It's my pleasure to introduce our next guest from Omega Therapeutics, CEO Mahesh Karande and CSO Tom McCauley. To start out, Mahesh, can you provide a couple minutes of overview for folks who are new to the Omega story? Yeah, absolutely, Keay. Thank you very much for having us here, Tom and I. Thanks, Rishad. What I'll do is I'll present just a couple of slides just to set sort of the tone and to talk a little bit about the company, and then, I'm sure we'll get into a great discussion. I'm Mahesh Karande, President and CEO of Omega Therapeutics, and what we are really doing is pioneering a completely new platform called Epigenomic Programming for Precision Genomic Control. If you think about our platform in short, essentially there are four pillars to our platform. The first pillar is really grounded in biology. What we did was we took biology that was delineated in 2016 that was the basis of formation of our company where you know Flagship and Rick Young from Whitehead you know really laid out the organization of the genome genes and their regulatory elements. They sit in these three-dimensional structures of folds of chromatin called what we call Insulated Genomic Domains and they act as fundamental regulators of the human genome in terms of gene- expression as well as cellular- programming. We have delineated all of that. There are about 15,000 of these across you know the human genome that encompass every gene ubiquitous in every cell of the body across the 23 chromosomes. This is a very highly conserved organization that is conserved across mammalian species. You see obviously different, you know, genes in some different locations when you go to lower order species, but between non-human primates and humans, the conservation's almost intact. You can have, you know, different sequences in these species other than non-human primates and humans. What we have done is we have delineated these IGDs and these sequences which essentially correlate with regulators that control genes. If you think about what nature does is it creates, modifies epigenetic marks at these regulators so as to tune genes. That's precisely what we do, right? Now, how do we do that? We do that with our first-in-class therapeutic called epigenomic controllers or Omega Epigenomic Controllers. These are mRNA therapeutics. This is the first systematic use of mRNA therapeutics as programmable epigenetic medicines. The way we do this is the mRNA, you know, goes through the ribosomal machinery, homes into the genome, and at the pre-specified mark, it expresses two proteins. One of them is a DNA-binding domain. That is our own bespoke DNA-binding domain that targets that location or that EpiZip, epigenomic zip code with high specificity, and then creates an epigenetic mark or creates an epigenetic change with the other protein which it expresses, which is an epigenomic effector. That literally tunes genes to the right level of tunability because if you think about disease occurs because of genes being over or underexpressed. If you bring them back to right level of expression, you treat and cure disease. We engineer in that tunability as well as the durability of action. That's the second part. The third part is obviously delivery. We are delivery agnostic as such, but we are going with lipid nanoparticles. mRNA and LNPs together is a biotech modality that is in more patients today than all other biotech modalities combined. We feel pretty good about that. At the base of the company, we really have a very strong AI ML platform, all the way from understanding the biology, going through vast amount of data, to actually developing our therapeutics, engineering them, and we are able to get to therapeutics in as short as three to six weeks and then start testing them. Our pipeline is exceptionally broad, and our leading program, OTX-2002, in hepatocellular carcinoma, is slated to enter the clinic any moment. You know, we only got cleared by FDA in July. You know, you can see the breadth and depth of our pipeline, and that indicates that this is an exceptionally broad platform that can be used in various therapeutic areas. One slide I'll show you is, I think, anyway, this shows sort of, you know, the central dogma. If you see those chevrons on top, it's DNA getting transcribed to RNA getting translated to protein. You know, all the different therapies that have been used in these areas. What we are doing is instead of going after the protein, RNA or DNA and making changes to the DNA or, you know, not being able to work in all therapeutic areas like RNA therapeutics can, for example, in oncology, and, you know, literally no specificity when it comes to small molecules or large molecules, we are able to go to the epigenome and really leverage nature's endogenous mechanism of leveraging the epigenome to tune genes back to the right expression. That's really our platform. I'll just pause here, and you know, I'm sure we can have a great discussion on this. Well, great. I mean, well, since you just came out of our panel discussion where we had another epigenetic-focused company, Chroma, plus there's others coming out of stealth mode because of the potential, how would you describe yourselves as being differentiated from those other initiatives? Yeah. Look, I mean, I think, you know, we are not a hundred percent fully familiar with all of these companies. I think the field is expanding, which is a good thing, right? What we are doing is, you know, we have looked at biology in its very fundamental sense, right? What we did was understanding the organization of genes and their regulatory elements and folding of these genes and regulatory elements was absolutely critical. Because, look, there have been attempts to go and, you know, hit promoters of genes or do something epigenetically with transcription factors, you know, with small molecules, right? Which have yielded results. What we are doing is we are literally looking at how nature regulates genes through these Insulated Genomic Domains and getting a control of these Insulated Genomic Domains, and we have, you know, tremendous amount of IP around this, right? These are the fundamental regulators of gene- expression, and we can bring all sorts of epigenetic mechanisms to bear on getting the single or multiple genes, you know, back to sort of a normal range of expression pre-transcriptionally. We do that by, you know, essentially correcting where nature went wrong. If you think about disease occurs because genes get over- or under-expressed. That means nature's program is not working. We go and rewrite that program, but now we have the whole armamentarium that nature uses to sort of rewrite that program and tune genes. What we do is we engineer in a property of tunability that, you know, if you want to bring it up or down by x% to bring it back to the normal range for a certain duration of action, which is disease dependent. You know, for an acute condition versus a chronic condition and anything in between, like oncology. We can engineer these therapeutics. One last point is, you know, our therapeutics, the epigenomic controllers, these are transiently expressed, right? mRNA dissipates within, I think, you know, less than a day. The proteins that are expressed at the genome level or the epigenome level, right, do their work and are, again, degraded, you know, by normal degradation processes within a couple of days. The effect that we engineered in stays for the duration that we engineered in for. That's the beauty. Imagine you're taking a drug in oncology once every 2 weeks, right? The effect stays as opposed to, you know, 800 milligram, you know, dosing every day that the drug needs to be resident, hitting every transcription factor of that gene, you know, ubiquitously everywhere. I think it's a pretty exciting platform from that standpoint. Okay. You touched on the fact that your lead is, it's cleared to go into the clinic. You can have dosing this quarter. Tom, maybe describe the design of the study, and then we'll talk a little bit more in detail about what we hope to see. Go ahead, Tom. Happy to. There's a part one and a part two. In the first part of the study, we'll be looking at a dose escalation, as would be typical sort of traditional design, where we'll be, you know, escalating to a recommended dose for expansion. At that point, we would expand that in part one into a cohort enriched for HCC patients in particular. In part two, we would look at combinations with both of the sort of predominant standard of care modalities, both kinase inhibitors as well as checkpoint inhibitors, to look at combination efficacy in that setting. Just given the epidemiology of HCC, we'll be, you know, planning to open sites in the U.S., Europe, and certainly in Asia, as well. You presented a couple of times this year some preclinical data for HCC. Maybe highlight the key findings and then how we hope to see this translate into the first in-human study. Go ahead, Tom. Yeah, sure. No, that's right. We've been pretty active in terms of presentation and publication this year at AACR and ASGCT and GCT and more recently at ESMO. I mean, what we've shown and we'll continue to sort of put out there in various forms is really the mechanism of action and why we think this, you know, our approach to pre-transcriptionally targeting MYC should really be effective where, you know, a number of approaches previously targeting, you know, as Mahesh alluded to, the, you know, at the protein or mRNA levels, you know, have not been successful previously. We're starting from our approach, you know, MYC sits in an Insulated Genomic Domain that's very large, about 2 megabases, by itself, which is dysregulated differently in different cancers. It's obviously, you know, in itself is a very promising drug target people have been interested in for a time. Our approach to this really was first to interrogate that Insulated Genomic Domain and understand the nature of dysregulation of the MYC oncogene in the context of HCC, and then to design our Omega Epigenomic Controller to target a couple of different points on that Insulated Genomic Domain to very, you know, tunably, you know, in a measured way, turn down MYC expression for a, you know, a prescribed period of time, in order to, you know, regress cancer cells. You mentioned the flexibility to address multiple points. For HCC, how much impact do you think just changing the boundaries of the IGD, which is obviously one of your objectives, versus perhaps affecting the effect of the other cis-regulatory elements, is gonna have on the effect you hope to see? I mean, we've not gone into, you know, explicit detail in terms of exactly what the effectors are. Certainly in terms of the, you know, I can say in general and in this case, we do see a significant, you know, profound effect from targeting the loop anchors as well as you said, the other regulatory elements inside the cell. We've certainly in designing the molecule in silico and then, you know, in practice and testing, you know, we've shown the contribution of both elements, you know, in terms of targeting to the ultimate downregulation, both in terms of degree of downregulation, but also, as Mahesh said, we engineered durability, specific durability into it by virtue of the mechanisms of those epigenomic effectors. This is actually an important question, right? Because look, I think, you know, if you think about drugs being developed, I mean, you know, you develop a drug for a particular type of cancer targeting MYC, right? Then you start expanding that to other cancers. That's typically how, you know, drug development has occurred. We have now at our disposal an understanding of biology and epigenetics, particularly in this case, and you know, since we're talking about MYC, where we know how the MYC IGD is dysregulated in different types of cancer. We can actually create medicines that will target that particular kind of cancer with better precision than just having one drug that fits all. Now, we can go with one drug that fits all in this situation or other situations as well, and we really take it, you know, case by case as to how we do it, right? For example, with MYC in different types of cancers, you know, epigenetic changes happen which changes the structure of this IGD. We are able to restore it back to pristine, you know, just to keep it very simple, to pristine levels, and that's how we actually treat disease, right? We could potentially have different drugs for different types of cancers when it comes to MYC, and that's why we talk about Precision Genomic Control. It's, it's precise and tailored to the disease. It's not tailored to the patient, necessarily. It's not precision medicine in terms of personalized medicine to patients. It's personalized to the disease, and that's the power that actually we have, you know, in this platform. Actually, if I could just add to that too. I mean, one of the things, you know, Mahesh alluded to it when he was discussing the platform slide here, but, you know, it's. We use this, you know, we've built over the last. You know, we were founded in 2017. As Mahesh said, we really took the time to understand the foundational biology and to choose our tools carefully and also to invest in areas that were gonna be critical to us, like computational genomics and sort of machine learning and artificial intelligence, which sort of underpins everything that we do. From the very beginning, the interrogation of how the IGD functions to design of the molecule to your question before, you know, algorithms that will allow us to predict the effect of perturbation of either regulatory element or loop anchor or something really allows us to accelerate this development process. You know, to go from target ideation and target concept validation and then design and testing of suites of molecules in a really very short time. 27 months, by the way. Yes. IND clearance from scratch. Since it's an open label study, is it reasonable for us to expect that we'll see some data from it reported in 2023? You know, it's I mean, to be very, very blunt on that, we are still, you know, in the process of figuring out how we will disseminate the data. It's funny. Today's market conditions, you know, Keay, I mean, I saw some slides, you know, from one of your competitors, Torreya, which basically showed no matter how great your data is, you're basically getting hit on presenting data. I mean, jokes aside, right? I think, look, you know, as we treat patients and get data, we will have an approach and a strategy, and we will actually put out data, you know, in a compelling manner. Because think about it, right? We are doing this. This is absolutely pioneering. Nobody has done this before. This is biology that nobody has tackled, and we have come up with a pretty elegant, simple solution that is now entering the clinic. We owe it to ourselves and patients and just the platform and its breadth to do this really well, and we will disseminate data appropriately. Okay. We also saw some preclinical data from non-small cell lung this year. What's the plan to disseminate additional preclinical data for either that program or your other pipeline programs? Yeah. Look, I mean, I think you will see. You know, with a company like ours and what Tom said, right? We took our time to make sure that, you know, we really built out the platform and our systems really well. You've seen our pipeline, right? Which is a very broad pipeline. I mean, you see, you know, the chevrons there, right? There are multiple programs that we are prosecuting on. As appropriate over, you know, as we have done with hepatocellular carcinoma as well as non-small cell lung cancer, as appropriate now over, you know, the course of time, at the right conferences, we will be definitely disseminating more data. Okay. You can see, you know. Yeah. more data coming out in some of our programs over time. Okay. Well, great. We're certainly looking forward to that. Yeah. Since you have the pipeline slide up here, you know, for all companies as they go into the clinic, you know, there's always gonna be this trade-off, you know, trying to balance, okay, here's all the data we have and our confidence, and we wanna address, you know, a target that has, you know, some attractive attributes, you know, size of the market, competition, what have you. But at the same time, for your lead, you wanna be able to get early indications of proof of concept, proof that it's working. Help us understand those kind of trade-offs and how you are designing your pipeline. Yeah. All of those things go into our thinking now as the company's maturing, right? Initially, I mean, you know, we set up our pipeline in a way that we actually wanted to test the breadth and depth of our platform, right? Really understand that the biology. Demonstrate that the biology is pretty broad, works in various disease types. If you look at this pipeline, you know, we have proved this biology and have proof of principle in vivo data across four completely uncorrelated diseases. This works. That was actually the idea here, right? We chose this particular pipeline out of, you know, I don't know, about 20 different experiments that we had done that we could choose, and then we interrogated that for exactly, you know, the things that you're alluding to, which is, you know, market fit, which is, you know, unmet patient need. If you look at all of these, right? There's tremendous unmet medical need in all of these areas, right? If you look at, you know, CXCL1-8, you know, this is, you know, a chemokine cluster that is implicated in so many different conditions and diseases. What we have today are great drugs, right? Monoclonal antibodies that target a protein of one of those chemokines. Not all. We are able to target all four. You know, this is nature's operating system. Nature works these in tandem, right? If you target one of them, some of the others go up. This is the kind of stuff we are actually understanding out of this. That leads us to an unmet patient need or addressing an unmet patient need that maybe we haven't even completely understood or figured out. That's how the pipeline has been set up. As we go forward, you're right, we have to make trade-offs, you know, in terms of what goes further in the clinic, what is it that we, you know, continue developing, how do we add to the pipeline, you know, how do we actually do partnerships potentially to expand our pipeline? Those are the things. What do we keep internal? What do we keep external? All those things we will be working through. Yeah, I mean, the one thing I would add, too, is, you know, as a platform approach, everything that we learn in the context of our first development- program is, you know. Oh, absolutely. informs everything else that we do in terms of sort of making it more robust, you know, faster development. Exactly. Okay, great. Let me shift gears here a little bit. You know, yesterday we had John Maraganore on a panel, and he part of it, he discussed company culture. Mm-hmm how important that is and how important that was to this and is the success of Alnylam. When we look at a company like you folks, and you're really trying to do something really different, it really calls out for the fact that you need to have a culture that, you know, is really challenging the old dogma and needs to be set up to be able to be successful. Mm-hmm in this type of initiative. Mahesh, can you describe the culture that you've tried to establish at- Yeah ... Omega that can underpin Yeah success going forward? Look, this is a terrific question, and, you know, I couldn't agree more with John, right? At the end of the day, if you're on a pioneering journey, you have to be able to create a culture that nurtures that nurtures the people that come in, that they can actually do the stuff that you hired them to do, right? I mean, that's a fundamental premise. You know, what we have at Omega is we are governed by our ethos that we set up very early in 2019, a few months after I joined, and then Tom came on board, right? Our ethos is clearly defined. It's ambitious, yet humble. Let me explain that to you. Ambitious, because when you're on a journey like this, when you are, you know, solving problems that people didn't even know that you could solve, right? You need the highest- level of ambition, right? Because you're doing experiments, you're doing work that nobody has done before. You need the highest- level of ambition to succeed in a pioneering journey, right? At the same time, you need a huge- level of humility on different fronts. One is you're standing on shoulders of giants, right? That's how you're able to look further, like, you know, Sir Isaac Newton said. Appreciating that. Secondly, you know, we are developing these and earning the right now that we have earned to, you know, go and, you know, try them in clinical trials in patient. That's a huge. That's a tall order, right? You need to have that humility. What we did was we laid out this ethos, and then, you know, we worked, you know, in late 2019. It was a company of 25 people. Everybody worked on these, and we actually created our values and behaviors that go with it. Those have stood the test of time, and we have a very, you know, a very solid culture from that standpoint. I just wanna be very clear that it's not, you know it's not a cultish culture or anything like that, right? It's a very cool culture, but I would like Tom to address it because Tom came in as a CSO, and at this stage, obviously, you can imagine the largest number of people in the company actually reporting to Tom. You know, Tom has been able to deliver on this pipeline that we showed, right? Through his team. Tom, why don't you, like, talk about how that has engendered scientific, you know, inquiry? Yeah, no, thanks, Mahesh, really, you know, appreciative of the. It's emblazoned on the wall of our boardroom, "Ambitious yet humble," to continuously remind us that for everything we know, there are other things we don't know and that we have to learn, right? We are, as Mahesh said, we've had to sort of, you know, technically and scientifically, you know, through the regulatory process, earn the right to test these in humans, which will further inform, you know, how we develop drugs in the future. You know, we as far as our ethos and our core vision and corporate values, I mean, it starts from the very beginning, I mean, in terms of attracting top- talent. We, you know, we hire for those characteristics. We want people who are, you know, who are scientifically facile. You know, they're agile, they can think. I mean, the Epigenomic Programming is. As I think Mahesh used these words in the panel, it's really at the nexus, the confluence of many different scientific fields. It takes people with really disparate, you know, eclectic scientific and industrial training to really bring together to make it work in terms of molecular design, you know, experimental work, pharmacokinetic characterization, analytics, you know, testing, manufacturing, all of that, you know, regulatory and clinical development. You know, bringing in people who share that vision and nurturing it as we go and supporting it, as Mahesh said. I mean, it's, you know, we have found, and I think it's true in general in science, that you can't be bound by dogma if you really wanna move the fields forward. Yeah. That's, I think, that's been critical to our- Yeah. The word dogma is something that we have an allergic reaction to, right? Really. I mean, dogmatic thinking is really the bane of existence of companies like ours. Like we literally will, you know, as a CEO of the company, I can say dogmatic thinking is the one word, the one sort of, you know, behavior that, you know, I won't condone because that by itself limits you. Maybe briefly, what is it that you think that investors really need to understand to fully appreciate the Omega story? Yeah. Look, I mean, I think the investors really are current investors as well as investors that we talk to really understand the story. I mean, if you think about, you know, Omega's journey, right? You know, it was founded and started by Flagship Pioneering, right? Which is a big part of us even today. We appreciate that a lot because there's a tremendous amount of ecosystem that we can draw on, that's one. You know, in our crossover round, we were able to bring in 70 new investors, right? We had much more of a demand than ever before. This was in, you know, June of 2020. June of 2020, right? Yeah, exactly. No, sorry, in March of 2021. Then in July of 2021, when we went public, we had even more investors and all of our current investors invested. You know, we have had very few investors who have left us, right? So I think that speaks to the understanding. Now, translating into what people ask, you know, the question, and I'm sure it's on everybody's mind, to the stock price. Look, biotech stocks, right? You know, biotech sector has taken a beating. I think generally speaking, biotech, early-stage biotech companies like ourselves, now we are entering the clinic. If you think about over the last- year, where the stock market has taken a beating, the preclinical company with high- risk, you know, it's a longer- term sort of value generating company, which in the short- term, people have walked away from, right? You know, when you look at our stock price, et cetera, that's what it reflects. It reflects the market. I don't think there is any, and we're talking to investors, I don't think there's any concern about not understanding our story or what we are doing. People are eagerly waiting, so are we. How this behaves in the clinic, that will be the ultimate proof. Having said that, because of a broad pipeline, we will have other programs entering the clinic over time, right? I think that is important. We have de-risked it significantly, right? For an early-stage platform company is as de-risked as possible. Secondly, you know, we have hit every milestone that we have talked about hitting, right? We talked about submitting an IND, getting that IND cleared, we have done that. We're talking about development candidates, we are in the process of doing that. What investors appreciate is a team. If you look at our leadership team, it's a very strong operating leadership team that has operated in big companies and small companies, right, run businesses. At the end of the day, that's what you need. Investors, beyond the science, want teams that will deliver on what they commit, and that's what we have done. Okay. Well, thank you so much for joining us today. Okay. Thank you very much. Very welcome. Thank you. Definitely wanna follow up with you more. Thank you