Good afternoon, everyone. I'm Salveen, biotechnology analyst at Goldman Sachs, we're really pleased to have with us the Omega team. We have Mahesh Karande, CEO, as well as Thomas McCauley, CSO. Maybe to start here, you know, I think you're at the cusp of finally, we're going to see some clinical data in light of this, you know, novel technology and approach. To level set, you know, who is Omega? How do we think about this data set that's coming up? Yeah. Salveen, first of all, thanks a lot for having us here, and thanks to you and Goldman Sachs. Look, Omega Therapeutics is taking the first systematic approach to use mRNA therapeutics as programmable epigenomic medicine, right? The company is really founded on tackling fundamental science, which has to do with the organization of genes and their regulatory elements. What we have figured out is, you know, let's call it nature's sort of control system that nature uses to epigenetically control gene expression, right? We figured that system out, and there is a very systematic and repeatable way in which you can control expression of genes, single or multiple genes, right? Thereby treat or cure disease, because all you really need to do is pre-transcriptionally bring the erroneous expression of genes back into a normal range. The premise is really that disease occurs because genes are either overexpressed or underexpressed, and if you bring them back into a normal range of expression, you're pretty much resolving disease, right? That was what the premise and the science that Omega, you know, has been operating on. You know, to your question, it gives me tremendous pleasure that we have taken that science, you know, the company is a little bit over five years old, we have made it into a drug development platform, now are in the clinic, studying it in a phase I/II trial by MYCHELANGELO for c-Myc in hepatocellular carcinoma, right? You know, that's where we are. You know, this is a tremendous moment for us because, you know, as we have studied this in all of our preclinical work, we have really delineated the MYC biology. You know, all our preclinical work is pointing towards a tremendous control pre-transcriptionally on MYC, which allows us to overcome autoregulatory issues and other issues that have plagued, you know, other technologies that have gone after MYC for 40 years. It still remains an undruggable target, the Holy Grail gene. We feel pretty optimistic. You know, the trial is running pretty well. We dosed our first patient in November. It's a global trial. We have sites in the U.S. as well as in Asia and, you know, eventually in Europe. As you know, hepatocellular carcinoma is huge prevalence in Asia. Over the course of the rest of the year, as we consolidate data, we will be talking about, you know, obviously, the safety aspect of it, which is predominantly what this trial is about. You know, some of the things that really excite us is that this is the first time anybody would be showing, you know, PK and PD, you know, in terms of epigenetic targeting, epigenetic change, that translates into mRNA change, that translates to protein change, and that actually translates into tumor killing. That's what we are really going to demonstrate, and, you know, that's what we're excited about. Very exciting. I like the name of the trial, too. Using your platform here, what range of modifications are you able to achieve? You know, what modalities can you use to achieve this? I think you've talked about some of them in the past. Are there specific indications that are better suited to your platform versus gene editing, uncertain? Yeah. Look, that's a great question, right? I mean, if you think about, you know, what we are doing, right, if you think about the central dogma, right. I mean, I think, you know, most of our lives we've been using drugs, and physicians have been prescribing drugs that targeted proteins in some manner, right. Small molecules, large molecules. You had, you know, non-coding RNAs, mRNAs, that have actually found a spot, and then, you know, people took aim directly at the DNA. Gene editing is one of those modalities where, you know, you actually change nucleic acid sequences. Now, the thing is, it works in... Look, it's a tremendous advancement in science and medicine, right. It works in narrow indications. Typically, you know, where, you know, gene therapy, for example, I mean, transgenic approaches work in areas where there is no other option, and there's no functioning allele, right? Gene editing has worked, but it's great. The challenge with gene editing is you change nucleic acid sequences, you don't know the collateral issues that you create. Now, what we are doing is we are looking at this holistically and looking at how it really controls gene expression. We are going at it epigenomically, right? What we are doing is we are recreating epigenetic marks or erasing them or deleting them, or all of the manipulations that are available to us, right? The way we actually did this was we looked at the biology and then chose the best modality that was applicable here, right? What we have done is we have used mRNA that expresses two proteins. A DNA-binding domain that hones into a sequence, which is 21 base pairs, a unique sequence, with high specificity and lays an epigenetic mark. We don't nick the DNA, we don't cut it, right? Our therapeutics are transient, right? They're transient because mRNA degrades very rapidly, as we know. The proteins that are expressed are gone in a couple of days, but the epigenomic effect that we engineered stays for the duration that we engineer it for, because we can use short-acting and long-acting mechanisms, right? That's the modality that we're using. From a delivery standpoint, as you know, genomic medicine need tissue delivery. As such, Omega is delivery agnostic, but our initial foray is with lipid nanoparticles. Simply because if you think of mRNA and lipid nanoparticles, that's a modality that has been de-risked for a young company like ours, where biology is new, modality is new. That's what we chose. Over time, you know, we are delivery agnostic, and we could potentially use other tools too, but mRNA and LNP make a lot of sense to us. Just given the novel, you know, aspect of the platform here, how comfortable are you on the safety profile? Tom, you want to take that? Yeah, absolutely. I mean, first thing I would say is that, you know, to the point you just mentioned on the modality side, we're not making any permanent changes to the DNA, right? You're not worried about the long-term sequelae of making the genome sort of over, particularly over long periods of time. That's one of the most critical things. That decoupling of PK and PD means that either as a monotherapy or even more so in combination, because we won't have a long exposure profile, you can combine this, we believe, very safely with other agents in the space, more easily than many other studies. I mean, the other thing I would say, you know, with specific context to the current program, but which, you know, reads through as far as mRNA and to the platform, is that we've really conducted a comprehensive preclinical safety package, you know, for the MYCHELANGELO trial and for OTX-2002. We don't see any concerns around safety or immunogenicity. Yeah. Let's jump into the MYCHELANGELO program. Your lead program is targeting c-Myc in liver cancer, as you just said. Mm-hmm via using mRNA therapeutics. It is. Can you set the stage as to why c-Myc is a suitable target in HCC? Yeah. I mean, why don't I answer some of it, and then I'm sure Tom will add. Look, first and foremost, I think, you know, if you look at HCC, irrespective of etiology, I mean, whether, you know, it's wildly induced or whether it's induced because of alcoholic, you know, abuse and insult, right? Irrespective of that, as well as irrespective of any point mutations that can lead to it, right, 70% of the patient population have an overexpression of c-Myc. There's a vast preponderance of, you know, c-Myc-mediated hepatocellular carcinoma, right? Look, our modality is such that because we target, you know, the c-Myc gene, which sits by itself in this, you know, mega, almost 2 megabase IGD, right? We target pre-transcriptionally, right? All of the, you know, point mutations that could potentially happen within the IGV. All of the etiology that could actually lead to it, leads to the gene being overexpressed. There is a level of homogeneity in the overexpression, no matter what the etiology is, no matter what those point mutations are, right? All you need to do is take that overexpression and bring it back to a normal range. Honestly, in HCC, we have seen that all you need to do is downregulate that overexpressed gene by upwards of 50% and you induce apoptosis, right? What all this knowledge has allowed us to really go after a pretty vast swath of population, 70% plus of HCC patients with our drug. I mean, that's what you kind of need for diseases like this, right? That's what gives us the comfort. Would you like to add to that? Yes. What I would add to that is that another reason from our perspective to target MYC as a first indication, and particularly, you know, as a pan-essential oncogene that's been refractory to attempts to drug it at the protein level and the mRNA level, is this is a prime example of a place where we think our technology will shine, which is the ability to pre-transcriptionally target gene expression. Obviating any concerns about trying to capture every transcript or every protein molecule, you know, you really sort of treat disease at its source. You know, certainly from our preclinical data, that seems to be highly effective. Yeah. You're running a phase 1/2 trial here with this drug as monotherapy and then in combination with TKIs and checkpoint inhibitors. Can you talk about the profile? Well, actually, before we even go there, could you talk about your preclinical data and, in your view, the translatability to clinical, and then maybe we could jump into profile? Yeah. Absolutely. I mean, let me make a general statement, right? I mean, I think because this is a platform, we have studied this, you know, the biology is conserved across pretty much all mammalian species. You know, the IGD biology is almost intact between non-human primates and humans, right? We have studied translational fidelity across, you know, these species in many different therapeutic areas, going after many different gene targets, the translation fidelity is excellent. I think that's the most important point to make, right, at a general level. Tom, you want to talk a little bit about, you know, MYC specifically in the program? Yeah, no, absolutely. MYC, and this is some data actually we presented recently at the ASCO meeting just last week. You know, we've shown previously, we've published, you know, that we see very strong antitumor activity. You know, and benefit as a monotherapy, both in terms of tumor regression as well as survival. But one of the key things that we think is critical here is really the sort of pleiotropic activity of MYC, which acts both at the cell intrinsic level but also at the tumor microenvironment level. you know, again, while we see very strong monotherapy signal preclinically, you know, there's a very strong rationale just based on that biology of MYC, to believe that it should act, you know, with additivity if not synergy, with both of the currently used standards of care, including kinase inhibitors, which tend to have a more cell-intrinsic activity, where, again, by downregulation of MYC, you tend to induce apoptosis at the intrinsic level. At the tumor microenvironment level, we know that MYC, for example, controls a number of checkpoint inhibitors, including CD47 and PD-L1. So, you know, you can pose the question, you know, if you can directly target MYC, as we're attempting to do, and tunably downregulate it to the extent that avoids autoregulation and impacts cancer cells and, but spares healthy cells, you know, would you ultimately obviate the need for something like checkpoint inhibition? So we've done a tremendous amount of work over the last year to sort of dig into the mechanism of action here. Some of the key takeaways from that were that in fact, as we expect, you know, one of the... I would say there are four key takeaways from our ASCO presentation. The first is following on what I just said in terms of direct inhibition of checkpoint factors in both HCC and non-small cell tumor lines. We show in vitro that we do directly and significantly downregulate PD-L1 in both of those tumor types. Then when we translate that to the in vivo setting, we see in the case of both in combination with both anti-PD-1 and anti-PD-L1 agents, that we see, you know, really very significant efficacy benefit, whether you look at that in terms of tumor growth or survival benefit. Really, you know, that, to your point about translation, right? What we have hypothesized and then shown in vitro, we've now translated in vivo to both of the currently used sort of standard of care checkpoint agents in the space. The other, sort of continuing on the mechanistic picture of how this is, how this is actually working at that tumor microenvironment level, we've also now done tumor immunoprofiling to look at the presence and absence of various immune, host immune cells in that microenvironment. What we see, a couple of things. One is that we're significantly downregulating the presence of immuno regulatory T cells in the tumor microenvironment, which normally act to create immune suppression there within the tumor and essentially exclude the host immune response from kind of coming in there. We also see that we're upregulating on the, on the positive side, we upregulate, or contribute to the upregulation of, you know, activated CD8-positive T cells, you know, which have an anti-adaptive, antitumor effect, right? We're relieving the immunosuppression and then, you know, invigorating the sort of cytotoxic T cells that as a part of the host immune response, would come in and take care of the tumor. One thing that's important to note is much of the data that's been shown previously has been in xenograft models. which are immune-compromised and don't necessarily give you a sense of what the. You know, the immune system is a major component of tumor clearance in a clinical setting. We've done these new studies now in immune-competent systems, which are really a much better model of human clinical patient, who will have a, you know, a functional immune system. The most compelling piece of data, I think, from the ASCO presentation really is the fact that we've been able to show that these OEC, even as a monotherapy and in combination as well, confer immunological memory to HCC tumors. To unpack that a little bit, what we mean there is that, you know, we've taken just to focus on the monotherapy setting for a second. We've dosed, you know, immune-competent animals with OTX-2002, as you know, every five days for a month, and in 70% of the animals treated, saw complete response, a complete resolution of tumors. If you then allow those animals to go without being further dosed for another two months for the last dose, and then re-implant them with the same tumor types, those tumors don't grow for months. We've really, again, opened up that tumor, you know, allowed by tunably downregulating MYC, we've reset the cellular program in these, in the tumor cells and allowed the re-engagement of the host immune system, which really, you know, from a clinical perspective, that's critical, we think, in terms of being able to provide not just a response, but also really potentially a durable cure. I mean, I think, you know, what has been shown before is, and, you know, the idea of potentiation of checkpoints leading to this outcome has been known. For the first time in an immune-competent system, we have shown this by downregulating MYC, you know, for a certain sustained period of time, right? If you think of what Tom is saying is, you know, of course, we have to prove this in the clinic, right? I mean, we can't say that we have proved it in the clinic. If you are able to prove this in the clinic, because this is following science and biology, and if you start bringing in sort of the overall translatability of this, now, of course, the immune systems have to translate in humans as well, right? For a minute, if you imagine that that actually can be done, which we are attempting to do in our clinical program overall, you're talking about something that's game-changing. You're now talking about not only intrinsically killing tumors by direct action of downregulating MYC, but you are, you know, reprogramming the cellular system, right? That has always been the promise of going after, you know, IGDs pre-transcriptionally. Remind us, you know, the difficulty that's played out in the past with targeting MYC and, you know, what the, what the consequences have been of that targeting approach. Yeah, absolutely. Tom, why don't you take this one? Yeah, no, absolutely. Again, to the point, you know, MYC is given its sort of essential function in the cell, it's highly autoregulated, so it regulates itself. If you're trying to antagonize, you know, in a binary fashion, if you're trying to turn it off by antagonizing every protein molecule or at the mRNA level, using an siRNA, for example, by, you know, chopping up every transcript, if you miss, you know, even a single one, theoretically, the gene will autoregulate. The key really here is to tune its expression down to the level, again, of therapeutic threshold. Here's is well established at around 50% of expression. You know, that degree of downregulation is sufficient to induce apoptosis and kill cancer overexpressing MYC-addicted, excuse me, cancer cells, but to spare healthy cells, you know, immediately adjacent to those and throughout the body as well. It's a, you know, where those other approaches have, again, because you're sort of fighting an amplification effect, you know, the clinical solution to that is to sort of increase the dose, and at some point you run into, you know, some sort of a dose-limiting toxicity. We, again, by targeting pretranscriptionally, we believe will completely circumvent that. Yeah. Pretranscriptionally also not fully abrogating expression, right? I mean, I think, look, you know, you asked earlier the difference between editing, right? I mean, editing typically is binary. Now, you can use editing technologies to sort of do some level of modulation with effectors, et cetera, right? What we are doing is not binary because that's not really how our systems work, right? Genes are not either turned on or off. I mean, you can turn them on or off, and nature does constitutively do that for long periods of time as well. Typically, genes are expressed transiently, right? All we are doing is making sure that we express it transiently at the right level. That overcomes autoregulation. I think one more point is, you know, when you think of small molecules going after the MYC protein, the MYC protein lacks a binding pocket. I think that has also been a difficulty. There is no direct way of going after MYC except the way we are going after MYC, right? Maybe frame for us the phase 1/2 trial and what we should expect to see at the upcoming read. Yeah. Tom, would you like to take that or? Yeah, I mean, I'll do the first part. Sure. Maybe you can jump in on the second part. The MYCHeLangelo-I trial is a first in human, which we hope will be the first to show clinical proof of concept of epigenetic gene modulation. It's a trial in two parts, where the first part is a monotherapy, testing OTX-2002 as a monotherapy, where we're currently in the midst now of the dose escalation portion of that, to be followed by an expansion in HCC patients. The part two for the trial is where we'll study combinations of OTX-2002 with both TKIs, as well as checkpoint inhibitors, again, both the standards of care. We expect to enroll, Mash may have mentioned, this is a global trial, so we're enrolling patients in the U.S., currently, in Asia as well, and ultimately plan to do so in Europe. Yeah. In terms of what this will show, right? I mean, I think, you know, look, I think you've seen our preclinical data, right? Just to put it in context, essentially, this is the first time, you know, we plan to show that you can epigenetically target, you know, a specific location in the genome. You can actually make the epigenetic change, which is measurable, right? That should translate into the mRNA change, that should translate into the protein change, and that should translate into eventually, you know, activity or efficacy, right? Tumor killing. Our clinical trial has a very solid translational plan built in. We are taking our time to make sure that, you know, show safety, obviously, because this is the first time this is being studied in humans. Safety is super important to phase I trial in that, in the sense that it's really a safety trial. The mechanistic piece of this is extremely important because it's the first time anybody will be showing this level of mechanistic data. Obviously, you know, at the right dose levels, we are going to start seeing efficacy or any measures of efficacy that you can measure in phase, you know, in early phase I, phase II trials, right. That's what gets us excited. What are these measures of efficacy, and are your initial doses, they're at therapeutic levels or? Yeah, I mean, I think, look, you know, So our preclinical data has informed us obviously, really well of at what dose escalation level we will see, you know, a real therapeutic benefit. We could actually be surprised because of, you know, these being epigenetic mechanisms, that you could see it at low doses, too. We are sort of really studying this. We have a sense of where we are going to see that, and that's within our dose escalation, and we'll obviously start our combination work as well, somewhere in that range, right? What we are doing is, as we escalate through the rest of the year, you know, in the second half of the year, which we are entering very soon, we will be talking about these data. We just want to make sure that because this is the first time we are studying it, right? Other than the MYC biology, the platform technology is translatable to everything else we do. We want to do this really well, really carefully, characterize it well, and then once we have a preponderance of patients that we can, you know, meaningfully say: Look, we are seeing X, Y, and Z, that's when we will actually present the data. That's the plan. You're not screening for MYC positivity. Do you think that would be an issue at all in terms of, you know, getting the benefit that you'd want to see from the group? Yeah. No, we don't think so. You know, I think particularly in HCC, you know, as we discussed, 70% of patients have, you know, overexpression of MYC, right? Look, I mean, in oncology, let's step back. I mean, even when we discussed with the FDA, right, as we presented our trial design, et cetera, right, everybody was very comfortable with us not screening for MYC, right? Now that's for HCC. If you think about NSCLC, which is another program in our pipeline, right, over there, whether it's direct MYC, you know, dysregulation or amplification, that only exists in about 25%-40% of non-small cell lung cancer patients. Over there, we definitely use an off-the-shelf diagnostic. HCC, we didn't feel the need of doing that. Got it. Could you speak to your non-small cell lung cancer there, and how the asset going after that indication might be different from what you're doing here in HCC? Yeah. Look, that's a great question, right? You know, typically, as we have all developed drugs over the years and we've seen drugs being developed, right, you develop a drug and use it in every possible indication. If you think about MYC as a target, you know, the logical approach would be the first drug that you are developing, use it for everything else, right? That's great. The beauty of our approach is that we study the epigenetic dysregulation of, in this case, MYC, in different tissue types and cell types. It's not surprising that the dysregulation of MYC in these different cell types or different cancers is slightly different. While there could be a commonality, there is a bespokeness in each cancer type. Think of it this way: If you could develop a drug that actually takes care of the bespoke nature right from the get-go, wouldn't that be a much better option for patients, right? That's really what we have done, honestly, that doesn't add anything in terms of timeline. Our ability to interrogate the IGD epigenetically, look at the epigenetic changes and home into the epigenetic dysregulation that happened in a particular type of cancer, in that particular type of cell or cells, right? Deciding where we want to act and how we want to design or control it, takes us three to four weeks, no matter what, right? That's what we have done. Another way to think of it, Salveen, is that our NSCLC drug, typically thinking, would have been a second generation. We're actually introducing right from the get-go. Yeah. It's a different drug. It's a different OEC, and of course, the LNP is a lung-tropic LNP that we are working on, but it's not the same as the first liver-tropic LNP. How do we think about that? Because we validated LNP delivery to the liver, but not necessarily to the lung here, so. Yeah. Look, I mean, you know, LNP technologies is maturing and expanding by leaps and bounds. I think, you know, the chemical space in terms of how you can modulate, you know, or modify these LNPs is vast. You know, Omega, under the leadership of Tom, we have an incredible LNP, you know, chemistry process team. That is really at the forefront of the industry. This is an industry problem that many people are trying to solve, right? I know one thing about our industry, that when people put their minds to it, they can solve these problems. This is an engineering problem, we feel very confident. Having said that, while we have an internal effort, right, you know, which has progressed really well across many different tissues, what we did was, in the interest of time and making sure we get these programs into the clinic faster, we have actually partnered, you know, for the lung LNP with Nitto. That has an LNP that for a different modality, has been used in the clinic, and we are characterizing it to be used with our modality. That's where the IND-enabling work is continuing. You know, that's a lung targeting LNP, which is very different from our first LNP. We feel pretty good about it. When might this program enter the clinic? Look, I mean, I think, you know, we are still working through it, right? Let's step back for a second, right? We declared a development candidate, only, I think, in October, third quarter or fourth quarter of last year. If you draw a parallel between our HCC program, right, we declared a development candidate in June of 2021. Sorry, January of 2021. Okay. Got an IND declared 18 months later, right? If you use that kind of a time frame, 18-24 months, let's say, because, you know, this is a lung LNP, you know, if you do the math, I mean, I think, you know, not in the too distant future, we could do it only 2, but that's kind of, you know, the framework. Anything you want to highlight from your other programs? I know you have a lot you're working on. Yeah. at this point, but. Yeah. you know, you know, how do you think about capital allocation? Yeah. These other programs, and when you start to. Yeah. further, you know, put effort towards those? Let me take that. Look, you know, one of the things, if you've seen our pipeline, it's actually pretty broad, right? We set that up. Tom and I set up that pipeline way back in 2019. The reason we did that was to demonstrate the breadth and depth of this platform. Oncogenes, right? Master regulators like HNF4 alpha, which is a master regulator of hepatocyte function, that you can literally regenerate hepatocytes. You know, looking at multigenic loops, because if you have multigenic IGDs, those genes usually are filed together because they act along the same disease pathway. One of the beauties of our modality is that you can modulate that entire IGD, you control that entire IGD, that can modulate all those genes at the same time without a compensatory effect. Typically, what happens is if you modulate one, the others compensate, so we can modulate all of them, right? That's our CXCL program, which is a broad application based in inflammation and immunology, right? We have a development candidate ready for that, right? We just didn't declare ADC because that meant we would need to choose a program. Our work in alopecia, right, continues. Now, you know, as an earlier stage company, obviously we were prosecuting everything. Now that we are in the clinic and we have a couple of more programs that are contemporaneous that we could take into the clinic, what we have done very thoughtfully and, you know, in light of obviously using investor money well, you know, the capital markets how are today, and making sure that while we have developed preclinical proof that we want to develop, you know, present clinical proof, we have, you know, done very thoughtful resource allocation. Our overall resources utilization hasn't changed, but we have refocused it so as to focus on inflection points, right? As we get those inflection points, as we are able to capitalize the company better, then we have, like I said, we have about, you know, 20-50 programs that we can run today if we had the money, right? Over time, we will actually expand that. Our cycle time of getting from, you know, in drug getting to get into an IND clear has just shortened. Like, Merck was done in 27 months for HCC. That's how we are really looking at capital allocation, you know, very conservative in terms of, you know, expansion of the team only in the right spaces. You know, 5 years later, having raised close to $400 million, we have 120 people, right, with 8 programs running. That hopefully gives you an idea. Great. With that, thank you so much. Really appreciate the time today. Thank you very much, Salveen. Much appreciated.