Foghorn Therapeutics Inc. ($FHTX)

Okay. We will continue with the next session, which is Foghorn Therapeutics. I'm Paul Choi, and I cover the SMID-cap biotech sector. It's my pleasure to have Adrian Gottschalk to my immediate left here. Maybe what we'll do is what we've done in prior sessions. And maybe we'll let Adrian sort of describe what are Foghorn's strategic priorities for the remainder of '26 and going into '27, and then we'll go into Q&A.

Sounds great, Paul. Thanks for having me. Thanks to everyone for being here today. Yes, look, I think next up and most importantly, as we think about 2026 is our FHD-909 program. This is the selective SMARCA2 inhibitor molecule that is partnered with our colleagues at Eli Lilly in a 50-50 strategic collaboration with them. So, our guidance hasn't changed over the course of the last 6 or so months. I anticipate that sometime over the course of the summer, we'll be in a position where the collaboration will make a decision whether we proceed to expansion or not. And I'm sure we'll get into some of the details around that. So that's coming up over the next several months. We've got an exciting proprietary pipeline behind the Lilly collaboration, roughly this order. We have our CBP selective degrader. That's for ER-positive breast cancer. We're -- we've actually completed our non-GLP tox studies. We're actually doing a bunch of animal pharmacology work, both as a single agent, but also in combination with oral SERDs and CDK4/6. That's gating for us to then go into GLP tox, which would likely come towards the end of the year, setting up an IND and potential entry into the clinic in 2027. We have our selective EP300 degrader, which is targeted for a range of heme malignancies, but certainly multiple myeloma, potentially diffuse large B-cell lymphoma. Very excited by that program. The gating or next critical step for us is formulating that as a once-a-week subcutaneous formulation. If we were able to do that, that's tracking to the non-GLP tox studies sort of in the Q3, Q4 time frame, also setting up a potential IND next year. Again, excited by that just based on some competitor data in the clinic that has already validated that target or program. We have an I&I asset that's not disclosed on our pipeline. We're still keeping that very much below the radar screen. I won't have too much to say about the target or anything related there. But that's a small molecule looks in several different animal models, looks as good as one of the major antibodies that's used in this particular autoimmune disorder. That's tracking to non-GLP tox studies towards the end of the year, also an IND potentially next year. And then lastly, our ARID1B selective degrader. We've made really nice progress on that much earlier than the other 3 things I just mentioned. That's tracking to in vivo proof of concept this year. That's sort of the setup and lay of the land. So a lot of different things between the clinical decision for 909 with Lilly and then our proprietary pipeline.

Great. Investors may be somewhat familiar with SMARCA given that there was a -- ARID1B that was being investigated for a little bit. I think it got put on hold. Can you maybe tell us what do we know about SMARCA, I guess, at this point and just sort of what is its prevalence across various major tumor types here?

Right. So maybe I'll just take a step back on this and just describe the biology at a high level why we're interested in the target and then talk about some of the relevant tumor types where we're interested and excited. So SMARCA2 and SMARCA4 are actually ATPases, they're actually part of a broader chromatin remodeling complex that's responsible for opening, closing chromatin vast oversimplification of the biology there. They're mutually exclusive, meaning that the machinery only has either SMARCA2 in it or SMARCA4. And the observation that has come out over the better part of a decade now is that in [Technical Difficulty] tumors that lose that SMARCA4 engine or ATPase [Technical Difficulty] for their survival on SMARCA2. And so, we had set out actually at the inception of the company roughly a decade ago to try and selectively drug SMARCA2. We ended up finding a selective allosteric inhibitor, which is 909. That's what we've actually put into the clinic with Lilly. The relevance here, specifically in non-small cell lung cancer is about 10% of non-small cell lung cancer harbor -- these individuals, these patients have a SMARCA4 mutation. It's about mutated in about 5% of all different solid tumors, but we don't know exactly the relevance of that. We don't know exactly the synthetic lethal setup there. The most well-established one that we've spent time on within the collaboration is indeed in non-small cell lung cancer. We'll see whatever the clinical data shows. But that's sort of why it's relevant. And maybe one last point that we know from the various literature and studies that have been done is the patients that have -- the non-small cell lung cancer patients that have a SMARCA4 mutation, their prognosis is far worse than those who are wild-type. There's plenty of literature out there that shows that the patients who receive chemoimmunotherapy, if you have a SMARCA4 mutation, basically, you cut their efficacy across all parameters in about half.

Can you maybe walk us through what is the reason for targeting SMARCA2 instead of SMARCA4 -- and why is selectivity important here? And I've always admired the medicinal chemistry prowess at Foghorn and how are you able to overcome that technical challenge of targeting SMARCA2 with an inhibitor here.

Right. So, we know from our own experiment. We had a prior molecule, which was FHD-286 that we stopped the clinical studies on. It was actually a dual inhibitor equipotently targeting both SMARCA2 and SMARCA4 [Technical Difficulty] healthy cells have both of these proteins by and large in it. [Technical Difficulty] hypothesis is that you'd have a much narrower therapeutic window. And that's actually what turned out to be true. We ran that experiment with 286. We ran it in uveal melanoma and AML. It just wasn't very well tolerated. We did see efficacy, but you just couldn't push the dose as high as you needed to, quite frankly. And so the setup here is to try and make sure you're only drugging or being more selective for SMARCA2. So you're not engaging SMARCA4, you're not going to get all of these tolerability side effects, potential safety issues that arise from dual inhibition. And again, I've commented publicly, I haven't commented on any efficacy. But by and large, so far in our clinical study, the drug has been generally safe and well tolerated. So again, we're still escalating. We're backfilling cohorts that we can talk about. So how do you drug it selectively, that has always been an issue and the 2 approaches that has sort of surfaced over the course of the last several years have been enzymatic inhibition, which we've obviously achieved as well as targeted protein degradation, which Prelude and some other current competitors are trying to tackle. The challenge with drugging this targets selectively is that SMARCA2 and SMARCA4 are about 90% similar if you look at the amino acid sequence of the structure. So it's really hard to find something that differentially engages one of the proteins, but not the other. And if you look at the ATPase binding pocket of the proteins, they're almost identical. And so we set out with our platform where we could make -- simplify this full remodeling complex with the relevant SMARCA2 or SMARCA4 protein, and we could then screen chemical matter and see actually which ones were more selective for one over the other when it was actually studied in its native context. That's a pretty great simplification for how we were actually able to find selective chemical matter.

Great. You mentioned earlier that SMARCA mutant patients might constitute approximately 10% of the non-small cell population. So pretty sizable here. But can you maybe walk us through currently, how are these patients identified? Do they fit into the sort of regular screens? Or do you need NGS here? And then more importantly, what is sort of the typical prognosis based on the available treatments that are out there for non-small cell lung cancer?

Right. So, my understanding, at least sort of in the United States is if you have lung cancer and you get a biopsy, this is just part of the standard NGS panel that's run. So as an example, the SMARCA4 mutations are in the Foundation screening and Tempus, et cetera. So, finding out whether you have a SMARCA4 mutation seems very readily accessible and available, especially in this day and age. The second part of your question, sorry, was...

Just what is the clinical outlook or prognosis...

Yes. What's the prognosis for these patients? So unfortunately, if you harbor a SMARCA 4 mutation, you have a far worse prognosis than not. Maybe some other important facts here, which is if you look at some data coming out of Memorial Sloan Kettering and you look and see when they sequence these tumors, there's, by and large, not a lot of overlap with other driver mutations like EGFR, ALK, RET, or MET. However, there's about a 33% or for every 10 patients that have SMARCA4, roughly 3 out of those 10 patients also will have a concomitant KRAS mutation. So, for -- let's just deal with just the pure SMARCA4 patients for a moment. So, in some of the literature and studies that have been done in the retrospective analysis on the patients and how they performed. So in a frontline study, first-line non-small cell metastatic setting, patients receiving a PD-1 and chemo response rate for wild-type is about, call it, 39%, 40%, median PFS of about 6 months, overall survival is about 15 months. In the SMARCA4-mutant population, you cut that in about half. So, response rate is about 22%, median PFS is about 2.7 months, median OS is about 8 months. So, they progress rapidly through the various treatments. They have about half the efficacy in that frontline setting. They're relatively nonresponsive to that frontline treatment. And again, because they don't overlap with any of the other major driver mutations, there's not a lot. I can tell you, without getting into any of the clinical data per se, we're seeing patients in the backfill cohorts as we're enriching for lung cancer. They're predominantly fourth- or fifth-line patients. They have progressed very rapidly through the other lines of treatment. And so, these individuals, unfortunately, have a much worse prognosis. The unmet need here is pretty significant.

Okay. You talked a little bit about backfilling. So maybe help fill in the picture on what is the Phase I design that you and Lilly are currently pursuing? How does this work in terms of the study you're conducting? And then you talked a little bit earlier about potentially talking about updates during the summer here. Can you maybe remind us what are some of the endpoints and metrics? And how do you assess this in this sort of later-line population?

Right, right. So just to set context here as well. So Lilly is responsible for all the day-to-day operations in the clinical study. We started dosing patients as a collaboration back in October of 2024. Initially, the sites we had opened were about 5 sites in Japan, 15 or 16 sites in the United States. We started -- and the escalation was sort of any solid tumor as long as you had any SMARCA4 mutation or SMARCA4 deletion. We've roughly cleared a cohort every couple of months or so. We've been at it 18-plus months. You can do the math, plus or minus in that range in terms of number of cohorts that we've gone through. In the latter part of Q4 of last year, per protocol, we started backfilling some of the cohorts. And the backfilling is relevant because that's where we're trying to enrich for non-small cell lung cancer patients, and we're also enriching for this loss of function or Class I type mutation. That was triggered by either achieving 1 of the 2 things, which was hitting the predicted IC90 exposure, right? So we're doing blood draws, so we know what the exposure, but based on the allometric scaling from the animal models, we believe we had either hit the IC90 or close to it and/or we had seen some clinical activity, tumor shrinkage, some sort of sign that this drug was actually in therapeutic range. We've not commented on whether it's one or both of those things. But needless to say, we started backfilling the cohorts roughly in the late part of Q4 of last year. That's the group that I'm most interested in assessing for efficacy because that's where the lung cancer patients are. So based on how things have unfolded, and this is my guidance, I'm in no way speaking for our colleagues at Lilly. I believe that sometime over the course of the summer, I don't know if it will be July time frame or August time frame, I believe we'll have enough non-small cell lung cancer patients, somewhere between 10 to 20, maybe a little more than that, we'll see, where we'll have enough radiographic scans to understand is the drug active as a single agent and is it meeting whatever bar that Lilly has in their mind. I can speak to the bar that I have. Again, won't speak for Lilly. So that's what I think what's going to unfold over the summer, fixated again on this non-small cell lung cancer patient population.

Great. Since we don't have a historical analog in terms of SMARCA targeting drugs in lung cancer, I guess, maybe, Adrian, can you elaborate on that? What, I guess, based on KOL feedback or physician feedback, have you heard would constitute a good response or a good result, I guess, rather in the fourth or sort of fifth line lung population here? Are we primarily focused on survival metrics, ORR, disease control rate? Maybe just help fill in the picture there.

Right. Yes. So obviously, it's a safety study, first and foremost. So we want to make sure whatever doses we get are well tolerated and generally safe because the end game here will be to ultimately move towards frontline and certainly in combination likely with pembrolizumab, but maybe with a KRAS inhibitor at the relevant point in time. So, this is -- I'll give you my view, and I'll tell you sort of anecdotally what we've heard from some of the KOLs. I'll start with the KOLs. Depending on who you talk to, someone will tell you 10%, 15%, 20% with some duration of response a few months. Keep in mind, I mentioned a few moments ago how these patients fare in the first line setting when they're given a checkpoint inhibitor plus chemo. Median PFS in a large population is about 2.7 months with a response rate of about 22%. Given that this is fourth, fifth line patients, there are no studies. There's not really -- there's just anecdotal conversations. Patients who are coming into our study are incredibly sick individuals, usually life expectancy measured in a number of weeks, not many, many months. And so my personal view on this is with a denominator of somewhere between 10 to 20 patients, I'd like to see 3 or so partial responses. I'd like those to be -- have some durability. So I'd like to see in the 3- to 4-plus month range to make a decision from a development perspective. We're not gearing this towards some overall survival, but we'll have a sense for how long people have been able to stay. I don't think we have to follow patients for the entirety of the lifespan per se in order to make a decision. We need to know that this is active as a monotherapy such that whatever we go forward with, we have a reasonable chance of actually helping patients when we move into the earlier lines of treatment. So that's how I think about it. We'll see, obviously, how things go over the next few months.

Great. Earlier, you mentioned about maybe 3 and 10 patients here overlapped with a KRAS mutation. And so, I guess, given that subpopulation here, how do you think about potential either sequencing of either your drug or a KRAS therapy in this population? Do the combinations rationally make rational sense here? And just sort of how do you think about the potential and developmental path given that this is a substantial chunk of the addressable population?

Yes. So we've done a lot of preclinical work in the space. We've actually had multiple models with pembrolizumab, one genetically engineered model, syngeneic model where we're using -- we haven't altered the animal's immune system. So those data are pretty striking. Those were presented at AACR just a couple of months ago. On the KRAS side, our colleagues at Lilly obviously have their own portfolio of KRAS molecules. The preclinical data that's been generated with their KRAS therapies. And again, the combination of the 909 molecule plus whether it's a pan-KRAS or a KRAS G12C or G12D look pretty striking. I can't comment on when Lilly would want to potentially run that study, what the sequencing would be. But I think there's a lot of rationale to actually go out and look at 909 with a KRAS inhibitor. At present, as you probably know, the KRAS drugs, at least the ones that are currently approved, tend to be reserved for a second-line treatment because they haven't yet demonstrated that they can outperform the IO-chemo regimen in the frontline setting. That may change with some of the newer therapies that are coming with different side effect profiles or improved side effect profiles and potentially better efficacy. So I think it's fair to say that is of interest to the collaboration in the fullness of time. We'll just have to see sort of how that field plays out. Obviously, there's a lot of exciting new data with KRAS these days.

Great. I want to touch briefly on your other approach to SMARCA, your degrader program, which [Technical Difficulty] -- but just sort of again, given the prelude analog in the category, what are sort of the learnings there, I guess? And how do you think about potentially improving with a next-generation degrader like yours?

Yes. So, one of the things that we know having studied this target for as long as we have is that you have to hit it really hard. If you're an enzymatic inhibitor, that means hitting at an IC90, not just in a brief little Cmax and pop down, but really sustained target coverage. The same is true, if not even more important when you're degrading this. And so, I can't comment about the specific details of the degrader program with Lilly or status per se. But we know that you need to be north of 90%, even maybe 95% on a sustained basis for degradation. And there's actually a very nice linear correlation with -- that we've been able to generate with ranges of degradation percentage and correlation, again, it's a very -- it's actually a very nice linear relationship with the TGI or regression you achieve. And the only time that you can get regression is when you're at 90%, 95-plus percent. And when you compare that actually to our inhibitor 909, we've not yet had a degrader outperform what we've been able to achieve with our inhibitor. Prelude's molecules, they had both a VHL, which was intravenously delivered. They had a cereblon, which was orally delivered. In our hands, those molecules never really got past about 80%. Again, we believe we made their clinical candidates based on their patents. We replicated the data. And I think that's part of the challenge is you need a very rapid degrader. Selectivity is important at some level, but I think you have to have a rapid deep degradation of that target. So I think the fate of the degrader program is obviously tied to 909. We'll see what happens with 909. I think then we'll be able to comment further.

Great. We've spent a lot of time talking about lung, but you are -- you have tested 909 and Lilly has tested 909 in other tumor types. And so maybe just broadly, what constitutes good results in those particular subtumor types from your perspective? And what, I guess, beyond lung would potentially make more -- the most sense to go after should the results be positive?

Right. So the gene or the protein is mutated in 5% of a range of different solid tumors. We have a relatively, I think I can say, eclectic mix of a lot of different solid tumor histologies in the escalation. I can't comment on which one would be the right one at this point to potentially prioritize, but I think the clinical data will sort of point us in that direction when all is said and done. I think it's all going to depend on the depth of the synthetic lethal dependency that exists, the type of mutations. Again, it's going to be a smaller N relative to lung cancer, which has always been the priority. So we'll just have to wait and see what tumor types could be of potential interest for us.

Great. I want to turn to some of your non-partnered assets and what else is in-house and specifically CBP and EP300. Can you maybe walk us through what is the meaningfulness of selectivity between these 2 targets? Why is that sort of clinically important? And how do you achieve that from a drug development perspective?

Right. So maybe again, just a context setting on CBP and EP300. These are histone acetyl transferases, [indiscernible] you just saying they're depositing acetyl marks on various proteins as they're regulating gene expression. This is actually -- these targets or these proteins have actually been drugged or attempted to be drugged by others before. Genentech way back when had a dual CBP, EP300 bromodomain inhibitor, Forma Therapeutics, which I believe was acquired or assets acquired by Novo, similar thing. Our colleagues at CellCentric most recently are the ones that are actually being [Technical Difficulty] demonstrated, I think, some very compelling data in multiple myeloma. The challenge with hitting both of these targets without selectivity is it ends up having a myelosuppressive effect. So you end up impacting -- or you end up with a range of cytopenias from impacting platelets, so you get thrombocytopenia, neutrophils and neutropenia, a bunch of other white blood cells and leukopenia. And I think that's been clinically now demonstrated by our colleagues at CellCentric in their dosing regimen on 3 on. So we've set out to try and selectively drug either CBP in the case of ER-positive breast cancer or selectively drug EP300 in the case of a range of heme malignancies, multiple myeloma, diffuse large B-cell range and potentially prostate cancer as well. And we've done enough of the experiments where we've done selective drugging. We have a dual degrader. We have all the dual inhibitors. And we can see that this is very much -- with dual inhibition or dual degradation, it's very much an on-target pharmacodynamic effect of impacting these other cell lines. And we think ultimately that, that's going to be rate limiting, or efficacy limiting is probably the better way to describe it. Once one is in the clinic, you're either going to have to down-dose as we're seeing with our colleagues at CellCentric or you're going to have to dose downdose and dose intermittently as they're doing 4 on, 3 off. So I think that's been the challenge, again, sort of in our sweet spot of drugging really similar proteins and finding a unique way to get at it.

The world of multiple myeloma has become increasingly complicated in terms of treatments, whether it's CD38, BCMA plus the classic Revlimid or IMiDs and things like that plus Pom and dex. And so I guess, as you think about the developmental path in multiple myeloma and other hematologies first, how are you addressing this and identifying sort of what is a relevant population from a preclinical perspective? And then as you think about sort of down the road, what is the sort of natural starting point from a clinical development perspective?

The MajesTEC study that you just referenced from J&J, the BCMA/CD38 (sic) [ BCMA/CD3 ] , I mean those are impressive data. And I think it's amazing for patients. I think over time, that's going to -- maybe faster than we all think that will certainly work its way into that frontline setting. But we know patients become refractory to treatment. And so I think there's still a lot of room and opportunity. Everything in multiple myeloma at this point, as you were just mentioning, is combination. And so I think the goal for us is to hence the selectivity and where I think we'll have a leg up over inobrodib is to be able to combine with a range of those different therapeutics and not be -- not have an additional myelosuppressive or myeloablative effect. I think the starting point for us clinically on this will be probably a straightforward dose escalation where we could take a range of different heme malignancies, maybe we'll focus in 2. And then as we get to relevant dose ostensibly efficacy, I think then you'll see some expansion cohorts where we probably focus 20 to 30 or 40 patients in multiple myeloma as an example, potentially a monotherapy, but likely combination minimally with an IMiD or Dex or maybe combination with anti-BCMA. I think you'd see sort of similar sleeves, if you will, again, obviously capital dependent, looking at diffuse large B-cell, maybe some of the T and B cell other lymphomas that we believe we're relevant in. At this point, every multiple myeloma cell line that we've tested I can't think of any exceptions right now seem to be responsive to the agent. The diffuse large B-cell, on the other hand, we believe we may have a marker, and it's about 60% of those cell lines. So there, you may be able to focus on. But those are both very competitive heme spaces. So I think we could certainly develop this through sort of a Phase Ia, Phase Ib dose expansion. I think longer term in the multiple myeloma market to compete with the likes of the J&J, BMS as they're continuing to iterate with their IMiD pipeline, we would need a strategic partner down the road for this is sort of my belief. But I think there's still room to play in these therapeutic areas. Obviously, it's going to evolve over the next few years. But until we cure every patient with cancer, I think there's still room to play.

Great. Yes. I think as you've sort of mentioned a couple of times here, the safety profile and the lack of issues in the heme compartment, right, probably suggests high combinability more than anything else. Turning back to the solid tumor space. You talked about potential combinations with CDK4/6 in the breast cancer side, SERDs and so forth. And so can you maybe tell us what preclinical work you've done there, both as a monotherapy and [Technical Difficulty] what early data suggests in terms of potential here?

Yes. So this is our [Technical Difficulty] program. We generated -- we initially generated a bunch of in vitro data where we combined -- we titrated in abemaciclib, the CDK4/6, we titrated in fulvestrant -- and we saw -- interestingly, we saw monotherapy when we didn't have either one of those 2 agents on board in Petri dishes. And then we titrated them and we saw pretty striking results above and beyond just CDK4/6 and the fulvestrant. So that was the in vitro stuff. We then set out and we ran over the course of the December time frame from last year, a range of PDX models and saw both in ESR1 mutant as well as wild-type some striking TGIs for PDXs. I would say when we looked and compared eyeballed against some of the KAT6A stuff that others have done, we found those monotherapy data to be impressive. It was a single dose. So obviously, we need to explore the dose. We need to understand in vivo additional monotherapy as well as combination. So we're actually right now in the process of running a range of PDX models with some dose ranging as a monotherapy. We are also doing combination with oral SERD and a CDK4/6. That's what's gating for us to move CBP forward to the GLP tox studies. We have a once-a-week subcutaneous formulation. The hypothesis here, which we're still evaluating is there's amplification of CBP. Interestingly, when you go read the literature as often is the case, CBP is a KAT3A. So it's part of this broader acetyl transferases that work. And we obviously know from what Pfizer is doing, the combination data they have with KAT6A, KAT6A is amplified in a bunch of ER-positive breast cancers as well. So we're pretty excited by this, but obviously, we need to validate all of this to the animal pharmacology.

Great. our remaining time, I want to maybe switch subjects a little bit, which is we've spent a lot of time talking about oncology, obviously. But can you maybe [Technical Difficulty] expansion into non-oncology areas. You mentioned I&I a little bit earlier with [Technical Difficulty] but just sort of as you think about broader chromatin biology and where the applications can be from a therapeutic development perspective, what sort of lines up first and second for Foghorn here?

Yes. I mean we know from the literature, and again, when you're regulating gene expression, that sort of makes sense. There's a range of different disease areas. We've seen stuff in neurodegenerative diseases, autoimmunity as you're altering sort of various T cell lineage populations, even in metabolic endocrine, we've had some interesting data actually there with CBP. So I think for me, the most obvious next space is in the autoimmune setting, right? Neuro is hard. I worked at Biogen for many years. That is a very hard space for a number of reasons we don't have time to get into here, but maybe that are obvious. So I'm pretty keen on stuff in the inflammation and immunity -- autoimmune area. And I think there's some potentially interesting novel targets to go after. I won't say more than that at this point, given what we're working on other than for our I&I program that we have. We've got multiple animal models that the asset that we have looks as good as one of the major antibody classes. In this case, it would be oral, and we're pretty excited by that. So I think there's a lot of room to continue to expand.

Great. Maybe in the minute we have left here, can you maybe update us on what is Foghorn's cash position? And how are you thinking about your cash runway over the near to intermediate term?

Yes. So as of the end of Q1, we had roughly $184 million on the balance sheet, very clean in terms of capital structure, there's no debt. The current cash runway guidance that we've been giving is into the first half of 2028, but there's some very important provisos or caveats to that. We assume as part of that cash runway guidance, this is not because any decision is made. This is just how we model it out, is that we proceed into further dose expansion with Lilly for 909. We've earmarked somewhere between $40 million to $50 million to ensure that we can pay our part of the 50-50, but also set aside some money of that for CMC work for drug supply scale up in the event that we go into a registrational study once that is completed. So there's about $50 million of that $180 million that are earmarked for 909. What that allows us to do is to move everything that I just mentioned in the pipeline, including the I&I asset to an IND. But we would need to either raise more capital, look for strategic partners or some mix of that to actually advance the rest of the proprietary pipeline in the scenario where 909 is moving forward. We'd need to raise additional capital to actually go and complete and run Phase Ia, Phase Ib type studies. So that's sort of how we think about guiding on the cash basis.

Got it. My thanks to Adrian and Foghorn for joining us today, and we'll end it on that note. Great. Thanks.

Thanks for having.

Thanks, Adrian. Appreciate.