily have commercial-grade material with our phase I/II study, we are using partners with a great deal of experience in being able to seamlessly transition.
Obviously, we have seen some of the initial hemophilia therapies come to market. As you mentioned earlier, some have struggled either in terms of patient interest or reimbursement dynamics. I guess, what are your thoughts on the hemophilia market overall? What can an editing approach offer that could be differentiated either on the reimbursement side of things or on just overall level of patient enthusiasm?
I would say despite the commercial struggles of the first gene therapy, in our conversations with key opinion leaders and advocacy groups, it hasn't limited the enthusiasm. It still remains an extremely attractive commercial opportunity. Patients are spending millions and millions of dollars over their lifetime in factor VIII replacement or memetics. That really provides strong pharmacoeconomic support for a one-time gene editing program. Truly, what they're most excited about is the larger value proposition beyond what can be done with gene therapy now, which is going into children who have the most to benefit from lifelong bleeding protection. I think that's where the biggest enthusiasm is: get proof of concept in adults, but then very quickly move into the pediatric population and give them a hemophilia-free childhood and ultimately a hemophilia-free mindset.
Maybe on the Ionis partnership, shifting a little bit, the company does have the opportunity to opt in on some of these programs. What will you be looking for, I guess, in the development of the Ionis programs to make that decision if you want to be a part of those programs or wait for something that's to come?
Yeah. We are very pleased with the progress of the Ionis partnership. All of those programs are focused around the cardiometabolic space, which is an area that they obviously are particularly interested in. In combination with them, we will be both announcing what the upcoming targets are for that first wave of programs, but then also making our decisions around the ability to opt in. I think it's still a little early for us to define which of the programs we're interested in. We're also obviously a small company and focused on our lead program.
The progress that we make with there will also weigh into that factor. The other thing to remember about that partnership is it is gated based on success of the first wave. Any of the first wave targets entering into an IND will trigger a second wave of four additional targets. Again, very pleased with that partnership and looking forward to continuing to work with Ionis there.
Maybe on that front a little bit, we'll dive into maybe some of the programs a little bit later. How do you see BD or sort of the ability, obviously of an expansive platform, to partner with additional players in this space? There's a lot of different indications that you can go after with editing. How are you thinking about, I guess, the indications you want to keep to yourself and those that you might be willing to partner, and sort of, I guess, the need for BD?
Yeah. From a BD strategy perspective, and then Sarah, I'll let you talk about specific applications that we want to keep for ourselves and others. From a BD strategy point of view, we've always felt that business development is important. This is, I think, the thing that gets missed sometimes with gene editing is it's a brand new technology, and you need to give it its time to mature and understand the science that really supports that technology. I've always felt that having a strong partnership with others is a great way to move the technology forward quickly. That being said, we have reached a point with our Toolbox where we have an extensive number and diversity of different capabilities. We are always on the lookout for opportunities for that.
We have some very active engagements underway with a variety of potential partners, everything from big groups down to there's quite a bit of activity in innovation and delivery, et cetera. We are actually talking to quite a bit of people, and that's something we will continue. The purpose of the Toolbox, and maybe this is a segue for you, Sarah, but the purpose of designing the Toolbox the way we did was really around being able to approach genetic disease by looking at the landscape and knowing that we had the capability to go in and fix that. Whether it's a knockout that a double-strand break could work with or a single base change or larger, that's really the goal for our current technology development is these very large changes in the genome.
We know that that has time to develop still because you've got more significant delivery challenges with these other technologies, et cetera. That's really been our strategy from the beginning is to be able to change the genome in any way possible. We're always looking for diseases that we can move quickly on. Maybe Sarah, you could comment on that.
Sure. Diseases where we would at least initiate on our own and plan to take it through some value inflection point on our own, those where we really feel like ourselves or with CDMOs that we're comfortable, we can manufacture, we have all the capabilities, they are smaller indications that we can move forward a disease community that we know. Disease areas where we may want to partner earlier, where we may need delivery technology. We have ultra-small nucleases that can fit within a single AAV base editors. We're working on ultra-small other gene editing systems.
This might be a great area, let's say in the neuro space where there's been a lot of improvements in capsid tropism, where a company with great expertise in delivery or the CNS expertise could be a good partnership fit. The other area where I'd say we would partner early is moving into larger disease areas. Cardiometabolic is a great example where we're partnered with Ionis and we have the opportunity to go into larger spaces. Other large spaces we may not want to necessarily start on our own.
I think funding has been a large focus for investors, obviously, in the gene editing space over the past couple of years. We've seen a couple of higher profile private companies that maybe haven't been able to make the jump. How do you think about expense management when it comes to gene editing? Is there an inherent sort of pay-to-play to be in the gene editing space? How much maybe can your early investment de-risk maybe future investment going forward?
Yeah, that's a great question and also one that I know is on a lot of participants of the conference's mind. This is a really challenging time, biotech, but I think gene editing space in particular is even more under pressure right now. It's something we're keenly aware of. It was also part of the decision that we made to go public last year. We saw an opportunity and we saw the ability to raise some important funds. That has luckily given us runway, as we said during the IPO, into 2027.
Since then, we have been focusing on reducing our runway, controlling expenses, operational efficiency, and are able to even push that out further now. I think it's critical. Unfortunately, as I mentioned earlier, this technology is new and it needs time to develop and we need to understand it from a science point of view. By definition, it's farther away from the clinic than I think the risk appetite is commonly prevalent right now. It is something that we're thinking about. Obviously, we really want to be able to see our lead program take a shot in the clinic, and that's what we are all blazing to get accomplished.
I would just add that each of our lead programs, both with Ionis as well as our hemophilia program, have a lot of leverage to them. Our hemophilia program, we can just insert another transgene and with limited future investment have multiple programs for deficiencies of secreted proteins. Similar with Ionis, multiple cardiometabolic knockdown targets. Each program really improves the likelihood of success and makes those future programs less expensive.
Perfect. With that, we are at time. Thank you very much for joining us today. We appreciate it.
Thank you.