All right, so welcome to this next Fireside chat. With us today, we have Adrian Gottschalk, the President and CEO of Foghorn Therapeutics. Adrian, welcome. Thanks for joining us. Thank you for having me. I'll just start out with a couple of high-level questions, Adrian. Foghorn was founded based on the premise to targeting the chromatin regulatory system and the BAF complex. Maybe just if we step back for a second, what makes this group of targets within oncology so interesting? Sure. Again, thank you for having me here today. If we take a step back, this is an area of biology that historically was not fully studied or fully appreciated for its relevance in disease pathology. If you look at cancer, just as one example, which is obviously the predominant area of our focus, about 50% of cancers have some sort of dependency or genetic mutation that links back to chromatin regulation. Very simply, chromatin regulation is just a fancy way of saying controlling gene expression in this case. The company, when we started, was very focused around a single chromatin remodeling complex, this BAF remodeling complex, which we can get into a little bit more detail on. The challenge has been, how do you drug this system and drug it in a very selective manner? A lot of the machinery or proteins in the system have sister proteins or paralogs that are, in some cases, 90%-95%+ similar. Getting selectivity against these targets has been challenging. Establishing the disease relevance, I think, only came onto the setting over the last decade or so as all of the shRNA knockdowns and CRISPR knockouts were revealing that, indeed, this biology was playing a role, especially in the setting of cancer. Yeah, I guess given some of these redundancies and paralogs of these proteins very similar, as I understand it, how do you approach that from a targeting perspective, chemistry-wise? Right. That actually has been the seminal challenge with going after the system. I know we'll spend a bit of time today talking about the SMARCA2 program, but I think that's a great place to highlight the challenge. SMARCA2 and SMARCA4 are enzymes. They are part of this BAF chromatin remodeling complex that sits on chromatin and effectively opens up and exposes the double-stranded DNA for transcription. The challenge with a target like SMARCA2 is that it's about 90%+ or so similar if you look at the primary amino acid sequence. It's about 90% the same as SMARCA4. If you look at the catalytic pocket, the actual ATPase binding domain, it's almost identical. This has been a target that for well over a decade, others, Novartis way back when, had tried to drug. If you set out to drug this protein, odds are you're going to find dual chemical matter. That plays out for other targets like our CBP program, which CBP and EP300 are very similar proteins. Same thing for our ARID1A-1B program. Again, very, very similar targets. Very, very difficult to get and engineer in that selectivity. In the case of SMARCA2-4, at least it's an enzyme, so you've got some other options. In the cases of ARID1A-1B, there's no enzymatic activity, so you don't even have a small molecule inhibitor approach to take there. Okay. You obviously managed to, you and your partner, Lilly, I guess, managed to design an inhibitor, FHD-909, that targets SMARCA2 selectively. Maybe remind us first of the scientific rationale for going after SMARCA2. Right. Absolutely. In the case of SMARCA2 dependency, this sets up what I think of as a classic synthetic-lethal relationship. I like to simplify this for those of you who like to ride bicycles. There are two wheels usually on a bicycle. The SMARCA4 protein is lost, so you can imagine that wheel goes away. Now you have cancer, in this case, riding a unicycle. Our goal is to take a stick and put it right into the middle of the wheel, that SMARCA2 protein, and throw cancer, in this case, off of the bicycle. The actual dependency had been pretty well established by Novartis back in the day with their Project DRIVE data. This is where they were taking shRNA knockdowns. They would knock down a gene expression, and then they would knock out another or knock down another protein. In this case, SMARCA4 was knocked. You could see that SMARCA2, when you took that out, it was able to kill the cancer cell. Same thing through the Broad Institute when they had Project Achilles. There, obviously, they were using CRISPR. Fast forward then from a clinical perspective, which actually is the most relevant reason beyond just the mechanism of action that exists here. If you look at patients in the literature who have been studied, I'll use the example of stage IV metastatic non-small cell lung. In that first-line setting where patients are given a checkpoint inhibitor and chemotherapy, you can clearly see that patients who harbor these SMARCA4 mutations have a far worse prognosis. The response rate is cut in about half. It goes roughly from about 40% to about 20%. And progression-free survival, median overall survival, are dramatically lower. There is clearly an unmet medical need. There's a clear biological dependence. Of course, we've demonstrated through multiple CDX models preclinically that if you have a selective molecule and you go into these cancers that have SMARCA4 loss of function, you can actually kill the tumors in these models. What is the size of the overall commercial opportunity in SMARCA4 loss of function cancers? Right. So there's obviously a myriad number of tumors, including cutaneous melanoma, some bladder cancers, others. We tend to focus predominantly on non-small cell lung, just given the size there. So roughly 10% of non-small cell lung cancer patients will harbor a SMARCA4 mutation. The literature then on exactly how many of those patients have the loss of function mutation, which renders this synthetic-lethal exposure, numbers vary from five out of 10 to six or seven out of 10 of those patients. So that's roughly how we think about it on an incident basis. And of course, that's just the U.S. So patient numbers in the U.S., rough justice sort of 220,000 patients diagnosed with non-small cell lung, 10%, right, 22,000. So you can sort of do the math, somewhere between 11,000-15,000 or 17,000 patients. Maybe just stepping back, so when I think about your pipeline, I mean, these are all sort of first-in-class opportunities, which obviously bring a lot of benefit, right? Being first to a market is always a great thing, especially if the targets are hard to address. There is obviously some clinical risk being first, right? What's interesting about SMARCA2 is we've actually seen some clinical data and single-agent responses in patients that have been treated with the SMARCA2 program or degrader in this case, but that was recently discontinued or deprioritized. Maybe talk about read-through, potential read-through from that program to your program and how your program may be differentiated from that. Sure. You're talking about our colleagues at Prelude who last week, I think, announced that they were stopping their efforts on SMARCA2. At least as we read the press release, I think they stated several things that we recognized a few years ago, hence the collaboration that we did with Lilly back in December of 2021, which is if you're going to go play in this area, you're going to end up needing to do combination studies, especially in non-small cell lung. The development path on that probably will benefit from a strategic partner who can help defray risk as well as cost, which is indeed what we did with our colleagues and friends at Lilly. It's interesting. Prelude had both a VHL protein degrader as well as a Cereblon-based degrader. I should actually just take a step back and say we've been working on this complex, this BAF complex and obviously related SMARCA2 target since almost the inception of the company, so eight and a half, nine plus years. What we know from studying this biology is that you actually have to hit this target really hard. In the case of an inhibitor, that means you want to have an IC90 coverage, and it's important to have a sustained coverage. In the case of a protein degrader, similar concept, you need to get up to at least roughly a DC90 range, and it needs to be on a sustained basis. The oversimplification of my I'm a simple guy. It's like it's a tug of war, right? It's between how much the cell is making that protein, in this case SMARCA2, and how much your degrader is chewing it up. You do not want the protein resynthesis rate overcoming the degrader. In the case of what our colleagues at Prelude have done, their VHL degrader, they have got published clinical data. We do not know what their data were for their Cereblon oral degrader. In the case of their VHL degrader, they actually showed, in our mind, really nice validation of this target. They had, I think, across a range of doses, but sort of five PRs, two in esophageal, one in gastric, two in non-small cell. Again, showing that if you can hit this target where there is loss of function, you can get regression of the tumor and certainly get resist-qualifying responses. I think the challenge, both for their VHL degrader as well as their Cereblon, and we have put some data in the appendix of our investor deck, we actually have made their molecules from their patents. At least in our hands, they are not degraders that we would have taken in the clinic. They get about 80% + or so degradation. Kinetics, which I cannot underscore enough how critical the kinetics are with degraders, they're not very rapid degraders. You end up, in the case of their molecules, we do see a hook effect where they've saturated the binary complex, which then abrogates the ability or prevents the ability to engage the ternary complex. Long-winded way of saying with some scientific words, they just didn't hit the target hard enough, and they weren't covering it hard enough. We saw that in their preclinical data for VHL. We've seen it in their clinical data for VHL. Have not seen their clinical data for the oral Cereblon molecule, but preclinically, it looks very much the same to us. At this point, our view is that they're just not hitting the target and covering it hard enough. Again, we've designed 909 along with Lilly in a way that the goal is to cover the target at an IC90. It's not a degrader, so just a little bit of apples and oranges, but really cover that target, hit it as hard as we can. Right. This is in phase one since last year. Maybe talk a bit about how the study has been going so far and what learnings have been to date. Sure. So maybe just to talk about sort of the study design, right? We're taking all histologies, so any cancer, with the requirement that the patient has to have some type of SMARCA4 mutation, or they could also have a deletion. That's sort of for this dose escalation portion. Once we get into areas where we believe we're getting closer to therapeutic range, we will do some backfilling. We're starting to do some of that already now. In those cases, we are prioritizing non-small cell lung cancer patients with clear loss of function of SMARCA4. The study has been ongoing since October of last year. Lilly is responsible for the day-to-day operations of the study. They have five sites in Japan that are open, 15 sites in the United States. Sites in France, Germany, Spain, and South Korea are being opened as we try and wrap up dose escalation, but also in preparation, if there is a go-to-dose expansion, we'll want those sites available as well. To date, we have not hit our maximum tolerated dose. We actually recently dose escalated again. What that sets up, assuming that we're getting close in the range, and based on PK and other things, I think we're starting to be pretty close, it sets up a potential go-no-go to expansion from our colleagues at Lilly. They will make that decision. We anticipate that that could be sometime in the first half of 2026. Obviously, if we keep going up beyond some of our projections, then that may move things a little bit. Right now, we believe that's going to be in the first half of 2026. I would just say overall, very impressed with what our colleagues at Lilly have done vis-à-vis enrollment. There's not been any issue in getting patients into the study and onto drug. Right. What are some of the potential adverse events or even expected DLTs for this mechanism? Can we read into the fact that the study is dose escalating at this point in time in terms of its safety profile, perhaps? Yeah. I mean, so far, obviously, if we haven't hit our MTD, we haven't hit the MTD. I can't speculate and obviously can't discuss sort of what we've seen within the study as of yet, but I think a good proxy for what we're on the lookout for, if you will, was what we saw with our 286 program that we stopped. This was a dual SMARCA2/4 program. And I would say there's just general tolerability-related issues we ran into: fatigue, muscle weakness, a constellation of things I would characterize as more chemotherapeutic-like, just where the patients just didn't want to take the medicine. So we're obviously very much keenly attuned to looking for that because if we hit that, then we know that we're hitting both SMARCA2 and 4. Otherwise, knock on wood, so far, so good to date. Okay. Ultimately, do you see this as a mechanism that could generate sufficient single-agent activity in something like lung cancer that could warrant a monotherapy study down the road, or is it more an agent that would benefit from combinations? Yeah. So I won't speak for Lilly, but I certainly have the expectation that this should have monotherapy efficacy. Keep in mind we're in these third, fourth-line non-small cell lung cancer patients. Depending on which literature you read that has done some of the post-hoc analysis on these patients, the response rate is somewhere between 0%-10%. Progression-free survival here is two months, maybe a little less than that. These are relatively ill individuals, unfortunately. I certainly would like to see monotherapy efficacy. The intent, however, is to move into the frontline setting in combination, certainly with pembrolizumab plus-minus chemo, likely with some other agents. As far as we think about clinical development, what the plan is for expansion right now is there'll be at least two monotherapy cohorts. One will be a non-small cell cohort. Other will be sort of other tumor types that we may be interested in. Other cohorts will include combination regimens. That is sort of what we are planning for, or I should say Lilly is planning for as we consider going into expansion. I think ultimately, and thankfully, cancer is a game of combination studies, but you definitely want some monotherapy efficacy in your agent. You need to understand that it is at least contributing something and not just praying and hoping and wishing under some biology construct that you are going to say there is synergy when you have not seen any monotherapy efficacy. I want to see monotherapy efficacy out of the study. All right. Looking forward to updates, hopefully next year on the SMARCA2 program from Lilly. Maybe just shifting over to your wholly owned pipeline. The CBP, EP300 program is your most advanced in-house program right now. Maybe stepping back, just remind us of the mechanism and opportunity for targeting CBP or respectively EP300. Sure. These are, again, two sister proteins, if you will, very, very similar. Historical efforts here have resulted in drugs that hit both CBP, EP300, Genentech certainly back in the day. More recently, our colleagues at CellCentric, who have a dual bromodomain inhibitor of both CBP and EP300. These proteins are responsible for histone acetylation, right, which is how they regulate gene expression. In our case, and my Chief Scientific Officer has worked on these on and off for the better part of two decades, the challenge with dual perturbation or inhibition of both of these proteins is you end up with myelosuppressive effects or an impact on the heme compartment, so specifically impact on platelets. You can end up with thrombocytopenia, neutrophils, you end up with neutropenia, and sort of anemia, which can be managed as we've seen with what CellCentric's done with a four-day-on, three-day regimen in the clinic. It is an extra tolerability and a tox liability that as you're thinking about combination regimens, I think is going to become very challenging. In the case of CBP, we've got for each of these, I think, are distinct programs. You've got a selective degrader of CBP and a selective degrader of EP300. Different tumor types in the case of both of these programs, which we can talk in more detail, but we're excited by what we've been able to do for CBP. We've basically got our pre-development candidate. We're actually right in the middle of the dose range finding studies right now for that program. EP300 is about six to nine months behind where CBP is. What's the size of the commercial opportunity for those two targets? Right. For CBP, there are two buckets of potential tumors there. Where you have EP300 mutant loss, you have a range of cancers, which include endometrial, ovarian, cervical, lung, and a few others are in there. Depending on how you look at the incidence there in the U.S., there are probably about 20,000-25,000 or so patients that have that mutation. Again, we are going to be interested in loss of function, so that is going to vary across those tumor types. There is also what we have observed with targeting CBP, a dependency that is created in ER-positive breast cancer, where targeting CBP downregulates signaling receptors as well as an impact on some of the other factors like MIC. That is something we are still exploring. Obviously, ER-positive breast cancer is huge, unfortunately, a very complicated indication. That is something that we would not go off and do by ourselves longer term. EP300, now talking about the reciprocal here, I'll start with the dependencies we've observed because that's what we're prioritizing. We've seen very interesting dependencies across a range of hematological malignancies, top of that list being multiple myeloma and diffuse large B-cell. There is a nice slide in our investor deck. You see a range of these tumor types. There, it's a question of how do you move forward in the treatment paradigm there given some excellent quality and standard of care medicines. Certainly, that could be very sizable. We also have the CBP mutant. Sorry for all the nomenclature here. It can get confusing. The CBP mutants, which again, similar type sizing that I just mentioned for the reciprocal protein. We're excited by both these programs. EP300, I think the beauty there is it's been in some ways from our colleagues at CellCentric. They've already de-risked some of the clinical pathway on this. Again, the bet we're making is that with the selective EP300 degrader, we're going to eliminate or minimize any of these tolerability effects. We'll make it a better agent for combination studies in a range of heme malignancies. Right. The nice thing is, I mean, there seems to be simulation activity with the unselective programs, right? To what degree does that validate? It's an obvious question, right? The selective approach though, in a way. Yeah. No, look, I think it tells you that the pathway is certainly valid to go after. And when we've looked at the CBP degrader and the EP300 degrader in the case of multiple myeloma, the majority, if not all, the efficacy is really coming from the EP300 component of the protein. So again, I think what our colleagues at CellCentric have done is fantastic for patients. I think they saw a 70%+ response rate, nine plus months duration. So I would expect us to, knock on wood, when we get in the clinic, generate similar, if not better, results. But we're not going to have to skip on dosing. I think they're dosing four-on, three-off to mitigate some of these issues. That should help you with combinations as well, especially in heme. Yep. Absolutely. Yeah. And then maybe lastly, just touching on ARID1B. And so maybe again, stepping back, how well validated is ARID1B in oncology as a drug target? Right. This is a target if you're looking at various gene panels. It pops up as one of the most mutated set of synthetic lethal targets in cancer. ARID1A in this case is mutated, creating a dependency if you go back to my bicycle, a little analogy on ARID1B. ARID1A is mutated in roughly, excuse me, 5% of all solid tumors. It is right at the top of the list. It has been a target that has been, frankly, intractable. As far as we know, publicly, we're the only ones to ever have found selective binders, let alone selective degraders to this target. We certainly know through conversations we've had with strategic biopharma over the years that folks have tried to drug this, but unfortunately without success. Right. Yeah. Maybe can you touch briefly on your degrader and, yeah, how were you able to generate a selective molecule and what is the status of the program? Sure. My CSO was at this targeted protein degradation conference a couple of weeks ago, and people said, "Well, how did you get it? How did you design it?" I can't tell you some of those specifics to give away the secret sauce. I think it's actually a very nice illustration of our platform where we've been able to make, and I'll step back for a second. ARID1A and 1B are very large proteins. A large chunk of those proteins, they're intrinsically disordered. It's not obvious where you would go to find binders. They're, again, very, very similar, so very hard to find selective chemical matter. This is where our platform has come into play where we can make this full one and a half million molecular complex containing ARID1A, very pure, containing ARID1B, very pure. We can screen against the full complex. We can find chemical matter. Long and short of it, that's sort of how we, over a few years, came up with selective binders. Then it became the challenge of, can you convert those binders with a linker with the appropriate, in this case, VHL and Cereblon ligase, which we were able to do. We are structurally enabled with the structure of the ternary complex. That revealed some very interesting insights in terms of exit vectors for the degraders. We're effectively in hit to lead. We're tracking to in vivo proof of concept sometime in 2026. Really excited by that program. I think that one really highlights some of the unique capabilities we have. Great. Thanks, Adrian. Unfortunately, we have to wrap up. Looking forward to learning more about SMARCA2 next year and then the CBP program into IND acceptance. Perfect. Great. Thanks for having me. Thanks, Adrian. Appreciate it. Yep. Great. Yep. Great.