Hey, everybody. Thank you so much for joining us. My name is Chris Howerton, part of the Jefferies Biotechnology Research Team. Really excited to be hosting a fireside chat with Omega Therapeutics. On behalf of the company, we have both the CEO, Mahesh Karande, as well as the CSO, Thomas McCauley. Thanks for joining us, gentlemen. Thanks, Chris. Thanks to you and Jefferies for inviting us. Excellent. All right. Maybe one, we can get started here in terms of saying, like, what is it that Omega Therapeutics does? Like, maybe you could give us a high-level overview of what your platform does? Yeah, absolutely. You know, like you said, Omega Therapeutics is a platform company. You know, what we are doing is Epigenomic Programming for precision genomic control. To say it very simply, we are the first systematic use of using mRNA therapeutics as programmable epigenetic medicines. You know, essentially, the platform is based on biology that was delineated in 2016, where, you know, Flagship Pioneering, which is a founder of Omega and Rick Young and his lab from the Whitehead Institute, sort of outlined the organization and filing system of genes in these, you know, three-dimensional loops of DNA called insulated genomic domains. Okay. Which essentially act as fundamental regulators of gene control. What we have done is and what nature does, if you think about how genes get expressed, nature essentially lays, you know, or modifies or deletes or what have you, epigenetic marks, add regulatory elements within these IGDs. IGD is big, you know, they're insulated such that regulatory and transcriptional action is contained within an IGD for the gene sitting in it. Yeah. What we have done is we have literally replicated nature's operating system of gene control as well as cellular programming. We are using exactly what nature does by using mRNA therapeutics to home into the specific loci of the regulators. Yeah. with high specificity. Okay ...very, very high specificity and essentially do an epigenetic modification, which literally tunes the gene pre-transcriptionally. That, if you think, treats or cures disease. I see. I guess or maybe would be helpful too, to compare and contrast, like how is your platform different than maybe past epigenetics approaches? Like, I think you mentioned specificity, so maybe you could talk a little bit more about that. Yeah. Maybe I can talk and then I'm sure Tom will add a few things to it. Yeah, absolutely. Look, I mean, I think, you know, epigenetics has been around for a long time, and the promise of epigenetics has never been sort of fully delivered, right? The reason we believe that we are different is as follows. All past attempts at epigenetics really were understanding transcription factors and then sort of going after transcription factors with, you know, old world modalities. Like from a protein base. From a protein base. Yeah. Right. Exactly. Right. At the end of the day, you're understanding epigenetics, which has been around for 40 years, people have understood that, right? All you're doing is you're going and, you know, either agitating a receptor or blocking a receptor, doing something at the protein level. Yeah. Right? Those things, you know, are small molecule, large molecule approaches, right? I think, you know, that hasn't worked or that has worked, but, you know, you're really not differentiating from anything else that you're doing. What we are doing is, which is very, very different, you know, we are literally going to the fundamental processes that nature, you know, and that's why I'm quoting nature here, right? Yeah. Liberally using nature. Mother Nature has a beautiful way of doing things that is never in ones or twos. What we have done is our team has really deciphered what nature does in terms of how genes get expressed. Yeah. How cellular programs get written. Okay. What we are doing is, you know, replicating what nature does. Because the premise of this is, you know, disease occurs because of genes either being underexpressed or overexpressed, right? Yeah. That's why you have an overexpression or underexpression of protein eventually. Sure That you can go after with small molecules. Yeah. If you are able to do something right where the gene sits pre-transcriptionally and control gene expression pre-transcriptionally, then the entire central dogma just works properly, right? For that particular expression. Sure. What we are doing is that's what we have figured out, and what we are doing is, you know, replicating nature's mechanism. Mm-hmm of epigenetic control. Yeah. That's why we call it Epigenomic Programming. Sure. We simply correct what went wrong in nature. Yeah. Tom, did you have anything to add there? Yeah. No, so that was a beautiful exposition of the sort of basic science of it. I mean, from a pharmaceutical and sort of product perspective too, I mean, the two things as Mahesh. The first thing you said, Mahesh, was about specificity, right? I think people have known for a long time that mechanistically, epigenetic mechanisms of action were the right approach to target transcription. Yeah. The vehicles, the small molecules that were used were highly nonspecific. They went into all different cell types and Sure. Would essentially, you know, as a result of HDACs or whatever. HDACs. Yeah. It hits everything. Hits everything, various things. Yeah, exactly. It hits everything everywhere all the time. You know, it ultimately leads to sort of safety concerns and sort of is the reason that those compounds along with having sort of, you know, unfortunate PK, they have to be dosed multiple times a day. Right at very high doses. Okay. The net result of all of that is that they have fairly narrow therapeutic index. They've been, you know, epigenetic molecules have been really relegated to oncology so far. Yeah. Part of what we're doing is really opening that up, you know, to the entire breadth of genetic disease. Yeah. Well, totally. I mean, look at your pipeline. It's got a little bit of everything? Mm-hmm. There's potential, which is super exciting. Yeah. Absolutely. Relative to epigenetics, I think what I'm hearing you say is that this has always been tantalizing. We know that this can affect gene transcription, but how to be specific about it is the new kind of thing that you added on to this. Absolutely. I think two things, right? Tom, you know, absolutely said the right thing. Look, where epigenetics, the promise of epigenetics, has faltered is on the specificity. Yeah. Right? That's one. You know, we have created this completely new class of drugs called, we call them Omega Epigenomic Controllers. You know, epigenomic controllers. What they are essentially is mRNA- Mm-hmm. That is delivered to specific cells, right? Yeah. The mRNA, essentially, when it hones in through the ribosomal machinery, eventually gets into, you know, the genome, and it expresses two proteins. Okay. One is a DNA binding domain that goes and attaches, you know, uses 21 base pairs. Yep. To go and attach to a particular locus. The other one is an epigenetic effector protein. Yeah. Which then creates that epigenetic action at that locus, which, you know from a simple standpoint, simply tunes the gene like a thermostat or rheostat and brings down the expression. Doesn't completely abrogate it. We don't do 100 or 0. If you think about small molecules or any of these other approaches, you have to send it ubiquitously everywhere and tamp down everything. Sure. We're not doing that. Yeah. We are bringing it down to a normal range of expression. Got it. Right? That means eventually the protein will be also normally expressed. The beauty of this is that our PK and PD is decoupled, and that's another very, very important thing. Because, you know, mRNA is transient. It goes away very, very rapidly. Yeah. Within a matter of hours or a day. The proteins that it expresses also degrade and are gone. Yeah. Within a matter of couple of days. What we engineer into that is the tunability, the level of tuning, and the durability of effect. We have Epigenomic Controllers that work for a few days, few weeks, and even few months. That explains the, you know, breadth of the pipeline's promise. Sure. Yeah. Okay. Well, I mean, that's amazing. I guess let's just put a fine point on this, though. Yeah. I think the other obvious comparison is to maybe gene therapy. I guess what do you think the important difference is between them? I'm gonna let Tom answer. Okay. Let me just say one thing, right? I was gonna say, you're gonna say something. Think about our lead program, MYC. Yeah. Okay? Which has been undruggable for a good part of 40 years. Mm-hmm. People have tried. If gene editing and gene therapy could do it, they probably would have, right? I'll stop there, but I'll let Tom answer that. Okay. Good. Yeah. Good. Yeah. Good. Yeah. Yeah. Just to tie it back to what Mahesh was saying before about tunability being key, right? There's two things. The first thing I would say is that, you know, whether it's a gene editing or a gene therapy, gene transfer approach- Yeah. It's really a binary effect, right? Sure. You're turning something on and off. Yep. In general, both of those things are not under the endogenous control systems within the cell. Because of the way they're introduced or whatever, yeah. Right. For a gene transfer approach, generally you're creating little, you know, sort of episomal factories that churn out- Yeah. Okay. Sure. Great. the product, right? Mm-hmm. They're generally not under the endogenous control of the cell. Similarly for editing. Yeah. those are permanent changes. This has been recognized by, you know, the regulatory agencies in terms of the long follow-ups that are required clinically for those programs. Yeah. Because if you see something untoward, it's you can't withdraw the therapy at that point. That's true. That's, you know, something that, as Mahesh said, while the delivery modality is transient, the effect is durable but not permanent. Okay. It can be undone if necessary. Right. You know, that's one piece. The other part is tunability. For, again, for a gene transfer approach or editing. Mm. Again, you know, it's either the accelerator is all the way down. Like copy number and it's stochastic. Mm-hmm. Right? Yeah. Yeah. The brake's all the way on. Mm-hmm. You know, in this case, we are, as Mahesh says, you know, taking a page from nature and being, you know, tuning by the same mechanisms that the body normally uses. You know, tuning gene expression only as much as necessary to return the target gene or genes to their normal levels of expression. Yeah. Okay, that makes sense. Right. It's again, like harnessing this endogenous machinery that we all use every day anyway. Exactly. Okay. Maybe let's, this is different than, maybe we had planned, but with respect to MYC, let's use that as a case study then, like as an IGD or a locus. I think as you were mentioning, Mahesh, this is undruggable, right? Like, we can't drug it. Mm-hmm. Now you guys say you can. I guess, how does that work? Yeah. I mean, I think, look, MYC has been undruggable because of two things, right? One is the protein, it doesn't really have a binding pocket, so it's been tough. Okay. I mean, you can. There are companies that. Like the protein itself? Yeah, the protein itself. Okay. Got it. Okay. Got it. Exactly. Right? Got it. It's an unstructured protein. Like, we've been trying to do these high throughput screens, nothing's sticking, basically. Exactly. Okay. Right? The second thing is that, you know, if you think about moving up the central dogma and looking at, you know, going after the mRNA, et cetera. Again, you can go a little bit more specific than small molecules with ASOs, et cetera. Okay that have tried, right? Yeah. if you think about it, none of these approaches have worked, some of them have failed. Okay. Again, the reason for that is, you know, we believe, our hypothesis is that some of these oncogenes, and MYC is a perfect example of it, right? They auto-regulate. The minute their protein- Yeah Their mRNA is ubiquitously under attack. Yeah In cancer cells as well as normal cells, because that's exactly how these mechanisms have to work. Right. Right? They have to go ubiquitously everywhere and sort of completely try to abrogate expression. Mm-hmm. You know, in oncogenes like MYC, that is a problem because these are very tightly auto-regulated genes, and I think they Yeah probably auto-regulate and crank out more and more. I think, you know, I'll speak simplistically. Of course. Which is, how much drug can you put in the system to control all of that all the time? Right. Right? That's the reason some of these things haven't worked. What we are doing is we are not completely abrogating MYC expression. We are bringing it down to a level where the overly dependent cancer cells are starved. Okay. Right? Yeah. Intrinsic mechanisms kick in, right? Apoptosis. But the healthy cells that require a certain level of MYC for normal metabolic reason, MYC is, you know, MYC affects a lot of genes in its cascade, right? I see. It's a very central. Yeah. sort of gene even in, you know, a lot of functions, metabolic functions. We allow the normal cells to, you know, basically operate normally. That's a big difference. I think, Tom, is there something else that we should add to this? I mean, I think that's the big differentiator, and we believe that. We've shown this by the way in our data. Oh, yeah. That's why we are now entering the clinic, right? We have shown the mechanistic. You know, we have shown the specificity of binding. We've shown the mRNA levels. We've shown the protein levels. We've correlated that to tumor killing. Yeah. That's what we want to prove in the clinic now. Sure. Okay. Yeah, totally. Go ahead, Tom. Did you wanna add to it? No, I mean, just to, you know, amplify everything Mahesh said. I mean, Again, MYC was chosen as a, you know, the first target for, you know, a particular purpose, in part because it has so many pleiotropic functions in the cell. Yeah. In terms of cancer, overexpression of MYC, you know, drives a number of checkpoint. Sure. Factors in particular, you know, and tends to create an immunosuppressive environment in, you know, within the tumor, right? Mm-hmm. Which, you know, keeps the host defense immune response from really clearing tumors, which is, you know, it's one of its primary functions. By tunably down-regulating MYC, and we're generating data now that really bear this out, by tunably down-regulating MYC, but not completely shutting it off, you are, you know, down-regulating those checkpoint inhibitors. You know, theoretically, we should potentiate the action of a checkpoint mechanism. I see. Right? Okay. Sure. Yeah. Okay. Sure. Yeah. Okay. Sure. Yeah. We're also, you know, we believe reprogramming the tumor microenvironment to allow the sort of reintroduction of I see. you know, T and NK cells and things that would normally be acting to Mm-hmm. to help regress those tumors. There's kind of two mechanisms in actually that come into play. Yeah. Right? Right. Yeah, no, totally. Essentially, you know, like, first of all, throughout my career, I've always kind of like MYC has been that white whale, you know, in the background like of oncology companies trying to target. I'm like really excited about the opportunity and your approach for this. Yeah, then I guess what I kinda heard you say about that is that other approaches hit that mechanism, but they hit it really hard, and that causes toxicity issues with, you know, in normally healthy cells. Your approach, because it's so tunable, can only hit the cancer cells, at least from a metabolic and that kind of functioning perspective. Yeah. Yeah. Absolutely. How? We have data that we have published. Yeah. That actually shows that. Well, absolutely, and I've written about it, to be fair. I guess the other side of it is that how do you deliver this, and is there a way that that's targeted in some way? If you wanna go for it. Yeah, absolutely. Just as we're sort of conferring genomic specificity by virtue of the DNA binding domain. Yeah. We're ensuring tissue and cell type specificity by virtue of the LNP. Okay. These are. The lipid nanoparticles. These are liquid, lipid nanoparticles. Yeah. you know, selected and optimized, you know, for specific tropism, in this case, to the liver, in particular. you know, what that allows us to do is an added layer of specificity, which concentrates most of the dose in the liver, which is where you want it to be, minimizes your, you know, systemic, exposure and therefore any concern about sort of off, you know, off target or off tissue, safety from that perspective. Mm-hmm. Okay. All right, sure. Now we're at like we got this all together, you know, the platform that it's tunable. We have this great target that is unique to your approach and I think certainly very valuable from a market opportunity perspective. Tell us about the clinical trial that just got going. Yeah. You know, as we have said, we'll be enrolling patients starting, you know, Q4, right? Mm-hmm. that work is ongoing. Awesome. Obviously we have to. You know, because this is our first clinical trial, we are doing it with exquisite care and. Yeah. You know, it's a read-through to the platform. Although MYC is our first program, remember, MYC is not the only target and oncology is not the only area. We wanna make sure. That's one thing. You know, coming to the clinical trial, you know, it's a phase 1/2 study, right? Right. We'll be looking at, you know, PK/PD, you know, tolerability, and eventually a level of activity in, you know, monotherapy, as well as eventually in combination therapy, right? Right. you know, we'll obviously, you know, in the first part of the study start with monotherapy. You know, it's an all-comer study. All-comer is solid tumors, right? Okay. At some point we'll enrich it with hepatocellular carcinoma patients. I see. Which kind of makes sense, right? Okay. To really study this really well. Sure. We have, you know, a very well laid out, you know, translational plan as well. Okay. Right? At the right time, at the right dosing, we will also, you know, go into the part two of the study, which will be combinations. You know, our combinations, as we have laid out, are gonna be with all sorts of standard of care, right? Right. Targeted therapies as well as checkpoint inhibitors. It's a global trial. Okay. It's being run simultaneously in the United States, Europe, and Asia. Mm-hmm. That's really how we are running the study. Awesome. You know, taking exquisite care to make sure that we study all parameters of these patients, not only for the hepatocellular carcinoma, but also it gives a really good read-through to the rest of the platform. Yeah. Totally. I guess I do wanna get to the rest of the platform and the other opportunities to make sure that everyone appreciates that, but specifically on the trial, I guess what is your perception of the regulator's view of safety? Like, do you have to start low and like, you know, really ramp up the dosing? I guess, what can you tell us about that? Yeah, I mean, I think, look, we have a, you know, as you can imagine, you know, definitely a dose escalation and, you know, eventually. We know we've had discussions with FDA. Yeah. It's been cleared for it. You know, we have discussed all of this. We know kind of where the efficacious dose will come from, right? Okay. We are pretty confident about where it will be. Yeah. We are just sort of taking our time to make sure that, you know, this is the first time this modality. That's what I was saying. Is being tried and tested. Yeah, totally. In human- Right. In patients, right? We owe it to the patients and ourselves. Yeah. To make sure that we take the right steps. Right. To really understand it. Because look, you know, you asked about safety and toxicity, right? If you think about, you know, this is a very well-characterized lipid nanoparticle that we're using. Mm-hmm. Lipid nanoparticle in the liver has been in the clinic. There's also already one approval, right? Yeah. With the LNP, liver targeting LNP with Onpattro, right? This is understood. You know, the one thing about our approach is that just given our modality and what we do, right? Most of the toxicity we expect or safety will eventually come from the lipid nanoparticle. I see. Because from a, you know, OEC standpoint. Yeah. What you're doing is you're laying epigenetic marks, and we are looking for off-target, if people think that that creates safety issues. We have designed it such that that is not an issue. I see. We have control follow-up, right? Sure. Sure. Sure. I think that's one of the things that we need to just make sure. Check the box on, yeah. That we check the box on that, you know, everything is going well, well-tolerated. I mean, like we Yeah. You know, we should responsibly as a. Right. Company that is introducing, excuse me, a new class for the first time. I mean, I wanted to just maybe highlight that all the preclinical data. Yeah. That you've had thus far, including non-human primates. Mm-hmm. I believe has been incredibly clean. Like, there's nothing that I'm worried about. Yeah. Just to be clear. Yeah. Tom, you wanna comment on that? Yeah. No, I would second that, right. We sort of characterized this extensively. Yeah. Sort of lower species. As you said, we published some of the primate data for that and, you know, we feel very comfortable with the safety profile. Yeah. Okay. We have published that. We have seen nice dose response. Yeah. In NHP, you know, in the rodents. You know, we see great efficacy at very, very low doses. I think we are pretty optimistic about, you know, how this will work. We need to make sure. Prudence is there. Exactly. Yeah. Got it. Prudence has to be there. Yeah, totally. You know, obviously the study's just getting started, but are you willing to say when we might learn a little data from the trial? Honestly, I think, look, you can think about it by induction, right? Okay. I mean, I think it takes a certain amount of time, you know. I'm sure sometime in 2023. We haven't. One of the things that we are doing right now is, you know, articulating. We have to articulate the strategy externally in terms of how we will talk about our data. Mm-hmm. Right? We haven't just done that yet. Okay. I'm sure, Chris, we'll be talking to you. I- You know, as soon as that is done. I'm ready. Yeah. Absolutely. Right. That's kind of where we are. Okay. You know, I'm sure there will be a preponderance of data that's gonna roll over time. We just need to figure out how to actually communicate that. That's fair. All right. Well, obviously we're all looking forward to that, and the initial clinical trial data. What about the other programs you have going on? We only have a few more minutes. Mm-hmm. you know, what are you excited about, I guess, Mahesh? Yeah. What might be next or whatever you wanna highlight, I guess? Look, we are super excited about what's coming next. We have said that, you know, we will be, you know, talking about development candidates soon, right? Mm-hmm. You know, our programs. I mean, if you see our pipeline, the next leading- That's what I was gonna say, I mean, like. Exactly. The next leading programs, right? There are a couple in lung. Mm-hmm. There's one in liver. Alopecia. Alopecia, right? Exactly. You know, it's a very exciting pipeline and, you know, we will be talking about development candidates soon. Okay. Taking them to our IND enabling work. All I can say right now is, look, first and foremost, I think we have proven in preclinical models that this biology and the platform works in completely uncorrelated areas. Yeah. You know, in HNF4α, where we are literally, you know, simplistically speaking, regenerating liver function or, you know, restoring liver function. Yeah. Right? We've, you know, our preclinical models show that, I mean, in mice that were under constant, you know, liver insult. You know, we've seen great data in alopecia. We've seen great data in, you know, MYC for a non-small cell lung cancer that we have actually published on as well. Yep. You know, it's gonna be out of this, and it's a pretty exciting pipeline. Awesome. Okay. Yeah. Maybe we'll just get through the standard Wall Street questions then. What about your cash position? Yeah. What have you said about runway? Yeah. The last disclosure, we talked about our cash, you know, I think it was in June. We, you know, had $174 million- Okay. On our balance sheet. Okay. Pretty healthy balance sheet. I was gonna say. Exactly. Feels good right now, right? Feels very good right now. Yeah. You know, with the guidance we have given is 12+ months. That's the standard guidance we will always give. Okay. Right? You know, the important thing is we have enough money to last us through all our inflection points that are gonna come, and we feel very, very confident about, you know, about our cash position. Excellent. All right. Maybe just one last question from me is that, what are the things that we should all be paying attention to over the next year from your company? We got the clinical trial. Anyway, go ahead. Tell me what to look out for. Yeah. I mean, definitely the clinical trial, right? I think, you know, as a young company, we initially laid out our milestones in terms of declaring development candidates, you know, IND filing, et cetera. We won't do that going forward. You know, one thing that I would like to make sure that, you know, people take away is that we have delivered on every operational milestone. Yeah. That we set very early on. Okay. Right? The company's executionally doing really well. We have lots of inflection points, right? We'll be publishing data, not only in MYC hepatocellular carcinoma, but in the other programs that go forward. Right. Lots of excitement. You know, it's a platform, and I think now we are at a point where it is really getting interesting, right? Right. It takes a little bit of time for platform companies to sort of create a groundswell. We believe that we are at the cusp of that groundswell now. Yeah. You know, I think we take that forward. Totally. Well, it feels really exciting to me too. We were chit-chatting in the hall, and it feels really exciting to you guys too. Yes. So- Absolutely. Well, this is awesome. Tom, Mahesh, thank you so much for joining us today. Thanks everyone else for joining us as well. Yeah. Thank you everyone for attending. Thanks, Chris. Chris, as always, thank you very much, and thanks to you and Jefferies for inviting us to this conference. My pleasure. Thanks, everybody.