It's my pleasure to introduce our next guest from Omega Therapeutics, President and Chief Executive Officer, Mahesh Karande. The format for this session is a roughly 25-minute fireside chat. If any of our audience attendees have questions during the session, feel free to type them into the question box under the video player, and we'll try to ask them on your behalf. Mahesh, welcome. Thank you, Keay. How are you? Great. Well, Mahesh, to start, could you provide a couple of minutes of introductory comments on Omega for investors new to the story? Yeah, absolutely. First of all, thanks a lot to you, Keay, and Chardan for the invitation. Very happy to give a very quick overview on the Omega story. I'll just use a couple of slides so that people can follow through much easier. Look, Omega Therapeutics was founded by Flagship in 2017 with the explicit purpose to harness the power of epigenetics. As we know, epigenetics is really nature's fundamental mechanism for gene control and cell differentiation. The question that we asked ourselves is, what if epigenetics worked through a universal operating system? Because nature very rarely does anything in ones or twos, right? What if we could drug that system and therapeutically intervene to control gene expression? As it turns out, nature actually has organized genes and their regulatory elements in these conserved 3D structures called insulated genomic domains, which act as the fundamental units of gene control. Within these IGDs, which we use as drug targets, there are several thousand across the 15,000 IGDs, several thousand very specific DNA sequences that we can target that are associated with the regulatory elements, as well as the binding CTCF sites, which allow us to control genes. That's what we've done, and that's really what nature uses in terms of controlling genes by laying epigenetic marks at these sites. What happens is, sometimes when nature goes awry, disease happens because of these IGDs experience a structural functional change. What we have done is, armed with this knowledge, really created the Omega Epigenomic Programming platform to co-opt nature's operating system. What Omega's platform simply does is we are designed to write epigenomic programs to correct single or multiple gene expressions, and that's where nature goes awry. Irrespective of etiology, diseases caused by a mal-expression of genes, and we correct genes to bring them to the right biological expression, and we do that with epigenomic controllers as programmable mRNA therapeutics. We are able to program in, engineer in specificity of targeting, where we can be as specific as 21 base pairs, controlled tunability, we are able to tune the gene up to the right level of expression. It's not a zero or 100 like editing would do, for example. We can actually tune it up or down, as well as engineer in a durability of effect, which is from an acute condition to a chronic condition, from a few days of action to few weeks to few months, right? We do all of this without changing nucleic acid sequence. If you really think what we are doing is we are delivering epigenetic marks to the genome to tune genes as opposed to delivering anything that goes and changes the nucleic acid sequences. Just to put it in context then, when you think of all of these iconic companies and where Omega can fit, essentially, you see that because we act on the epigenome and use true epigenetics to control what is the central dogma of biology, by definition, it allows us unprecedented breadth in disease control. That's how we have set up with eight different programs in different disease areas. I'll stop here and see if that suffices, and if you have any questions on that. Well, I guess the first question is, you've done all this work to try to understand the structure of the IGDs and 15,000 of them. What's important is going to be how do you distinguish the structure between a normally set up IGD and how it works to facilitate gene activation and repression, expression, compared to a structure that's been perturbed in some way, so that the anchor CTCFs are mismatched from where they normally would be. How well understood is the normal, the wild type, if you will, versus the diseased? Yeah. That's a great question, Keay. Look, I think we have, over the course of 4.5 years since the formation of the company, really delineated these 15,000 IGDs. We have a very strong computational and AI base to our company. We understand these IGDs like the back of our hands. To use these IGDs as drug targets, fundamental premise and what we realized is when disease occurs, other than bacterial or viral infections, direct bacterial or viral infections, most disease occurs because of dysregulation of gene expression. That in turn happens because of dysregulation, which is either structural in nature or functional in nature in the IGDs, right? If you are able to then compare the pristine IGD to a diseased IGD, you know where actually you can act and what you need to correct. For example, in certain conditions, particularly in oncology, which happens to be a poster child for epigenetics, what happens is the IGDs undergo a structural change where many times oncogenes get expressed because they come under the control of a super-enhancer, which was potentially sitting outside the IGD. Because of an erroneous CTCF sort of binding, which is not normal, it gets recruited, let's say, into the IGD, thereby comes under sort of the regulatory action of that CTCF and that IGD, and thereby expresses that oncogene, right? In that case, we can go and correct it by opening up that CTCF site and then actually allowing it to naturally bind to the spot where it has the highest natural proclivity, and that's how you treat disease. That's structure, right? This is just one example. From a functional standpoint, imagine in the age of COVID, we know about ARDS that happens, and that happens because of the overexpression of cytokines, right? What if you had an IGD with cytokine genes in there, right? Because of a viral insult, those genes got overexpressed, and we can actually go back and fix those and bring those back into normal expression. There, it's a functional dysregulation that happened. The structure by itself doesn't change, but because you understand disease biology, you can go and bring that expression back to a normal range. That's really how we go about doing this, through computational genomics upfront, really figuring this out, and then empirically testing it, and then actually getting to operative controllers. Yeah, and I think people want to understand the specificity or the affinity of the proteins that you're generating. Again, you've done all this work to profile the target IGDs in creating what you call the EpiZips. For a given enhancer promoter site within a specific gene within an IGD, talk a little bit more about how you engineer in the specificity for the protein you're creating. Absolutely. I think, first and foremost, right, when you use these IGDs as drug targets, the reason you can do that, precisely to the point that you just made, right? Any of the regulatory elements inside the IGD, as well as the flanking sequences for CTCF, are unique in the entire genome. First of all, once we figure out where on the IGD we want to act, to figure out which of those regulatory elements have what level of control on gene expression, we have the sequences. What we do is we design our proprietary DNA-binding domains that actually target those sequences. Like I said, we have a very solid computational base, and we have some whizzes here who actually have created algorithms that allow us to design these DNA-binding domains very, very quickly. They basically target a 21 base pair. That's where you get that high level of specificity. We obviously test the specificity throughout our biological experiments as well. We have demonstrated incredible specificity of targeting. That's really how we go about targeting those very specific locations in the genome, which are the EpiZips. Okay, for your constructs, which you refer to as OECs or Omega Epigenomic Controllers, how big of a challenge is it or was it to be confident that the delivered mRNA that you're delivering for the specific proteins can properly assemble in vivo into the fused or linked construct? Yeah that consists of these two important jobs, if you will, the programmable DNA-binding domain and the epigenomic effector protein? Yeah. No, look, as you can imagine, right? The science was really delineated in 2016. 2017, the company was formed, and the team has been working diligently. Initially, we had an idea that we had to actually prove out. It wasn't very difficult because we know that mRNA can be encoded, right, for these proteins. As the mRNA uses our ribosomal machinery to enter the cell's nucleus and then home into the genome, where it expresses these proteins, these proteins can then go and target that specifically. We were able to test this in cellular systems, in vitro systems very well. When it came to in vivo, we did some early experiments, right, which allowed us the confidence of ensuring that we designed these correctly and then encode them in mRNA to actually be sent. The interesting thing about what you just asked me, right, is we have obviously demonstrated this in four completely uncorrelated areas right now, right, across our pipeline. Completely uncorrelated disease models, single gene, multi-gene, master regulator, oncogene, all of that, right? There's a very interesting proof point that we got, which is an external proof point, right, which is outside of Omega, which was actually the data that Intellia put out a couple of months ago. If you remember, what they did. They essentially sent mRNA that encoded for a Cas protein, a dCas protein, I think, that was taken up in the nucleus, that homed into the genome and went to a particular gene and did an edit at the DNA. If you really think about what we are doing, we are not editing, so we are not making any cuts in the DNA or any changes in nucleic acid. We are pretty much doing a lot of what Intellia did, but instead of going and delivering an edit, which is possible for a single gene, we are able to go and multiplex, if needed, controllers to different locations in the genome and lay down epigenetic marks that durably tune the gene. Your question about whether this can be replicated or what confidence level we have or we had in vivo systems, I think it's pretty high because I think it's been demonstrated not only by us in animal models, but by some of the peer group companies in the world, Intellia, in human systems. I think there's a tremendous amount of confidence that this can be done. Okay. Given your understanding of trying to really fine-tune and optimize your technology, there's different ways you can influence gene expression factors, whether that's histone modification or chromatin remodeling. At this point, which of these are maybe easier to do or you can more tightly control? Yeah. Look, I think our team of epigeneticists and our scientists are just incredible in what they have been able to do. One of the things that we set on to do early in the life of the company is we literally created a library of these epigenomic controllers, epigenomic effector part of the controllers. Where if you just think of a two-by-two matrix, on the Y-axis, you have up or down regulation. On the X-axis, you put duration, whether it's a few days, a few weeks, a few months. We were able to characterize several epigenetic controllers or epigenetic effectors across various cell systems. Now we have a library of over, I would say, 100, 150 that we can pull from, and they contain all of these mechanisms that you talked about. It really depends on what it is that we are trying to do. Whether we are going to actually do something as straightforward as methylation or demethylation, or whether we have to go in and open up the chromatin loop and access some regulatory element that's hidden inside. We have the repertoire of all of these mechanisms at our disposal. It is really on a case-by-case basis, in a bespoke fashion that we decide upfront in the computational process when we are interrogating the IGD for that disease phenotype as to what exactly we want to do. We build our controllers to test them, first empirically and then in cell systems, and then eventually get to in vivo work. We have all of that at our disposal. Okay, great. In targeting gene expression in this manner, basically at the end of the day, it's an RNA therapy. How does this change how we should be thinking about the duration of the therapeutic effect of your OECs? Yeah. Look, I think the beauty of what we are able to do is we call these engineered modular therapeutics. There's not only the DNA-binding domain, which we obviously engineered. The epigenomic effector, what we can do is the DNA-binding domain brings in the high specificity that we can engineer. The epigenomic effector domain, we are able to engineer the tunability. How much do you want to actually tune the gene up or down? You don't want genes to be, let's say, completely shut off in a disease process. For example, our leading program, MYC, you can't shut off MYC completely because that actually leads to autoregulation. We need to tune it down only to a certain level where it starves the overly MYC-dependent cancer cells, but spares normal cells. We engineer in that tunability, and then you asked about the durability. We engineer in durability. For an acute condition, let's say, in oncology, which is not necessarily acute, but you want to treat it for one week or couple of weeks, give it a holiday, treat it for a couple of weeks, we can actually engineer that property that the action will last for one or two or three weeks. If we want to go for a more chronic condition, we have controllers that we have demonstrated that work for over 70 days. Now if you think about a chronic condition that you need therapy every day, you are able to deliver a controller that works for, let's say, one to two months depending on the therapy. That's what we are aspiring to. That means five to six applications a year. That's a whole game changer. That's one of the things that we can do, and look, we just need to step back and look at what nature does. If you think about what we are doing is we have co-opted nature's operating systems. As we develop from an embryonic stage to full-grown human stage, nature uses these mechanisms to constitutively shut genes down when their work is done. If you just consider that for a second, we should be able to eventually replicate that. That means the duration of effect should not really be a constraint as the company develops more and more, as our understanding of this grows more and more, we will be able to actually build in as much duration as we want. That's one thing. The other important thing about our therapeutics is that this is a very important point here that I want to make, which is that conventional therapeutics that we know about, whether you take small molecules or large molecules and even some of these drugs that treat epigenetics in terms of going after transcription factors, they go after the proteins. They need to be in the system all the time for their effect to be had. I'll give you a postulation. In our case, the PK and the PD of the drug is decoupled. I'll tell you how. Essentially, what we do is we send in the controller. The mRNA degrades, as we know, in a matter of a few hours. The proteins that we are sending in, the epigenetic effector lays its epigenetic mark and degrades in a matter of a few days by normal protein degradation mechanism. What is left behind is that epigenetic mark that we engineered the durability and the tunability into for the time period. That means that drug doesn't need to be resident in the system because we have actually created the epigenetic mark. That is true epigenetic. Based on that, we can really engineer the durability without having to constantly drug the system. That is really what we are working towards, and that's how we can build in these durabilities without having to drug continuously. Does that make sense? Yeah. Well, let me ask you a different type of question. The degree of innovation that you're pursuing, big ideas like this come with big risk, and it really requires challenging the dogma of wanting to apply old ideas to a new field. Can you describe the culture you've established at Omega that's going to help you achieve your goals here? Yeah. Look, I love this question because I agree with you. I think, when you are on a pioneering journey that Omega is in, look, we are a part of Flagship Pioneering. I think the sort of the orientation there really is challenge all dogma. There is no sort of sacred cows. Look, the only way you can advance science, and we are living in an age of unprecedented biological advances, that we have immense control on biology that has never been had before. To translate that pioneering spirit into Omega, one of the first things that we did was very early on in my tenure, we established our culture and our ethos. Our ethos, Omega's ethos really is ambitious, yet humble. What that really means is you have to have the highest level of ambition to succeed in a pioneering journey. You can't be on a pioneering journey with dogmatic thinking. You have to have the highest level of ambition to succeed, to be able to fail, but fail early, fail fast, and actually learn from that. When you're thinking of creating these kinds of groundbreaking, pathbreaking, first-in-class therapeutics, you better have that level of ambition. Along with that comes a tremendous sense of humility, saying, "Look, we are standing on the shoulders of giants who created some of these things," like mRNA therapeutics, all the science that came before us, even the understanding of gene editing, for example. The most important thing is we are putting these drugs eventually into patients. If you think of what Omega is doing is we are advancing science and changing medicine for benefit of patients. We have to earn the right to put this into patients. That means we have to do this really well with a tremendous sense of humility. That is the culture that really embodies Omega and Omegans. The entire team in 2019 worked on this, and we came up with our values that reflect this. The team loves to call it blazing a trail. It's trust, resilience, authenticity, innovation, and leadership. These are ingrained into everything we do. I think there's a culture which people embrace, and that's how we are actually succeeding on a pioneering journey. You can't do that without having a culture that thinks in that direction. Well, great. When we think about how you've selected your first targets to pursue, obviously, you got to balance some things. You want it to be an attractive market. c-Myc expressed on a lot of cancer, so certainly checks that box. What else about it as a target did you guys feel was valuable in terms of establishing that early proof of concept? Look, I think if you step back, we have been around for 4.5 years. In the initial couple of years, we had a team that had great successes in terms of unraveling the science and really understanding it. In the last 2.5 years, we laid out our approach to get to a pipeline. The way we did that is essentially, we first went where the science took us. We wanted to establish the breadth and depth of this platform, whether it's single gene modulation, whether it's multi-gene modulation, whether it's a master regulator, whether it's an oncogene, a holy grail oncogene like c-Myc, whether it is SFRP1 for alopecia. We had about 15, 20 projects that we could choose from to take forward. There, we actually, once we had that, we sort of intersected that with areas where there's tremendous unmet patient needs. For example, our program in HNF4α, it's a master regulator that actually is sort of a regulator of hepatocyte function. You can, in fact, even grow hepatocytes. Imagine those people who are on the transplant list, 17% of those who will die waiting for a liver transplant. If you could restore hepatocyte function or even better still, actually restore hepatocytes, isn't that game changing? That's really how we intersected where our science took us to patient needs and unmet patient needs and the impact that we will have, and that's how we crafted our initial pipeline. Having done that and having delivered proof of concept across four very uncorrelated areas, as we now think about the next steps in our pipeline, we are doing that very thoughtfully, judiciously, internally, as well as partnering with external partners to sort of expand that pipeline, which is fairly expansive. Well, we're coming close to the end of our time here, but I could speak to you for another hour if we had the time. Let me just squeeze in one last quick question here, and that is, you recently went public, a successful IPO. Mahesh, what do you really want investors to take away and summarize what we've talked about and how you're differentiated and what would they really want to understand about Omega? Yeah. Look, Omega Therapeutics is the first systematic approach to use mRNA therapeutics as programmable epigenetic medicines. We have delivered proof of concepts stage appropriate across four very different, unrelated, uncorrelated therapeutic areas, right? We have a lot of other programs in our back pocket in our pipeline, we will add that to the pipeline stage appropriately, right? c-Myc, which has been the holy grail of oncology, implicated in 40%-50% of all tumors, solid tumors in over almost 100% of all metastatic cancers, is just the first one that we are going for, right? Our pipeline is very broad. It goes beyond oncology. We are seeing tremendous amount of success. We have been fortunate to bring in 17-20 investors in our crossover as well as our IPO and many more in the IPOs, highly oversubscribed crossover and IPO rounds. We took in the money to make sure that we deliver these proof of concept, taking things to IND stage as well as human proof of principle. We use our money very judiciously. If I were an investor, right, the science is incredible, and there's really good proofs of concept, right? It's a very strong team, and I can vouch for this team any day and even more on Sunday. Thirdly, it's a operationally very strong team that has had successes in the past that will get success in the future. We have a very clear plan to get to these things. I think that's what I would really encourage investors think, and I'm always happy to have detailed conversations. Keay, this is such an interesting conversation that I can go on and on, like you said, we could chat for another one hour, and I'm more than happy to do that with prospective investors as they want to learn about the company. Well, great. Really have enjoyed this, Mahesh. Thank you so much for joining us. Keay, thank you very much for taking the time. Thanks a lot to Chardan as well for this fireside chat. We are obviously available to chat with anybody who wants to contact us. Thank you very much for all of those who dialed in to even listen to this fireside chat. Thank you. Great. Thanks.