Good morning, ladies and gentlemen. My name is Mitchell Kapoor. I'm a senior biotech analyst here at H.C. Wainwright. Today I'm joined by Mahesh Karande of Omega Therapeutics. We're gonna have a fireside chat with a few questions back and forth. First, I think, I'll just let Mahesh talk and present a few slides to get us going. Mahesh. Mitchell, thank you. Thank you very much for having me, and thank you to H.C. Wainwright to invite me and Omega Therapeutics to this conference. I thought it would be a good idea to just do a few setup slides, and then we can get into the discussion. Omega Therapeutics was founded in 2017 by Flagship Pioneering with the explicit intent of looking at epigenetics and really understanding, you know, what is nature's fundamental mechanism to control epigenetics, and how does nature do that? The question we asked ourselves is, if we could actually replicate that and control that and create a drug development platform, that would just be tremendous. That's precisely what we have done. Our platform is epigenomic programming for precision genomic control. The forward-looking statement. The platform really has, you know, four pillars to it. First and foremost, it's the biology, which is essentially, you know, the delineation of the genome and how the genome is organized. Genes and their regulatory elements sitting in these three-dimensional structures, folds of chromatin called Insulated Genomic Domains. This biology was really discovered in 2016, and the company was created in 2017. What we have done is we have looked at the entire genome. We understand all of these 15,000 IGDs that house genes, single or multiple, and their regulatory elements. Those regulatory elements control gene expression, as you can imagine. Activity is restricted only to those regulators that sit inside that IGD. If you think about it, IGD becomes a central control unit of gene regulation. What we have done is we have used these IGDs as drug targets, and we've delineated all of the genomic addresses. These loci within the IGDs are unique in the entire genome. You can target thousands and thousands of genomic loci very, very specifically. We call them EpiZips, epigenomic zip codes, and that's what we have done. The way we actually target them and then deliver, you know, an epigenetic program there is through our medicines, you know, which are first-in-class medicines called epigenomic controllers, Omega Epigenomic Controllers. These are mRNA therapeutics. This is the first systematic use of using mRNA therapeutics as programmable epigenetic medicines. You know, the mRNA goes in through the ribosomal machinery, homes into the genome, and at a 21 base pair, we attach a you know a DNA-binding domain that is our own proprietary DNA-binding domain. We lay an epigenetic mark or change an epigenetic mark or erase whatever epigenetic mechanism we wanna use. What we are able to do is, besides the specificity of targeting, we are able to engineer in a duration of you know how long that should act, as well as a tunability of the gene in terms of how much we need to tune the gene up or down by to bring it to normal expression. We do this pre-transcriptionally. Right? Third leg to the platform is really delivery. You know, we are as such delivery agnostic, but we're using lipid nanoparticles. Lipid nanoparticles have come a long way, you know, and we can target several tissues. You know, you'll be hearing more and more from Omega over time. That's what we are using. You know, mRNA and LNPs is a modality that is probably in more, you know, more patients today compared to any other biotech modality. The basis of our company is truly a digital AI ML company, that we use AI and ML as well as heavy recombinant genomics really to do everything that we talked about in terms of delineating the genome, in terms of prospectively designing these controllers and then actually testing them, you know, in silico before getting into in vitro. That whole process to design just takes us, you know, anywhere from three to six weeks. Look, we filed our first IND and got it cleared, and that took us, you know, a total of 27 months. We'll talk more about that. This is our pipeline. As you see, the first program is in c-Myc for hepatocellular carcinoma. I'm sure there's a lot of interest in c-Myc and, you know, hope to chat about that. Then you can see a very robust pipeline because the breadth and depth of the platform is just tremendous. I mean, there's a lot that we can do, and there's a lot that Omega can't do by ourselves. You know, we are going to declare a couple of development candidates and file another IND in 2023, as we have talked publicly. One last thing is, when you think of Omega as a company, on this slide you can see a bunch of iconic companies, right, that we all recognize, you know, since we were growing up to, you know, today, where companies have made a tremendous foray like Moderna. If you think about what's being shown here, this is the central dogma of biology. You see DNA that is getting transcribed to mRNA that's getting translated to protein. Interestingly, drug development has always occurred in the reverse order, right? You know, so small molecules, large molecules. Large molecules put Genentech on the map in the 1970s. You know, in the 2010s, you had the mRNA and the non-coding RNA companies, and they have had success, and they work in certain areas, right? Then over time, people moved even further up and said, "Well, why don't we take a shot at just modifying the DNA through gene editing or putting in transgenes, you know, that stay constitutively on?" These things work, and it's tremendous that there's been this level of progress. If you think about it, you know, you don't know what the collateral is when you edit. You know, if you put in a transgene, nothing in nature stays constitutively on. It's not using nature's intrinsic, you know, properties in terms of how nature controls genome. What we are doing is we are looking at the epigenome, and we have figured out what nature's operating system is. We have really co-opted that system, and wherever it goes awry. That's where disease occurs because genes get mal-expressed, either over or under expressed, and we correct them pre-transcriptionally, bring them back to whether you call it a normal level, homeostasis, whichever way you think about it, and that's precisely what we do. If you think about it, Omega has a tremendous breadth to its platform. I mean, we can pretty much, you know, resolve any disease, single, as well as multiple genes that we can control with a single therapeutic. That's the promise from Omega, and those are the few setup slides. Great. Mitchell, I'm ready for a discussion. Thank you so much, and this was wonderful. Could you just take us back a little bit and think about the broader landscape of the epigenetic space? There's so many ways to target the epigenome and control the epigenome. Can you just tell us how Omega stands out from the pack? Yeah, absolutely. Look, I mean, I think, you know, epigenetics has been sort of talked about for, you know, a good part of the last 40 years, right? People have really tried, you know, various ways to, you know, create epigenetic medicines. Look, there have been successes, but if you really think about it, you know, companies that have had successful products like Epizyme, for example, right? They have, you know, targeted transcription factors or proteins. Essentially, if you look at the central dogma, they're really playing all the way down there, right? You know, you can even look at mRNA and say, "Well, you know, I can target epigenetics through mRNA," and companies have tried that, right? What happens is either, right, you have a situation where you're targeting a protein and your drug stays resident in the system, you know, 400 milligrams BID, 800 milligrams a day, but you're not able to sop up all of the protein for some of these genes, especially in oncology, right? With mRNA as well, you know, people have taken an approach where, you know, genes auto-regulate because of which these approaches haven't really lived up to the promise. The way we have looked at epigenetics is we, you know, in 2016, a paper was published by Rick Young of Whitehead and his team, as well as, you know, Noubar Afeyan and David Berry were working on this at Flagship. You know, sort of the forces combined and what that paper in Cell, the seminal paper, really outlined, you know, this organization and filing system of the genome and how epigenome really controls that. What we have done, which is very, very different, we actually figured out that fundamental biology and then looked at what is the best technology to actually, you know, create a platform, right, and control genes pre-transcriptionally. If you think about in oncology, you know, because you control them pre-transcriptionally, and we are not an on or off switch like some of the editing companies that are taking an approach that could be, right? We literally tune the gene like a rheostat or a thermostat, right? And bring it back to normal expression while leaving residual expression that is required. Think about MYC or any other, you know, mega oncogene. MYC, you know, normal cells require MYC for normal functioning. If you shut it down completely, like other epigenetic companies might do because of small molecules or mRNA, they sop up everything, that's where the genes auto-regulate. That's the big difference of Omega. We are not a technology that's waiting for an answer. We actually looked at the biology and said, "This is the best technology to use to actually tackle this biology." That's the promise. That's very helpful, and it sounds like the fine-tuning is a key component of the Omega platform. Diving into the protein and c-Myc, could you talk to us about just c-Myc in general and why no other company has been able to target c-Myc? Mm-hmm. Yeah. You know, how you're leveraging your platform to do that. Yeah, no, absolutely. That's a great question. Look, c-Myc is, you know, and it's probably not a debatable point. It's considered the Holy Grail gene in oncology. The reason it's considered Holy Grail is because it's implicated in over 50% of solid tumors and pretty much 100% of metastatic cancers, right? It controls several genes in this cascade. It's a major gene that is required for a lot of metabolic functions, right? You know, people have tried to target the c-Myc gene, you know, its protein. The challenge with that, it lacks a binding pocket, so it's not the most easiest gene to actually target using, you know, small molecules or large molecules. There have been attempts, you know, to use non-coding RNAs like siRNA. You know, like I said earlier, what happens is with this gene particularly, and others as well, you know, but we have studied this one, which is these genes auto-regulate. The minute it sees that its protein or its mRNA is under attack, it auto-regulates and cranks out more. So think of it as a garden hose, right? You have a garden hose with a spigot that is turned on full, and the garden hose has a few leaks in it, and the water's coming off at the end, right? If you think of small molecules, they try to sop up that water. You think of siRNA or non-coding RNAs, they try to put patches on the garden hose, right? What this does is, you know, that doesn't actually absorb, you know, that system of the pressure. In fact, the pressure goes more and more, right? At some point, the whole system loses integrity. What we do is we just come and turn the pressure down a little bit, right? That's why we think we'll be successful. Look, you know, our preclinical data, you know, in mice as well as in non-human primates has actually demonstrated that we demonstrated the mechanistic part of our platform as well as tumor killing through both intrinsic and extrinsic mechanisms. We also believe that because we are able to bring MYC down and leave residual, the normal cells, you know, function, whereas MYC is also a potentiator of checkpoints. What we are able to do is we essentially are able to bring in sort of the extrinsic mechanism to work. You know, if you think about sort of, you know, the tumor killing activity that, you know, turning cold tumors hot, basically, right? The tumor killing activity, that mechanism is completely shut down. We open that up. We do apoptosis as well as these, you know, allow for the intrinsic mechanisms to sort of, you know, come in. Okay. Great. Thank you. Could we just talk a little bit about your clinical programs and the MYCHELANGELO trial that you're conducting and kind of the setup, the tumor types? Yeah. You know, what are we looking for there? Yeah. On that trial? Yeah, no, look, we are super excited that, you know, we submitted for an IND, and within 30 days, the FDA accepted. We feel pretty good about it. Now, you know, in the fourth quarter, we'll be dosing our first patient. This is a MYCHELANGELO program, and MYCHELANGELO I is our phase I/phase II study, right? We are gonna look at, obviously, safety, some signals of efficacy, as you can imagine. This is a classic 3+3, and what we are doing is, you know, initially looking at monotherapy, and we'll be looking at, you know, a host of MYC-related tumors, right? Then we will enrich for hepatocellular carcinoma, and we'll obviously, you know, get to the right dose. We are gonna do this very carefully. I mean, we kind of have a very good idea of where this is gonna land, as you can imagine, but this is the first program in the platform, first clinical trial, so we are doing it very carefully. We are gonna study biomarkers, really understand the MYC biology, understand the mechanistic nature of our platform, right? at some point, we are gonna actually go into combinations. again, we are combination agnostic, so we will be, you know, this is a global clinical trial, 190 patients, you know, US, Europe, Asia, and we are gonna go with the standard of care combination. think about TKIs as well as checkpoint inhibitors. you know, our hope eventually is that we see good activity, you know, in monotherapy as well as in combination therapy, which we have demonstrated already preclinically, right? Even in non-human primates. That's really in short what the trial is gonna be. You know, hopefully, we get good readouts in terms of, you know, exactly what we're looking for and then are able to move the program forward. Yeah, absolutely. Could you give us a little context on maybe that readout whenever it comes to the extent that you could comment on when that could be or what we're, you know, looking for in terms of what would be positive and meaningful? Yeah. You know, would you correlate with any biomarkers like c-Myc or anything of that nature? Yeah. We have a very rich biomarker plan, you know, and a very rich translational plan in the program. You know, it's all on ClinicalTrials.gov. I think, you know, ClinicalTrials.gov that we can, you know, go and look. Look, at the end of the day, right, we haven't sort of decided yet, and we haven't disclosed when exactly we'll be disclosing data, but if you think just by induction, right, we are starting the clinical trial in quarter four, and, you know, data will start rolling out obviously in, you know, in 2023. You know, we'll really look at that and decide how that actually needs to be disseminated to make sense of it, right? We are still working through those plans. Sure. Those strategies, and at some point we'll be, you know, telling everybody how we're gonna do that. Great. Okay. Then, you know, thinking about what we have today to kind of de-risk, you know, the clinical efficacy and safety profile and how the preclinical data. Yeah. Could translate into the clinic, can you just talk a little bit about that? Yeah. I mean, look, you know, we have obviously conducted, you know, an immense amount of preclinical work, you know, as you can imagine. You know, and earlier, at a couple of conferences, we presented data in rodents. Then at ESMO GI, we actually presented data in non-human primates where you saw tumor killing, but even good efficacy readouts. We also showed a complete mechanism. We have actually shown epigenetic downregulation of, you know, MYC, the mRNA going down, you know, in terms of the proteins getting, you know, created and going down. I mean, the proteins, our proteins getting created in terms of the epigenetic effectors and then, the MYC expression going down and then correlating that to tumor killing. We also have shown combination data, right? With, TKIs as well as, you know, some of it is not obviously in the public, but we have tremendous combination data even with checkpoint inhibitors. That preponderance of data has been our package to the FDA, and FDA has actually, you know, given us the green light to proceed with the clinical trial. We have a very robust preclinical package that, you know, we have seen really good signals in monotherapy as well as in a combination and, you know, obviously it needs to be proven out in the clinic, right? That's what we're going to do now. Absolutely. You know, when we get that validation, what does that mean for your pipeline? Yeah. What does that translate into for other targets that you might be going after? Yeah. Look, that's a great question because, you know, as opposed to, you know, many sort of, you know, many initiatives that we have in the biotech world, right? Where, you know, you take one program and sort of just run it through to completion, and then you have maybe a second program that is completely uncorrelated that you run through. We are truly a platform company. If you look at our pipeline, you know, and if you look at what we have actually demonstrated with, you know, a few programs heading towards IND, right? And if you think about what those programs are, there's one in regenerative medicine with HNF4α. There's one where we are going after chemokines, which is a, you know, a loop with four different chemokines that we are actually bringing down, you know, the expression of with one single therapeutic. There's a SFRP1 program, which is for alopecia, all forms, as well as, you know, a second program in c-Myc for non-small cell lung cancer, right? If you think about what we have been able to do, we have been able to prove the platform preclinically in four completely uncorrelated areas. Where I'm getting at with this is that this is fundamental biology that works, right? This is a biology platform that, you know, we have demonstrated that works. You know, in a platform company like ours, there's tremendous read-throughs that you get for everything that you do. You know, it reads through to all the other programs. Look, you know, I talked about the AI ML base that we have, right? We have an incredible way of codifying our learnings and applying it to the next platform. You know, from a timeline standpoint, right, from the day we start looking into an IGD and, you know, interrogating that IGD for a particular disease type to getting to, you know, development candidates that are optimized takes us, you know, about six to nine months. Then IND enabling work and then, you know, getting it approved. If you think about MYC, it has taken us. You know, we started working on it in earnest in middle of 2020. January of 2021 we declared it development candidate. June of 2022 we filed for an IND. July we got it cleared, right? This is a prospective platform. This is not a high throughput screening that we do. We look at the IGD, we design the Omega Epigenomic Controller, and then we sort of test it. All those read-throughs basically will get through and sort of apply to all of the platform. That's what we're hoping for. The you know, one program applies to everything as a platform company. Does that answer your question? Does that make sense? Absolutely, yeah. It sounds like there's a lot of read-through between the programs, so that's very helpful. Maybe in our last few moments, we could just tie it back, talk about, you know, the upcoming milestones and catalysts for Omega. Also, you know, just highlight the cash position that you have to- Mm-hmm to carry out all of these initiatives. Yeah. Look, I think from a catalyst standpoint, and you see them on this slide, right? We've talked about, you know, getting another couple of development candidates ready and talking about it this year, right? Look, as an early-stage company, right? Over time, we won't be talking about these kinds of, you know, milestones. As an early-stage company that went public last year, we wanted to make sure that people understand and investors understand and everybody understands that the management team is delivering on the commitments, and that's exactly what we've been doing, right? We have a couple of DCs, and then in 2023 we'll be filing another IND, right? That's what we have committed to. These are some milestones. Of course, as we prosecute the clinical program, there will be, you know, I'm sure interesting data like we talked about, we haven't decided when actually to talk about it, but those milestones will be coming. The other thing is, look, I mean, I think, you know, a platform this broad and now that we have some good validation in entering the clinic, right, we cannot prosecute all of this on our own. We are definitely gonna look and we, you know, will be talking and are talking to partners to do potential transactions, you know, which is a part of our strategy. Without saying anything more of that, right, I mean, I think you just have to imagine that there is no way, you know, that Omega can actually deliver this promise alone, right? We are a young company of 120 people and, you know, our cash position right now is very solid. We have, you know, in June, in the last filing, we talked about over $174 million. You know, the guidance we give is always 12 months plus. That doesn't mean it's 12 months. You know, it could be anything more than that, but that's. We feel very, very comfortable with our cash position. Then we have some really solid investors backing us, right? Considering the cash we have, investors backing us, the market turning as well as, you know, BD deals, I think we are in a very formidable position to continue work on this platform. Great. Thank you so much. Thank you everyone for joining us, and thank you, Mahesh and Shailen. Thank you. Thank you. Really appreciate it. Thank you very much. Thank you, everyone.