Good morning, everyone. Welcome to 2024 Jefferies Global Healthcare Conference. My name is Roger Song, one of the senior analysts cover biotech in the US. It's my pleasure to have the fireside chat with our next company, Omega Therapeutics, CEO Mahesh and the CSO Tom. Welcome, gentlemen. Roger, thank you. Thank you very much to you and Jefferies to have us back here. Super excited to tell you the progress on Omega. Awesome. Great to have you. All right, so, we have a lot to talk. You have a, you know, epigenetic controller platform, and obviously you have a couple program going. Before we dive deep into the pipeline and the, and the platform, can you give us some, you know, intro remark regarding the recent updates, and then we can go on to the Q&A? Yeah, absolutely. So look, we are extremely excited about the progress of Omega overall, right, over the last 5 years. To speak very specifically about the platform, I mean, you know, this is a first-in-class approach where we are prospectively engineering therapeutic properties into mRNA based epigenomic controllers that essentially tune genes at the genomic level. We have been able to do that in a very capital-efficient way, and we have been able to pre-transcriptionally target and modulate and create in silico, in vitro, in vivo data in somewhere between 50 plus almost 100 different genes that we know that we can target. The platform is prolific in the sense it can pretty much go after every human disease, right? Independent of structure, chemistry, location, mutational status of target. So it's incredible, you know, great genomic specificity, you know, controlled tunability and durability, where we have demonstrated downregulation for over 6 months, consistently in several targets, and we have also demonstrated, Tom can talk about those data later, upregulation, which is not something a lot of companies can do. Actually, I don't know whether too many anybody can do that at the genomic level for over 2 months. We have signed this, you know, this deal with Novo Nordisk for the next generational, you know, obesity medicine, right? As they think about a more lasting, permanent solution. So super excited about the platform, but I think even excited about the trial and the clinical data that we have generated so far, right? We have demonstrated unequivocal proof of platform. If you think about the mechanism, what you really need to demonstrate in a, in a trial, phase I trial, first in human, you know, study for a completely de novo platform, is that the mechanism works, right? In our case, we have demonstrated exquisite genomic specificity that we have measured, that we have shown data, and that continues with every dose level. We have shown the right epigenetic change that we are engendering. We are actually able to measure that. We have demonstrated robust and durable downregulation. In this case, we are going after the MYC gene in hepatocellular carcinoma, so we have demonstrated the consistent downregulation for the duration that we intend this drug to work, which is every 2 weeks, you know, of mRNA expression. And, you know, we have—we are the first company that has done this, right? So essentially, this trial has provided us tremendous insight into OTX-2002, which is our medicine, and the broader class of epigenomic controllers applicable across our entire portfolio, because other than the biology, everything else remains the same, no matter which disease area you go into, right? That has told us, and I think where we are right now is proceeding in dose escalation. You know, our, our study has been designed to really find the RDE, and we are, we took, you know, very aggressive steps, Roger, if you remember, with dose level 4 and 5, just to try to get to, we are in the efficacious activity range, just to try to get to a RDE or, you know, a maximum tolerated dose. You know, we have now actually established with dose level 5, the outer bounds of our, of our, dosing. So dose level 5, at 0.3 mg per kg, we actually believe that we exceeded RDE. So now what we have done is we've gone down to dose level 6, which is 0.2, which is typically how a clinical trial is run, and now we are enrolling patients in that. So now we have a really nice range between 0.12 and 0.2 to play with. Mm-hmm. You know, and we went down from 0.3 to 0.2, so there could be a play even between 0.2 and 0.3. So there's a nice wide range to play with, and we expect to complete and declare a RDE soon enough, and then get into expansion and combo therapy, as we have always, you know, put out our strategy. So all in all, platform's doing really well. The clinical trial is progressing exactly as it should be. It's a phase I dose-ranging, dose-finding study, and then the real proof we expect really comes in expansion, you know, which would be the phase 2 part of this. So we're super excited about the progress. Excellent. You know, we'll make sure we touch on the platform and the metabolic and some other early pipeline, but maybe we can spend first part of the conversation focusing on your OTX-2002 this program. You just give me something new here, I think, for the benefit of the audience. So you have shown us dose level 1 to dose level 3 for OTX-2002 earlier, late last year and earlier. And then, you know, we have seen PK/PD kind of profile. We have seen the safety looks pretty supportive into the next stage, then moving on to the higher dose, and then you give you dose the 4 and the 5, now 6. 6 is lower than the 5. Tell us, what have you seen for the dose 4 and 5? What make you make the decision to go down to, point 0.2 as the dose—the next dose level? Yeah. Why don't... Look, I think, you know, what we did was, if you remember from dose level 3, we took a huge step from 0.06 to get to 0.12, so 100%. Mm-hmm. And then from 0.12, we went to 0.3. Mm. Right? Which is a significant jump again- Right ... in the 90% range. And we did that purposely to make sure that we get to the RDE or at least get to sort of a maximum tolerated dose so that we can really create an outer bound. That's why we did it, and that's what we have seen in dose level five. Tom, why don't you actually, as CSO, address what we have seen in dose level five? Sure. No, absolutely. So just to, you know, to go back, start at dose level 4, right? Yeah. So in the, you know, we saw activity, pharmacodynamic activity, even at the very lowest dose we tested at 0.02- Right ... and then 0.05 and 0.06. And then, as Mahesh said, we took a, you know, significant jump based on the safety at those doses to 0.12. Because it's so safe, and you start to see the PD, but maybe you wanna—you know, you wanna drive the real clinical response. Exactly. Exactly right. So at 0.12 is really when we started to enter the zone based on all of our preclinical data, where we saw robust tumor efficacy- Right ... you know, where we believe we're in a clinically, you know, active zone from, you know, in human. Yep. And so at the, you know, dose level 4, that was, you know, showed very good safety. So again, we, you know, had the confidence based on that to escalate further to 0.3 as well. Again, a significant jump, right? I mean, this is all part of a 3 + 3 design, which is, you know, the intent of which is to help you explore and escalate in dose rapidly, right? Mm-hmm ... with an eye on safety. And so at point three, we did see some adverse events of, elevated liver enzymes and also, one infusion-related reaction that led to a- Mm ... an interruption of the dosing, administration for that patient. And so again, per our protocol, we have now, you know, de-escalated to a dose that is still in that active range of 0.2, but which still gives us, you know, as Mahesh said, quite a bit of real estate on either side of that to further explore if we need to. But in terms of those safety signals, they were things. I would note, those are things that are associated, and note, you know, previously have been documented to be associated with lipid nanoparticle administration. Mm-hmm ... in terms of, you know, liver enzymes and IRRs and things. They were transient and resolved, you know, very rapidly without other intervention over the course of, you know, hours to just a few days. So we are now enrolling in dose level 6 at 0.2, and we'll continue to build out that cohort over the summer. Got it. Couple of things on that, right? Yeah. Just to add, Roger. I mean, I think- Mm ... we have always talked about, you know, the epigenomic controller having the LNP and then the, you know, the mRNA itself, right? So everything that we have seen and that we showed, even with dose levels 1-3, the data that we have put out, and eventually in the second half, we'll put out the rest of the data in detail, right? We have seen that none of this actually is attributable to the epigenomic controller itself. It's all driven by the LNP, which is expected. And remember, these are significantly impaired patients, you know, particularly liver's compromised, the hepatocellular carcinoma, and then you are actually adding a liver LNP. So this is expected- Mm ... in these patients, and these patients typically enter with a life expectancy of, you know, not more than 12 weeks. And the great thing is that, you know, our... As we even showed earlier, we, in the, in the patients where, who continue on the trial, you know, you have actually extended their life. That's, in our opinion, a pretty big clinical finding, and that's exactly what we, what we want to test, you know, in an expansion, because that's, that's how you want to run this clinical trial. Mm. We feel pretty good about where we are. Yeah. Yeah, understanding, I believe starting from those cohort 4, you are enriching or you only enroll the HCC population. Starting 3. Starting 3. Yeah, starting three- Exactly ... you only enroll the HCC- Exactly ... and then those are later line HCC as well. Mm-hmm. Okay, and then so just to confirm, for the safety, dose level 4, nothing. Moving to the dose level 5. Yeah. I agree. You know, dose level 3 is 0.06, and the double in dose level 4, and then triple in dose level 5, right? Exactly. So you just try to push the boundary, so where- Exactly ... how high you wanna go. And then you start to see the liver signal, and then go down to the 0.2. Got it. And then how about the clinical activity there? So what you have seen for the dose level 4 versus 5, now you are in the middle. How should we expect to see- Yeah ... the response there? So look, we haven't, you know, at some point in the second half, we'll come out with the more details on activity and, you know, PK, PD. But what I can tell you is that the drug is behaving exactly like we expect it to behave. You know, it's the same behavior that you saw earlier, right? In dose levels 1-3. You know, would love to actually come back later on in the second half and give a comprehensive update, you know, of all of the doses as we home in into our RDE, right? Mm-hmm. So I think it suffices to say that the drug is behaving exactly like we expect it to behave, and, you know, looking forward to continuing patients being dosed on dose level 6, which is 0.2. I always get it confused because it's below dose level 5, dose level 6 at 0.2, where we are enrolling patients and treating patients right now. Got it. Okay. And then so, understanding you, you have not, you know, disclosed any kind of material information in terms of the clinical activity here. Mm-hmm. But how about the PK/PD profile? You say very similar because, in the last data update, we see this decoupling PK/PD and the internal peripheral versus the tissue. How do you see that, you know, consistent and- It's the same. I mean, I think it's absolutely consistent. So, and look, Roger, you ask a really good question because that sort of first-in-class therapy, first in human, that's what you hope for, right? I mean, look, we can all hang our hat on wanting efficacy in phase I, right? That typically. If you think about all of the HCC drugs that have been approved, that are in the market today, there was no real efficacy signal in any of them in phase I, right? Now, we would love to get an efficacy signal. Yeah, in phase I, you don't typically expect it. You know, years and years of drug development and oncology drug development tells me that, you know, that's very, very rare to expect unless you're doing something completely fundamentally different. You know, here, what we are doing is going after a completely undruggable target, c-Myc, and we are seeing that we can control the c-Myc gene exactly to the therapeutic levels that our preclinical data and the literature and biology has told us will have an effect. So as we get the right kinds of patients in expansion at the right dose, at the, you know, RDE, that's really where we, you know, we, would love to see, because that's where it will be statistically powered to even actually deliver efficacy or activity, right? Yeah. If we get anything before that, that would be incredible, and you've seen in dose level 2, for example, that patient, right, where we saw at 12 weeks progression but stayed on the study because the PI thought he was deriving benefit from it, and then, at week 18, you saw it regress back to original and continued that way till eventually the patient had to get off the study. So there is something happening with this drug. We just need to get to the right patients and enough number of patients. Yeah, sure. So you say the next data update will be second half. Yeah. You probably will do two things. One is, you know, the next expansion dose, dose level, so that's number one. Number two is to give the street the data from the existing dose cohort. Either kind of go hand in hand in the next update, or you will separate them, in terms of the, the- I mean, the plans right now would be to do it together, right? Because I think once we come out and talk about it, we want to talk about it comprehensively, right? We'll talk about... You know, and the strategy that we have laid out for the trial is to get into expansion but also get into combination. All that really will be driven by the data that we see. You know, that we are seeing, it's an open label trial. So as we make those decisions, we will definitely be talking about it comprehensively. Got it. And then so, just to confirm, the criteria moving to the expansion is not necessary you need to see the clinical response, but, you know, whatever you have seen for the PK/PD and the safety will support you to the expansion. And then tell us a little bit about the potential expansion dose, if expansion cohort design, what's the line of therapy? Yeah. I believe it's HCC. You know, so what's the next step for the expansion? Sure. Tom, you want to take that? Yeah, sure. So, you know, as we think about expansions, right? The, the goal there would be to, to focus really on true second-line patients, which is our, our target population, which will have sort of less compromise in terms of liver and greater life expectancy- Mm-hmm ... to be able to stay on trial for long enough to really reap clinical benefit from that. The other piece there is enriching in the expansion to, you know, in a 3+3 design, that, you know, there's no provision for sort of powering those for any statistical way to be able to see any kind of efficacy signal, you know, in terms of signal detection. But in the expansion phase, we'll be looking to expand to, you know, something on the order of 15-25 patients- Mm-hmm ... in those cohorts, which gives you, you know, for a reasonable effect size, gives you a very, very good chance of detecting a signal there. So that would be the primary thought on the monotherapy expansion side. And then in combinations- Mm-hmm ... you know, we showed previously, based on our preclinical data, there's, you know, significant synergy with both standard of care classes of agents, including kinase inhibitors as well as checkpoint inhibitors. So we'll be looking to proceed initially into combinations with checkpoint inhibition, but we'll be giving more detail on that later, you know, after we've identified the RDE. Yeah. I mean, Roger, if you remember, we have a supply agreement already with Roche, right? Yeah. For atezolizumab. And, you know, if you remember our, you know, data that we put out in combination, like Tom was saying, was incredible. But I also want to remind you, look, phase two will be the right setting, you know, expansion, because you will have second-line patients, right? These patients that we are studying right now, many of them come with four, five, six prior therapies, right? With very short life expectancy. You know, so we want to determine safety in these very, very impaired, you know, patients with very impaired diseases, right? Mm-hmm. Once we get that, then we get to a healthier population. That's where we'll expand. That's where we expect to see. We fully expect to see ORR in that patient population. But also, I would like to remind you about that study that we did in immunocompetent mice. Mm-hmm ... right,... There's 2 mechanisms that eventually come into play with this drug, right? One is obviously direct, you know, apoptosis and direct tumor killing. But the second one, which we demonstrated in that mice study with competent immune systems, which is as close as you can get to sort of the clinic in terms of testing. When we gave them doses that are in this range, equivalent, for a month, you know, every 5 days, and then we stopped treatment, and we got a complete resolution in 14 out of 20 mice, right? It was a robust study. And then we let those 14 go without treatment for 70 days. Mm-hmm. After the 30 days, and then at day 70 or day 60, I think, we implanted two tumors, one on the right flank, one on the left flank. Mm-hmm. On the right flank, we implanted the tumor that they had actually seen before, that we treated, and on the left flank, we implanted a tumor that they had not seen before, the immune system had not seen. What you saw over the next 30 days is without any more treatment, again, so now they are 100 days past their last treatment, right? You saw that the tumors that they had seen before did not grow, while the other tumors that their immune systems had not seen before grew. This proved the hypothesis in rodents, that the hypothesis has always been that there is cellular reprogramming that happens, that it drives the immune system to mount an immune response. So eventually, our hope is that we are able to replicate this in the clinic, and for that, you actually have to have patients who are, you know, earlier, who actually have a much better chance of, you know, a long prognosis. So that's the power of this drug. So everything so far that we have demonstrated is right on the dot, right? The efficacy should come in expansion, and then in that, and later, you should also see the two mechanisms working. That's, that's our hypothesis. Yeah. And then, so for the combo, the PD-1 combo, you will start in parallel with your monotherapy expansion, and how should we think about the cadence of those two cohort? Look, the idea has always been to do it in a staggered manner, right? Mm-hmm. Because once you have the RDE, you obviously start the- Mm-hmm ... monotherapy expansion, and then you have the chance to do a safety run-in first, right, in six patients, and then start the combo. So yeah, the plan has always been to do it in parallel, in a staggered manner. Mm-hmm. Got it. Okay, good. And anything else before we talk about the other early pipeline, maybe coming out of—we just read coming out from the ASCO, anything external validation? I know you don't have data there, but any external kind of read-through for your c-Myc or epigenetic controlling, so kind of from the field you want to highlight for people? From ASCO particularly? Not necessarily. Or recent. Yeah, I mean- Any, yeah ... I think what I would love for Tom to talk about is, look, we have been very busy in the spring, right? We went to the two spring conferences. And, you know, in one, we presented data in lung preclinical data, so Tom can talk about that. And then the ASGCT one was, actually, you know, equally exciting because we, for the first time, demonstrated upregulation, right? And we showed those data. Tom, you want to talk a little bit about that? Okay. Because that sort of tells you that this is not, you know, a company that is looking at one clinical program, you know, only, but there's so much richness in our platform and our pipeline. Why don't you talk about those two? Yeah, no, happy to. So just starting with AACR, so we submitted a couple of abstracts there. One was on our, some details on the clinical assay that we use to detect target engagement and methylation- Mm-hmm ... you know, to extreme degree of sensitivity, where we can detect sort of one in less than 1 to 10 million methylated alleles versus non-methylated. Mm-hmm. So exquisitely sensitive. And in the non-small cell lung program, we showed data showing that our lung-focused MYC targeting EC was active in EGFR inhibitor-resistant tumor cells, and also that we show, you know, strong synergy in terms of potency against the osimertinib resistance, you know, acquired resistance to osimertinib. So, you know, it gives us a lot of confidence going into, you know, additional models and thinking about the clinic there for use of that, both as a monotherapy and as in combinations. And it, ASGCT, as Mahesh mentioned, you know, we've shown very, very durable downregulation, you know, on the order of more than six months. And so what very few people have been able to do so far is show durable upregulation. And so that was really the focus of what we showed at ASGCT, where we showed across, you know, a large panel of different genes and also using different epigenomic effectors, that we're able to modulate and upregulate not just genes that are turned off, but also genes that are already on and expressed, and we can tune those up further- Mm-hmm ... you know, to augment for therapeutic benefit. Mm-hmm. You know, at peak level, we can upregulate anywhere between 10-fold and, you know, more than 1,000-fold at peak. And over timescales of a month or more, you know, we can maintain those upregulation levels at, you know, therapeutically relevant levels, you know, for that whole time. So really, you know, tremendous advance both for the platform and I think for the field. Mm-hmm. Excellent. Okay, last minute, I know we haven't really talked about your, the metabolic and obesity program with Novo. Just to, highlight here is Novo is very research-focused organization, and the fact that they want to sign an early collaboration with you, they know the power of the platform. But any updates from that program? Understanding it's early stage. Yeah ... but anything you want to highlight with us? Yeah, I mean, I think it's early stage, and, you know, we can't talk much about that contractually as well. But, you know, what we can say is it's right on track.... Right, so obviously we are working, and it's super exciting to, by the way, work with a company like Novo that's an expert in this area, right? We are learning a lot. They are learning a lot from us. And, you know, our milestones are right on track. So as they come to fruition, we will definitely talk about that. So all I can say, Roger, is that we are super exciting about this program, and by the way, so is Novo. You know, Ulrich Stilz actually saw the value of our platform and, you know, so did Marcus, and they continue to remain excited about what they're seeing right now. We just met them a week ago. Okay. You know, all I can tell you that the excitement continues. Okay. Look, I mean, for those of you who may not have fully followed the news, what we have done with Novo is we have signed a deal where they will take license to one epigenomic controller. You know, that will allow trans-differentiating white fat to brown fat, and brown fat is metabolically active, and it burns itself. So just imagine a state. Today, people are taking GLP-1s, but they have to take them all the time, and once you stop taking them, sort of the weight loss returns. And GLP-1s are great drugs, right? Fantastic. I mean, I think it's a sea change that has happened. But they work, you know, in sort of three mechanism. One is, they essentially, it is satiation or gastric emptying or things like that, right? Or nausea, right? So essentially, you don't take food. In this case, what we are together looking for the vision really is to change the metabolic state of your fat so that you don't need to take this drug all the time. So imagine a state where you take a few applications of this drug, depending on the patient's, you know, levels of obesity, and once that fat is burned, it's gone, right? And then maybe you can get into maintenance. This could potentially be curative. So that's what we are, and for Novo to choose Omega to help with that is incredible for us. I believe we're gonna talk a lot more about that.