Introduce our next fireside chat guests. We have Dr. Brian Thomas, CEO, Dr. Sarah Noonberg, CMO, and Dr. Allan Brooks, head of Preclinical at Metagenomi. Thank you all for joining us today, and Brian will also be participating in a mini panel later this afternoon to talk more about gene insertion, so this is your first year participating in our conference as a public company.
It is.
Can you provide some high-level overview on Metagenomi today, and also walk us through the key catalysts that are anticipated over the next year or so before we dive into more detail?
Sure. Thank you, Gula. Pleasure to be here, and thank you all for joining the presentation. So Metagenomi is a genetic medicines company. We are using gene editing capabilities that we have discovered using metagenomics, which is the ability to go into the natural environment and to identify novel enzymes that can be used to develop gene-editing therapeutics. We are excited about the capabilities we built in the toolbox. We have nucleases that are programmable and allow us to achieve targetability across the human genome, high degrees of efficiency and negligible off-target specificity profiles. In addition, we've been able to leverage these enzymes to build other capabilities that allow us to do single base changes, as well as small insertions and corrections using both RNA-mediated as well as DNA-mediated technologies.
The purpose of this toolbox is really to be able to approach genetic disease with the right capability in mind. If you look at the 5 thousand -8 thousand estimated genetic diseases out there, they obviously come with a variety of different genetic signatures in the genome. So we really wanted to set out at the beginning to be able to address any disease with the capabilities in our technology toolbox. Our lead program is in hemophilia A. This is the most abundant bleeding disorder, and the aim for us is to develop a curative one-time treatment for both adults and children. Excitingly, about a month ago, we announced some of our proof of concept data. This was a 12-month durability study. One of the big concerns about hemophilia A is around durability of these treatments.
That's why we chose to go forward with that study very early. Excitingly, we've seen stable and consistent expression of the Factor VIII protein across that time period and have now decided to extend that study out to a full two years. In addition, the positive results we've had from the NHP readout, both the durability study as well as other studies in this development program combined with our positive interaction with the FDA, allowed us to declare a DC candidate for our Heme program. Finally, the progress we've made with Heme, we're excited about because it also gave us the idea that there is a platform available using this exact modality.
We can swap out the payload of the donor DNA and go after other secreted disorders using the exact same combination of system components. And then, in addition to that, we have a partnership with Ionis. This is pretty exclusively based around knockout of genes. Right now we have, Ionis has selected all four of the targets in the wave one of that partnership. There's a second wave that includes an additional eight targets. We're excited about the speed at which those programs are moving forward, and all four of those wave one programs are in lead optimization, and as part of our upcoming developments, we're anticipating further readouts of data from the eme program, as well as the declaration of one to two DC candidates with the Ionis partner programs.
The additional capabilities in the toolbox we're leveraging towards large diseases where large gene integration is critical, and those include diseases such as A1AT and Wilson's. And we continue to advance the capabilities in our technology toolbox as well.
Mm-hmm. Great, thanks for that overview, and maybe let's just jump into your lead program in hemophilia A.
Sure.
So there are several medicines on the market, and this is also an indication that's been of interest in the genetic medicine space for some time. There is an approved gene therapy, but durability, as you alluded to, has been suboptimal, and the commercial uptake has been pretty limited thus far. So can you expand on what you think you can do differently with your program to achieve a better clinical and commercial profile?
Yeah. So maybe, Sarah, I'll let you handle that.
Sure. I think there are three limitations that are really, kind of, major obstacles to commercial uptake of Roctavian, which is the only approved gene therapy, and that is durability, as Brian mentioned. The product was intended to be a permanent cure for adults with hemophilia-
Mm-hmm.
A nd unfortunately, as clinical data unfolded, durability is quite limited. So over the first several years of treatment, Factor VIII levels declined significantly, so at best, it is a transient cure. And given that it uses an AAV, patients only have one time-
Mm-hmm
To get that cure... and they really believe that, you know, a cure is at hand. So I think the lack of durability is probably the most important aspect limiting uptake of Roctavian. We now have de-risked that in non-human primates. We obviously have to prove that again in humans, but we believe the integrated nature and the use of endogenous promoter, which differs from an episomal gene therapy, using an exogenous promoter, has a really strong rationale, coupled with the durability data that we've shown-
Mm-hmm.
In non-human primates, that we can overcome that. Second is the gene therapy, and the approved gene therapy uses a pretty high dose of AAV 60 to the 13 vg per kilo. That has required a significant duration of corticosteroid use over the first year in the Roctavian program. The average use of corticosteroids was roughly eight months, and that's obviously a huge limitation to patients, given the current standard of care, which is really advanced. We have taken great pains to optimize a number of different components that are gonna allow us to really reduce the dose of our AAV, which we believe is going to translate, as others have seen, very dose-dependent effects and toxicities, to minimize use of corticosteroids as prophylaxis.
Lastly, but still importantly, AAV gene therapy was never gonna be a feasible approach for children that have the most-
Mm-hmm
T o benefit from lifelong bleeding protection. Whereas an integrated approach, as cells divide, you continue to have the same percentage of transgene in your daughter cells. Unlike gene therapy, episomal, as cells divide, that gene therapy gets progressively diluted out. So we think based on those three components,
Mm-hmm
O f durability, of a lower AAV dose and better tolerability, as well as suitable for children, that then can really broaden that patient population. We believe that this is an important advance, and we've really pressure tested this, not just internally, but outside with key opinion leaders and members of the hemophilia advocacy community.
Mm-hmm. So maybe let's talk a little bit more about the data that you've shared and what our takeaways should be. Can you walk us through the data from the NHPs?
Mm-hmm. Allan?
You want to do that?
I can do that, so this was actually an early study for us. We started it well over a year ago now because, as we said, we wanted to get that early proof of concept for durability, so this is not our, with our development candidate, so we've actually improved on that since then, and so it's three animals only, but all three animals have Factor VIII levels in the blood, in the therapeutically relevant range, so one animal is about 8% of normal, one animal is about 30% of normal, and the other one is about 80%-85% of normal. And that level of Factor VIII in the blood is measured using a clinically relevant chromogenic activity assay, and that level is the same between month nine and month twelve as it was between month three and month six.
Really, no significant change over that period of time. That study continues. The animals are doing well, and we plan to continue to monitor that for at least eighteen months total, possibly out to two years. That depends upon what we think about the value of additional data. I would say that one year is already sufficient, we think, to de-risk the program. We would have expected to see a decline within that period if it was gonna happen.
Mm-hmm. And so you mentioned there was additional optimizations that have been implemented in the platform after the start of the durability study. So can you expand a little bit on those and how you expect those to impact the profile?
Oh, yeah, sure. So two major changes in the DC. One is to the mRNA that encodes the nuclease. So, we further optimized that mRNA sequence to improve delivery to the nucleus, so that gave us about a twofold improvement in potency. So what that does for you is allows you to lower the dose of the LNP further. That's important in the clinic because we want to be within a really safe therapeutic window. We do know that LNPs can have toxicity at higher doses. So that's the first one. The second one is the use of a bioengineered version of Factor VIII. We aren't able to disclose exactly what that is today, but in a number of mouse studies, together with more recent monkey studies, we've seen somewhere around a tenfold improvement in the activity of Factor VIII in the blood.
And so, again, what that does for you is allows you to dose significantly lower with your AAV than you would otherwise, which, as to Sarah's point, you know, allows you to get into a very safe range for AAV, not have to use steroids in the clinic.
Mm-hmm. So when could we see data with the development candidate that you're going to be taking forward?
Yeah, I would say probably early next year or so. We're about to start IND-enabling studies. Those are those finding studies in monkeys. Those will initiate towards the end of this year. I think once we have that data, we'd probably be willing to share that information.
Mm-hmm. Got it. And you alluded to, I think, receptivity of the hemophilia space to new gene therapy approaches. Can you expand on the type of feedback that you've received from stakeholders, including the hemophilia community, as well as regulators regarding the approach?
Sure, so starting with regulators, we've had our first FDA regulatory engagement, and that was extremely positive. It gave us a very clear roadmap as to not only what it would take to get into the clinic, and we're well on our way in understanding and implementing that guidance, but also creative ways that we can get more rapid data within the U.S.-
Mm-hmm
Despite the higher standard of care. We have had several clinical advisory boards with-
Mm-hmm.
Key opinion leaders, really the top enrolling sites across innovative programs in hemophilia A and hemophilia B, really to gauge their level of enthusiasm
Mm-hmm.
Gain their input on clinical study designs, but also, again, pressure test this desire of patients
Mm-hmm.
For a gene editing cure, and, you know, we received overwhelmingly positive response. I think, as we've heard, you know, the 40 years ago, the Factor VIII gene was identified, cloned, and there was this immediate sense that a cure was at hand, and the field has been waiting for a cure. Roctavian was poised to be a cure for adults. It didn't quite meet that mark, but that has not really satisfied the... and, you know-
Mm-hmm
Caused any diminution of that desire within the hemophilia community. So it is something we've thought a lot about. This is an $11 billion market.
Mm-hmm.
Patients and payers pay, you know, for a given patient on an average of, you know, maybe $11 million over the course of a lifetime.
Mm-hmm.
So it is quite, quite an attractive idea for patients as a one-time thing, for payers, for physicians, and again, there, it has to be safe, and things have to play out in the clinic, but we don't believe that just because Roctavian has had a slow commercial uptake.
Mm-hmm.
That in any way diminishes the desire for a single curative approach for patients.
Mm-hmm. Got it. Great. And as you think about further expanding your internal pipeline, you talked about how you could leverage the same insertion approach as in hemophilia for other protein secretion strategies. How are you approaching the indication selection for some of those approaches?
Yeah, you know, we aren't disclosing the targets that we're going after, but we've already, we're already off to the races and advancing those programs preclinically. I would say the things that we are looking for is, it's obviously, it's got to be a secreted.
Mm-hmm
P rotein disorder, so not necessarily a disorder of an intracellular protein. There's got to be an important clinical unmet need that we're going after and a favorable competitive landscape, and, you know, also, like hemophilia A, a wide therapeutic index. I mean, the goalposts for success with hemophilia A are quite wide. Anywhere from 10%-150%-
Mm-hmm
Factor VIII expression is really a functional cure that should be in the safe and tolerable range. So, you know, that's a very wide bar. So we're looking for other diseases like that that have that very wide bar, and we are very excited about the progress that we'll be making, so you'll be hearing more about that-
Mm-hmm
Y ou know, in the coming quarters. Mm-hmm.
I think that also takes advantage of some of the comments we've heard recently from Peter Marks in the FDA about really-
Mm-hmm
... thinking about platform approaches.
Platforms. Mm-hmm.
So we can...
Yeah.
Yep.
Exactly. We have the editing component already done. We don't have to repeat off target. We've got the LNP, the guide, the nuclease, the manufacturing, so it shaves time and cost off those next development candidates, so really leverages all that we've put into this program to date.
Mm-hmm. Got it, and then on the partnered side, you mentioned a collaboration with Ionis-
Mm
... and I think you also have a collaboration with Affini-T. So can you talk a little bit about how those are progressing and when we might see data, for example, from the Ionis one? Although I appreciate that they're probably the ones that make those decisions.
Yeah, so yes, we have a partnership with Ionis, that we've been almost two years in.
Mm-hmm.
It's going very well. I think one of the things that's noticeable is the speed at which those programs are accelerating, too. As I mentioned, they're all in lead optimization, and we're anticipating that early in the year, one to two additional.
Mm
... development candidates. The data that we're generating for those is coming now. We're anticipating that there will be some in vivo animal studies that-
Mm-hmm
... are happening this year for those programs. And as I mentioned, there are four additional targets that unlock when these, any of these first four targets get into an IND. The partnership with Affinity is on the ex vivo space. Metagenomi is focused on the in vivo application of its technology, but we think that there's quite a bit of opportunity for ex vivo-
Mm-hmm
... partnership, and one of the examples is with Affinity. That was a close partnership that we developed several years ago. We've actually built the core capabilities in the company to carry out manufacturing as well, and so-
Mm-hmm
... we're actually producing that enzyme for the clinical trials for-
Mm-hmm
... for Affinity in our facility. We also announced at our last quarterly report that we are focusing on the in vivo space.
Mm-hmm.
And so as a result, you know, we are considering taking the technology that we've developed across the technology tool bench.
Mm-hmm
... and leveraging that for improving cell therapy applications.
Mm-hmm. Got it, and on the in vivo side, delivery remains a key for genetic medicines that can shape both the safety and the activity profile. So in the LNP space, on the one hand, we've seen a pretty clean safety from companies like Intellia, but we've also seen some safety signals come up. So what is your approach to delivery for your programs with respect to kind of internal optimization, working with partners, and the approach regarding safety in general?
That's a great question. Maybe I'll do the first part, and I'll hand it over to Allan, and you can talk a little bit more about it. But, you know, one of the Achilles heels of a new technology like gene editing is getting it into the organ and the cell type that you need it to get into, and sometimes that can be a challenge with LNPs. Safety is another obvious consideration, and this is why you heard Allan mention some of the optimizations that we're doing on our lead program so that we can really try to lower the dose of some of the components to get around that. In terms of accessing the...
technology and developing it, we both have in-licensed capabilities as well as developing our own internal capabilities for both targeting the liver as well as getting outside the liver in LNP, and then also not LNP, but AAV related, we also have a significant number of enzymes that we've been able to show really nice data in some undisclosed targets on very small enzymes that are packageable-
Mm-hmm
... in an AAV. And then, Allan, I don't know if you want to add anything there.
Yeah, I think so over the last year and a half, we've built internal capability for LNP development optimization. We felt that was important to have our own platform for the liver, I think because it's a core capability for the company. And so we put a lot of effort into that, and we're able to go from LNPs that basically were almost inactive in vivo in mice to ones that are highly potent and can give you saturating editing at very low doses. So that optimization process is in place. I would say there's some payload dependency there, so some optimization needs to be done depending on the payload, but we feel very comfortable with that particular LNP, given what we know about that lipid in the clinic.
So it's something that we are putting a lot of effort into and, we'll be moving that into our programs as they develop.
Mm-hmm. Got it. That makes sense, and taking a step back, 2024 has been a pretty challenging year for smaller biotechs, especially preclinical platform companies in the genetic medicine space. You have exciting tech development that are ongoing, and you're fortunate to have cash out to 2027, but it is still a constraint, so how are you prioritizing efforts and spend in that context, and what's your latest thinking on partnering further?
Yeah, so thank you for saying that, and yes, it has been a challenging year. I don't think that the gene editing and platform companies are the only ones that are feeling some of that pain. We're very aware of that, and I think you see in the most recent quarterly report press release that we had that we're focusing, and we are trying to make sure that fiscal responsibility is our guiding principle. We have really made an effort to prioritize programs that we feel we can have an impact in and that really leverage the capabilities that we have in the toolbox. So, I think that's first.
The other area that, you know, we're really thinking about is given the fact that Metagenomi has a variety of capabilities, everything from nucleases to capabilities that allow us to do single and single-base changes as well as broader, larger integrations throughout the genome, we think that there's a lot of options for business development, and we're actually encouraged by the amount and quality of the conversations that we're having.
Mm-hmm.
As I mentioned, we have some sort of concerted efforts in the cell therapy space, but we're also thinking about areas where we can partner the toolbox more broadly in the in vivo space as well, again, given the depth of the capabilities in the toolbox.
Mm-hmm.
Um...
Yeah, I mean, I think our base editor platform is among the best, if not the best, in the industry. 'Cause we've developed a number of editors that have a diverse range of PAM, so you can access a wider-
Mm-hmm
... range of sequences in the genome, and we've shown that we can do multiplex editing, so we can do three knockouts simultaneously. We can even do three knockouts plus a gene integration with a nuclease in a single step. So that's really important for cell therapy as companies move towards doing more complex cell engineering, and when you do those, those four edits, you don't affect cell viability, you don't affect the ability to scale up those cells and expand them in vitro. So-
Mm-hmm.
Also very high levels of efficiency.
Oh, yeah, yeah.
You know, over 95%-
95+
... editing it for a-
Mm-hmm
... multiplex editing, which is pretty spectacular.
Yeah, and we look for translocations. We don't see any translocations.
Mm-hmm.
so it looks like a very safe
Yeah. And with regard to the fact that it's been a challenging year, I agree. I mean, for preclinical companies, I think, you know, investors, and rightly so, it's been a challenging several years for them.
Mm-hmm.
We respect that, and I think, you know, one of the areas that we are trying to emphasize is the fact that from the very beginning, we have had a strategy that we have set out, and we continue to come back and execute on that strategy and show that we're making progress in a timely manner on these-
Mm-hmm
... on our developments with our lead programs as well as our technology.
Mm-hmm. In the last couple of minutes, what do you think investors might be missing about the story? Although I think you may have touched on some of those points just now, but-
Yeah.
Yeah.
Yeah, I think I'd, I did. I don't think I remember that question, so I hope I didn't jump the gun there.
Mm-hmm.
But I do think that the company we've built is pretty unique in that from the very beginning, from the outset, we you know really knew that we wanted to be the premier gene-editing company, and in order to achieve that, we knew that we were gonna have to build out expertise in everything gene editing, everything from having a novel selection of capabilities of gene-editing tools, but also being able to really deeply understand those tools. So building a company that does extensive off-target specificity analyses as well as has also you know developed the capabilities to produce these molecules, that's thought about.
Mm-hmm
... LNPs, and again, as I mentioned, sort of focusing on the track record of execution-
Mm-hmm
... that we continue to deliver what we have said we're gonna deliver. And I mean, look, gene editing, it's a new space, and-
Mm-hmm
... it's something that's gonna take time to demonstrate that it's here to stay, and I think we're starting to see that. We're very encouraged by, you know, the peer companies in the space with some of the clinical successes that they're having, and, you know, we're excited about the future-
Mm-hmm
... of the space. I don't know if anyone adds anything.
Any other thoughts?
I think that's well said.
All right. Perfect. We're just about at time, so-
Okay
... thank you all again.
Thank you
... for the great discussion.
Yeah.
Thank you.