Metagenomi Therapeutics, Inc. Common Stock Chardan's 10th Annual Healthcare Conference

Sure. Just to add, we don't just methylate or remethylate. We do histone acetylation. We basically regulate genes up and down. As you noted, the work that was done by the Nobel laureates for CRISPR was amazing. I grew up in GSK, where developing a drug was really hard and took a really long time. To come across this technology where within months you could come up with a construct to bind to the location needing correcting was just so exciting and mind-boggling. However, we really needed to advance that.

What we've done is said, okay, now that we bind to the precise location, rather than cutting the DNA and really taking that brute force approach and potentially having genomic instability and not being able to really regulate it precisely, what we've done is we've deactivated the nuclease of the Cas molecules that we don't cut, and instead we bind to it one of our proprietary modulators so that we can then precisely control gene regulation. Where the power in that is that if you're trying to activate, you may want to sometimes only do twofold activation. For example, in a haploinsufficient disease, you've got one bad allele, one good allele. You only want to double the expression of the good allele. You sometimes really want to be careful not to go much higher because it can be toxic.

So that kind of precise activation is critical, so you want to have a modulator that could do that. In other situations where you have a compensatory gene that you want to express, like utrophin to make up for a lack of dystrophin, you want to be able to shout that one out. So you want to have modulators that do that. So that kind of precise regulation is critical, and really controlling the expression is kind of the next generation, is the way I would put it. In addition, just from a safety perspective, most of our DNA is non-coding. So if you even had off-target in the 80% non-coding and you methylated or remethylated or did something, it is not going to make a hell of a difference already there. But if you cut it could make a difference.

Regardless, you still have to make sure you are looking at the off-target. For example, for our lead indication in the clinic, we looked inside, upside down to make sure there was no off-target anyway. So it is really a way to precisely control that gene regulation. Hope that helps address it.

Yeah. So first of all, this is a really debilitating disease with nothing on the market for these patients. So it is something that really needs attention. While it is rare, it is not that rare. It is kind of medium rare, 40,000, 50,000 in the U.S. alone, so it really needs help. And where we can make such a significant difference is that we can go into the root cause of the disease, as you stated, is the expression of DUX4, because there is this region that is hypomethylated that allows DUX4 to leak out. We can literally go in, bind upstream, and suppress that expression and stop that poison coming out and killing the muscle cells. Where we stand out and why we were very deliberate about that indication is that today, to deliver these kind of constructs, the only known way to I should not say known way.

The only clinically validated way to get into the muscle was with AAV, and as we know, the AAV payload is really small, and Cas9 couldn't fit. We have our own proprietary Cas molecule, which is truly compact. We're in a unique situation where we could fit our Cas molecule in, our modulator in, our guide in, still with room to spare, and really use our superpower to use AAV and deliver it and stop that poisonous DUX4 from leaking out.

Sure, yeah. We were really pleased that one of our PIs gave a talk at the World Muscle Society meeting a couple of weeks ago. What he highlighted was we finished dosing. We had six patients at the starting dose, six at higher. Our first six patients have made it to their six-month visit. He reported on the interim data, and what was really remarkable was that the six patients, when we did imaging to look at their lean muscle volume, all gained lean muscle volume where they were all projected to lose lean muscle volume because that's what happens with this disease. What was even more remarkable was when we looked at quantitative muscle testing to see where they were gaining strength or losing strength, they gained strength in the maneuvers that were tied to where they gained lean muscle volume.

That really gave a nice totality of data to say we're having a drug effect. To complement that, we showed with a circulating biomarker that we did in fact reduce ZBTB17, which is a direct transcriptional target of DUX4, and the fact that we could bring that down again complemented that we were having target engagement. That really was remarkable. As you know, the others in the field are also doing MRIs, but nobody's talking about their data, which you can speculate is good data if they're not talking about it. It really stood out in terms of other ways to go about this.

First, just a little bit about the digital twin. We are working with Springbok Analytics, who is a company that really are experts in doing muscle imaging. They look at whole-body images and measure lean muscle volume, fat fraction, and such in about 140 muscles across the body. What they have done is they have read in MRIs from hundreds of patients over time, and based on that, they put a machine learning algorithm in place so that if you give them a baseline MRI for a patient and some basic demographics, they can then tell you what that patient's MRI is projected to look like in 6 months.