Foghorn Therapeutics Inc Stock

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.

Welcome to the Foghorn Pipeline Update Conference Call. [Operator Instructions] As a reminder, this webcast is being recorded today, October 30, 2025.

I will now turn the call over to Karin Hellsvik, Vice President of Investor Relations and Corporate Affairs. Please go ahead.

Thank you, everyone, for joining us today. This is Karin Hellsvik, Vice President of Investor Relations and Corporate Affairs for Foghorn. Today's call will primarily focus on our selective ARID1B degrader as well as updates from Foghorn's other proprietary programs, our selective CBP and selective EP300 Degraders.

Before we begin, I will remind you that we will be making forward-looking statements on this call. Please consult our October 30, 2025, news release for our forward-looking statements disclaimer and our 10-K and other SEC filings for a full understanding of risks in our business.

Speaking on the call today, we have Adrian Gottschalk, Foghorn's President and CEO, who will provide an overview of Foghorn and a perspective on our recent progress. Steve Bellon, Foghorn's Chief Scientific Officer, who will provide an overview of the progress made on Foghorn's proprietary pipeline programs, ARID1B, CBP and EP300, including new data presented at the Eighth Annual TPD and Induced Proximity Summit yesterday on ARID1B; Alfonso Quintás-Cardama, Foghorn's Chief Medical Officer, who will provide a perspective on the clinical opportunity for these programs. We will take questions after the presentation. Kristian Humer, our Chief Financial Officer, will join for the Q&A. We have posted the slides on our website that will be used during this call. This call is being recorded, and a replay will be available on our website.

I will now turn the call over to Adrian Gottschalk.

Thank you, Karin, and thank you to everyone joining us today. I will provide context for today's call with a brief overview of Foghorn's R&D engine and a reminder of our collaboration program with Lilly in clinical development, FHD-909 before handing it over to Steve and Alfonso to cover important developments in our wholly owned pipeline.

Foghorn was founded around the idea that there was an important set of molecular targets in the chromatin regulatory system that were strongly implicated in cancer, but have so far appeared to be undruggable. The chromatin regulatory system controls gene expression. In cancer, this system often goes awry in very specific ways. For a long time, researchers in industry and academia had attempted to drug the chromatin regulatory system, but with very limited success.

At Foghorn, we have demonstrated that we can systematically drug the chromatin regulatory system. The chance to have a transformational impact in cancer was very clear. Mutations in the chromatin regulatory system are implicated in up to 50% of tumors. Successful drugs targeting this biology represent multibillion-dollar opportunities. We have now advanced a portfolio of novel programs targeting hard-to-treat cancers based on our proprietary insights into chromatin biology and protein degradation.

And specifically, we have succeeded in bringing forward the first molecules that are drug-like and highly selective for several targets that were previously undruggable. Today, we are on the verge of demonstrating the clinical impact of our innovations with FHD-909, which selectively targets SMARCA2 and is part of our partnership with Lilly.

What distinguishes our platform and what has enabled us to make these precision medicine breakthroughs? Importantly, we are focused on novel biology and novel targets. We take a biology-first approach. We have been deliberate in developing a deep mechanistic understanding of the chromatin regulatory system, how the various proteins and complexes interact and how these interactions can be modulated. We have built an integrated platform that allows us to study the targets in the appropriate biological context and have developed a wide range of small molecule drugging capabilities, which includes targeted protein degradation. We have demonstrated multiple times now that we can selectively drug targets that others have failed to drug, and I am excited for Steve and Alfonso to provide updates on our progress today.

Before we get into the updates on our wholly owned pipeline, I want to say a few words about FHD-909. We are very excited about this program. FHD-909 is a first-in-class selective oral small molecule inhibitor of SMARCA2 and has the potential to make a difference for patients who have tumors with SMARCA4 mutations. This program is currently enrolling patients in a Phase I dose escalation trial and Lilly is responsible for the day-to-day operations. Sites are open in both United States as well as Japan. The dose escalation portion of the Phase I includes patients across various histologies with the requirement that the patient must have a SMARCA4 mutation. We will backfill cohorts as we enter therapeutic range and will enrich for non-small cell lung cancer patients with loss of function SMARCA4 mutations. Select backfill cohorts may contain up to 20 patients. At present, the trial is enrolling well, and we anticipate that our collaboration partner, Lilly, will be in a position to determine whether to advance into dose expansion sometime in the first half of 2026, recognizing that we have not yet hit our maximum tolerated dose, so there may be some error bars around the timing.

Beyond FHD-909, our pipeline is broad and advancing. We have made important and critical progress on our wholly owned programs with the goal of building our pipeline beyond FHD-909 to a potential multiple shots on goal. Yesterday, we reported important breakthroughs for our selective ARID1B program at the Eighth Annual Targeted Protein Degradation and Induced Proximity Summit here in Boston. And details of these breakthroughs, together with recent progress on our selective CBP and selective EP300 degrader programs are the key updates on today's call. We are pleased to see how our capabilities are now enabling us to crack the code on numerous technically challenging but highly promising targets.

Before I turn it over to Steve and Alfonso to go into the details, I want to summarize the critical takeaways on these exciting programs. Foghorn is the first to publicly show robust degradation of ARID1B. We have made significant progress developing both VHL and Cereblon-based degraders. The opportunity with this program is significant as ARID1A mutations, which lead to a dependency on ARID1B, are found in up to 5% of all solid tumors, including but not limited to endometrial, gastric, gastroesophageal junction, bladder and non-small cell lung cancer. As you will hear shortly, we have achieved significant selectivity and are tracking to in vivo proof of concept in 2026 with this program.

Our selective CBP degrader, which has potential in EP300 mutated cancers and ER-positive breast cancer is on track for non-GLP toxicology studies this quarter with our predevelopment candidate CBPd-171 and is tracking to be IND-ready in 2026. We have established a long-acting injectable formulation that allows for subcutaneous dosing weekly or every other week for convenient administration. Importantly, we have overcome the challenge that has plagued dual CBP/EP300 programs. That is the impact on platelets, and we have demonstrated preclinically that we have avoided this tolerability issue.

Lastly, our EP300 degrader program has made significant strides. And Steve and Alfonso will go into more detail on the potential of this program in hematological malignancies, specifically multiple myeloma. This is a very compelling program as we have seen clinical proof of concept of this mechanism from a competitor in multiple myeloma, which validates our approach. We believe the highly selective nature of our EP300 degrader will avoid the tolerability issues that are seen, again with dual CBP/EP300 programs, which may limit the combinability and broad potential in these areas for those programs. We are tracking to IND-enabling studies in 2026 for this program.

I will now turn the call over to Steve and Alfonso to take you through the progress in more detail.

Thank you, Adrian, and thank you again to everyone joining the call today. I'm excited to tell you about our wholly owned portfolio consisting of selective ARID1B degrader, selective CBP degrader and selective EP300 degrader programs.

Foghorn is focused on the chromatin regulatory system. The important point here is that the structure of chromatin dictates its function. Open chromatin leads to gene expression and closed or compacted chromatin prevents gene expression. Our targets control gene expression by determining the structure of chromatin. Because many components of the chromatin regulatory system lack enzymatic function, we have been building our protein to greater capabilities to drug these difficult but very important targets since the inception of the company.

I've highlighted a few select key areas. Our linker toolkit is comprised of proprietary chemistry, which has formed the basis of the selective degraders that we are advancing towards the clinic. We place a premium on understanding the mechanism and kinetics of degradation and have put in place a suite of assays to quantitate these properties.

Finally, we have invested considerable efforts into formulating our degraders for subcutaneous delivery where oral bioavailability is not tractable and we have examples of this in the presentation.

Foghorn is focused on some of the most relevant and highly mutated genes in cancer. Mutations in these genes in many cases set up synthetic lethality or dependency on the sister protein, as is the case for ARID1A, which sets up a synthetic lethal dependency on ARID1B, and of course, mutations in SMARCA4 set up a synthetical lethal relationship with SMARCA2. As you will hear for CBP and EP300, not only do we have synthetic lethal dependencies between the 2, but also frank lineage dependency in some tumor types on these genes.

I'm excited to now share with you the progress that we've made on our ARID1B degrader program, which was disclosed yesterday at the TPD and Induced Proximity Summit.

I'm now going to turn it over to Alfonso to set the clinical context for this program.

ARID1A is the most frequently mutated subunit in the BAF chromatin remodeling complex. Mutations resulting in ARID1A loss of function have been shown to accelerate tumor genesis, promote the development of metastases and induce chemo resistance across multiple human cancers. Approximately 5% of human cancers have mutations in the ARID1A gene. As shown on the slide, these mutations are present at high frequency in endometrial, gastric, bladder and non-small cell lung cancers. This is a very large population of patients whose progression-free survival after failure of frontline therapy is very short, thus representing a high unmet medical need.

Let me now turn the call over to Steve.

Thanks, Alfonso. Our drugging strategy for addressing the very large ARID1A mutation population is to selectively degrade ARID1B. This approach takes advantage of the synthetic lethal relationship between ARID1A and ARID1B, where tumor cells are dependent on ARID1B for survival, but normal cells have their intact copy of ARID1A to compensate for selective degradation of ARID1B. This approach opens up a tolerability window as demonstrated with the colony formation data shown on the right-hand side of the slide. Here, we see that only cells with ARID1A loss are affected by the selective knockout of ARID1B.

ARID1B is the most difficult target that I've worked on in my career. ARID1B has no known enzymatic function. The protein is mostly disordered, and it is very similar to ARID1A, making selectivity very challenging. Our approach has been to first find selective binders and then turn the binders into heterobifunctional degraders.

I will now share the data and progress with you. Our platform has yielded multiple selective binders to ARID1B, and 2 example series are shown here. On the left, I show the raw screening data with numerous selective hits shown in the box. On the right, I show the ITC traces for a representative selective molecule from a different series. Using selective ARID1B binders as starting points ensures that selective degradation is built in to the resulting degraders, which gives flexibility as we advance our chemistry efforts.

We have taken these selective binder starting points and use both the Cereblon as well as VHL ligases to preserve optionality. For both approaches, we have seen -- we have been able to progress the series, achieving 80% percent degradation for the VHL series. This degrader demonstrates robust degradation in several different cell lines with no evidence of a hook effect shown by the kinetics on the right-hand side of the screen. It's also important to note that degradation occurs at early time points, such as 6 hours.

We have demonstrated that this selective degradation is on mechanism via the ubiquitin-proteasome System using various proteasome inhibitors that all rescue degradation as shown on the right-hand side. In addition, we see no effects on viability across the concentration range shown here. This gives us confidence that our results are not biased by off-target effects on proliferation.

In addition to robustly degrading ARID1B, this molecule spares ARID1A and also the BAF complex members, SMARCA2 and SMARCA4.

Looking broadly across the entire proteome, we see high selectivity for ARID1B, which highlights the progress we have made with our selective degrader. Other members of the BAF complex, including ARID1A, are shown in red, where you can see no effects.

Our chemistry efforts on all 3 of these programs that I'm speaking to today are guided by structural biology. And a nice example of this is shown here with the ternary complex of ARID1B, our degrader and VHL. One result that emerged from the structure is that the degrader molecule adopts an unexpected confirmation in the ternary complex, but not in the binary complex. This seminal insight has paved the way to improve degrader molecules that capitalize on the confirmation observed in the ternary complex.

I'm gratified to see that the selective degradation that we observed with ARID1B translates into effects on known ARID1B target genes. On the left is treatment with shRNA, which downregulates the levels of gene A and upregulates the level of gene B. On the right, I show the effect on the same 2 genes after treatment with our selective ARID1B degrader. The corroboration between the 2 provides strong evidence that we're on the right track with our selective ARID1B program. I'm extremely excited by the progress that we have made against this difficult target, and I'm looking forward to advancing the program to in vivo proof of concept in 2026.

Now I would like to transition to our selective CBP degrader program. CBP and EP300 control gene expression by acetylating their targets, leading to open and closed chromatin. Because of the central role they play in controlling gene expression, they have been targets of interest to the industry for decades. The challenge, as shown here, is how to selectively drug these targets given the high degree of similarity between CBP and EP300. Our approach has been to utilize our platform to design selective protein degraders for each of CBP and EP300. We will focus first on CBP and then on EP300.

Before we get into the scientific details, Alfonso will provide clinical context for CBP. I'll now turn the call over to Alfonso.

There are 2 distinct patient populations that could benefit from selective CBP degradation. First, given the synthetic lethal relationship between CBP and its paralog EP300, a selective CBP degrader could target EP300 mutant cancers, while sparing normal tissues in which EP300 is intact. This strategy may provide a wider therapeutic window than that observed with dual CBP/EP300 inhibitors, which result in hematological toxicities. The patient population amenable to this approach involves a meaningful proportion of patients with either bladder cancer or gynecological malignancies, such as endometrial, cervical or ovarian cancer.

Second, tumors that exhibit the dependency on CBP function, regardless of EP300 mutational status, could also benefit from CBP targeting. For instance, CBP is a well-known co-activator of the transcriptional activity of the estrogen receptor in breast cancer. This represents a very large patient population as more than 200,000 cases of estrogen receptor positive breast cancer are diagnosed every year in the United States.

I'll now turn the call back over to Steve.

Selective CBP degradation has utility in the context of EP300 mutations as well as in other context of EP300 wild type where our lineage dependence exists on CBP. Here, I show 3 examples of EP300 mutant cancers where selective CBP degrader demonstrates a range of efficacy between stasis and complete regression. Of particular interest are the 2 gastric cancer examples, 1 PDX and the other CDX that show complete regression of the tumors.

Importantly, we are able to achieve efficacy with no significant effect on platelets and sparing of megakaryocytes. I include a dual CBP/EP300 bromodomain inhibitor clinical stage asset as a positive control, which has a market effect on platelets and megakaryocytes.

From a mechanistic perspective, treating with our selective CBP degrader results in down regulation of genes responsible for cancer cell growth, for example, MYC, which results in G1 arrest and consequently, potent antiproliferative activity, as shown on the right-hand side.

Exploring dependencies beyond the synthetic lethal EP300 mutation revealed that selective CBP degradation results in reduced expression of ER and its target genes in representative breast cancer models. This downregulation of ER results in cell growth inhibition as shown by the colony formation data on the right-hand side.

Addition of CDK4/6 inhibitors and Fulvestrant leads to a dramatic effect on these breast cancer cells as shown inside the green box on the right hand of the slide. We are currently in the process of validating the translation of these in vitro colony formation results into the in vivo context.

I'm proud of what our platform has enabled us to do with the selective CBP degradation. As shown here, we have a CBP degrader-171, which is our pre-DC candidate and demonstrates exceptional selectivity and fast and sustained degradation kinetics. Looking broadly across the proteome, we can see that this is an exclusively selective degrader and notably does not touch EP300 or any other bromodomain-containing proteins.

Recognizing that convenient administration is needed for patients, we have invested significant time in our long-acting formulation technology. We are now able to formulate once a week, if not every other week or in some cases, once monthly subcutaneous delivery. Here, I show our pre-DC candidate CBP degrader-171 dosed in 2 different formulations in the AGS gastric cancer model. The degrader is dosed daily subcutaneously in light blue and dosed once a week subcutaneous in dark blue. The weekly subcutaneous long-acting formulation performs at least as well as the daily dosing arm, achieving complete regression in this model. Degrader CBP-171 has initiated its non-GLP tox studies this quarter, and we are progressing this forward to be IND-ready in 2026. We now move to our selective EP300 degrader program, which has significant potential in hematological malignancies.

I will now turn it over to Alfonso again to set the clinical context for this program.

The role of EP300 in cancer is complex, acting both as a tumor suppressor and oncogene, depending on the specific cancer type. In specific cellular context, overexpression of EP300 results in increased cell proliferation and survival across a wide range of hematological and solid malignancies. For the purpose of this presentation, we will focus on the role of EP300 in hematological malignancies, where its disregulation is linked to the initiation and progression of multiple myeloma and different types of leukemias and lymphomas.

The central role of EP300 in these malignancies is further supported by the data presented on this slide, where a selective EP300 degrader induces a profound antiproliferative effect in cell lines representative of the spectrum of hematological malignancies.

These data have important therapeutic implications because they suggest that the EP300 lineage dependency observed in multiple myeloma, myeloid malignancies and aggressive lymphomas could translate in the United States alone into approximately 100,000 patients who could potentially benefit from therapy with a selective EP300 degrader.

I will now turn the call over to Steve.

As with our selective CBP degrader, here with our selective EP300 degrader, our platform has yielded highly selective and fast protein degraders. EP300 kinetics are shown to be very fast and sustained with the data on the left and the data on the right show no effect on CBP protein levels over time. Note also the lack of any hook effect with the EP300 degrader.

A familiar slide again as we look across the proteome, we see exquisite selectivity for EP300 over CBP and other bromodomain-containing proteins.

Ternary complex structures of VHL and either CBP or EP300 bromodomains proteins reveal the molecular underpinning for the selectivity that we see across both CBP and EP300. In all 3 panels, I have fixed the VHL proteins in a common orientation for reference so that differences in the bromodomain confirmation can be easily compared between the complexes. Focusing then on bromodomain, one can clearly see that comparing a dual degrader to the respective selective degraders results in markedly different confirmations of the bromodomain, which we believe accounts for the selectivity. Structural biology is a strength of ours and an important often differentiating capability within our protein degrader platform.

Mechanistically, we see here that selective EP300 degradation downregulates a set of transcription factors that are the very TFs on which multiple myeloma depends on for its survival. On the left, you see MYC, IRAK4 and other genes affected across multiple cell lines that's mirrored by the dependency graphs on the right.

Furthermore, we demonstrate that selective EP300 degradation induces apoptosis in multiple myeloma cells in vitro. One of the reasons EP300 is a high-priority program for us is the clinical validation that a dual CBP/EP300 inhibitor in inobrodib has shown compelling results in relapsed/refractory multiple myeloma. Here we compare our selective degrader in a preclinical multiple myeloma model where it performs favorably, inducing a complete regression. Of note, we dosed the dual CBP/EP300 inhibitor inobrodib daily, but we understand that clinically, it can only be dosed 4 days on, 3 days off due to tolerability matters. Of note, here again, we show that our selective EP300 degrader does not have a significant impact on platelets. We believe the selectivity of our degrader may enable better tolerability in the clinic and ultimately better combined ability with other agents in the hematological malignancy area.

To preserve maximum optionality for this target, we have pursued both Cereblon and VHL scaffolds. Here, I show data with our Cereblon-based degrader in the MM1S model of multiple myeloma in both parental as well as mezigdomide and iberdomide resistant cell lines. Because Cereblon obviously shares a binding site with the IMiD-class drugs, including mezigdomide and iberdomide, we note the decrease in potency of the Cereblon-based scaffolds in the resistance setting due to the aforementioned competition.

For this reason, we have focused our EP300 degraders in the context of multiple myeloma using VHL-based ligases. In contrast to the prior slide with Cereblon, here with VHL, we see no loss of potency using the VHL degrader in the resistant context. Furthermore, when our VHL-based EP300 degrader is combined with the standard of care IMiD such as pomalidomide, we demonstrate synergy. This is an important finding because multiple myeloma therapy involves combinations.

I hope I've impressed upon you the significant progress we have made with our selective EP300 degrader program. As you see here, we are on the precipice of a predevelopment candidate. I show representative molecules A and B along the line of progress we have made to molecule C. I highlighted green the various properties that we have now incorporated within a single molecule, including potency, selectivity, solubility and clearance. We are tracking towards IND-enabling studies in 2026.

Overall, as you've heard from us today, we have made significant progress with our wholly owned portfolio. I'm very pleased and proud of the progress with our degrader platform and associated programs and look forward to keeping you posted in 2026.

I will now turn the call back over to Adrian.

Thank you, Steve. As you can tell, we are very enthusiastic about the progress of these programs and the meaningful scientific breakthroughs with these novel targets. We believe the potential with ARID1B is significant, given its prevalence in approximately 5% of all solid tumors, and we are aiming for in vivo proof of concept in 2026.

With CBP, we have demonstrated promising potential in ER-positive breast cancer in addition to EP300-mutated cancers. This program is on track to be IND-ready in 2026.

Our selective EP300 degrader has significant potential across a range of heme malignancies, including multiple myeloma. And we believe it is advantaged over dual CBP/EP300 programs that have already demonstrated compelling clinical proof of concept. This program is tracking towards IND-enabling studies in the next year. We believe all these programs represent important drivers of value inflection for Foghorn. Based on our track record of engineering promising selective therapeutics that target gene regulation, we are poised and positioned to be a durable leader in this area of novel biology.

Thank you again to everyone for attending today's call. Operator, you may now open the line for questions.

[Operator Instructions] So our first question comes from Gavin Clark-Gartner at Evercore.

Thanks for putting on this really informative event. I just had 2 questions on the ARID side. First, could you just help us quantitatively draw the link between SMARCA and ARID since they're both targeting the BAF complex? Like based on what you're seeing preclinically, is the level of inhibition or degradation required to see efficacy similar? And if it is similar, doesn't that indicate that the SMARCA efficacy that you do see in patients next year is a pretty direct link as to what you could see with ARID?

Gavin, thanks. It's Adrian. I appreciate the question. I'm going to let Steve answer that question. Maybe, Steve, just to summarize this, what do we see as the linkage between the SMARCA programs and ARID and the amount of degradation in this case or inhibition in case of 909, how does that link to any read-through potentially?

Yes. Great question, Gavin. So I think quantitating the amount of ARID degradation that we will need to see optimal efficacy, that's a process that is ongoing. And it's possible that we see similar behaviors where we need to have really robust degradation in order to see maximal efficacy, but we're still in the process of quantitating that.

I think the read-through between the 2, obviously, is appealing since they're both members of the BAF complex, but there are some subtleties where SMARCA2 is present in all forms of BAF. ARID1A and ARID1B are not present in the noncanonical forms of BAF. So there are subtle differences that make it a little complicated to say that there's going to be complete lead-through, but I think that's unavoidable.

Yes. And I'll just follow up on that last point then. So we know the ARID has scaffolding function within the BAF complex and by degrading it, you could actually disrupt the whole structure. Do we -- what do we know about the nonenzymatic activity of the BAF complex? Like I'm trying to get a sense of ARID could actually drive greater efficacy than SMARCA2, SMARCA4, which just hits the enzymatic subunit alone.

Yes, that's a really interesting point, Gavin. Yes, the extent to which ARID does contain some scaffolding functions, to that extent, we would expect greater efficacy. And we're certainly looking to better characterize and understand that across both biochemical as well as in vitro settings.

So our next question comes from Steven Ionov at TD Cowen.

This is Steven Ionov on for Yaron Werber at TD Cowen. We first had a question about the ongoing FHD-909 study. Any visibility on how much backfilling Lilly is doing? And any idea what an initial data readout could contain in terms of efficacy and safety? And given backfilling, how long a follow-up might we expect and for which dose cohorts?

Second, it's, of course, very early, but are we initially thinking of a basket trial with multiple tumor histologies for the CBP program given the multiple tumors you've outlined that are affected similar to the SMARCA2 program?

Thanks, Steven. I'll briefly address the first question on 909. Remind me if I missed any part of it, and then I'll let Alfonso comment on CBP. So we're not commenting at this point as a collaboration on status of backfilling other than to say we have the ability as we get into a therapeutic range. I think the expectation at some point once the collaboration has made the decision to move to expansion, assuming that's where we land, as we would communicate high-level efficacy and tolerability, certainly to the investment community. But what I can say about the study is it's enrolling very well. We have not as of yet hit our maximum tolerated dose. And again, we expect that -- we should be in a position sometime in the first half of 2026, assuming that we continue to dose escalate as we all are assuming that backfilling will happen along the way, we should be in a position to understand whether we're moving to expansion or not.

Alfonso, do you want to comment on the punitive trial design one could consider for CBP, depending on whether you go with EP300 mutant for breast cancer?

Yes. As we mentioned during the talk, there are 2 patient populations we could target. One is the EP300-mutated patient population. And in that sense, I think a basket approach, as you suggested, is probably the right approach because there's a smattering of different histologies that we could target and recruit for.

But the second bucket is even bigger than the first one is the ER-positive breast. And so if we decide to go for that indication, I think that will merit its own study.

Our next question comes from Clara Dong at Jefferies.

I appreciate you putting together this very informative presentation. So within the compelling landscape, we also saw CBP/EP300 dual inhibitor for multiple myeloma. We saw initial clinical data. So just curious compared to the dual inhibition mechanism of action, so what's the key differentiation offered by selective degradation? And maybe for those 2 targets, what kind of advantages does a degrader have over an inhibitor in your view?

Great. Thank you, Clara. And I'll repeat the question just to make sure we're clear, and then Steve and Alfonso can tackle this, which is how do we see selective degradation is differentiating from the dual CBP/EP300 inhibitor, sensibly an [indiscernible] that has been in the clinic, what are the advantages of having selectivity? And then maybe secondarily, degradation versus inhibition, any commentary there. So maybe, Steve, if you want to start off. Alfonso, follow-up.

Yes, great question. Thanks. So our strategy is that by selectively degrading these 2 targets, we can achieve optimal efficacy, but avoid effects on the heme compartment, which we demonstrate. As far as efficacy is concerned, we didn't show data with selective binders, but they don't have much effect in the multiple myeloma setting. We need to -- we see a bigger effect in multiple myeloma with a degradation effect -- selective degradation effect and selective binding effect.

So in other words, our selective degrader approach allows us to have a superior efficacy, which we demonstrated with the multiple myeloma model in the talk as well as a superior safety by avoiding the effect on heme tox. So we think it gives us the best of both worlds, both efficacy and tolerability to selectively degrade these targets.

And maybe Alfonso, if you want to comment as an oncologist, obviously, given the stage of -- state of multiple myeloma combinability, maybe some of the challenges that Steve just mentioned with dual inhibition or targeting of CBP/EP300 versus selectivity?

Yes. So the main advantage, as Steve alluded to, of selective targeting is the avoidance of myelosuppression. And that has profound clinical implications because as you all know, especially for a first-in-human study, we'll have to go into probably fourth, fifth line at best in multiple myeloma. These are patients that have gone through multiple rounds of chemotherapy and other agents. They have a very limited bone marrow reserve. And I think there's a great need in that space for new mechanisms of action, particularly with known myelosuppressive properties. So bringing -- if we can bring to bear that feature of selective degradation, the avoidance of myelosuppression, I think those patients will benefit significantly from it.

The other aspect to it is that not having that element that myelosuppressive liability will allow us to combine more safely with other agents. And given the fact that multiple myeloma is a combination game. I think we're going to be able to play along with other agents that are active in that setting.

So our next question comes from Paul Choi at Goldman Sachs.

Thanks for putting up the session. It's very informative. My first question is on the CBP program. And I think you said earlier that you were looking at Q1W, Q2W and Q4W as possible dosing schedules. Can you comment on whether this is -- involves any changes to the candidate molecule? Or is it just more drug and higher Cmax that is allowing you to do this?

Yes, that's a great question. Great question.

And then my second question on the EP300 program in the various hematologies. Can you comment on sort of what indication, I guess, would be targeted first potentially here? I think myeloma time lines typically would be longer, whereas AML would be shorter with large B-cell sort of falling in between. And in terms of your preclinical work, have you done any safety or combination work with existing standards of care in any of these agents? I know you showed some data in resistant lines, but just sort of any combination work there would be informative.

Yes. Thanks, Paul, for both of those questions. Steve, maybe if you want to take the CBP question and then Alfonso to discuss sort of initial thoughts on clinical development for EP300. Steve?

Yes. Great question with respect to the long-acting injectable technology. So the strategy is that we can tune the half-life of the subcutaneous injection by adjusting the formulation of the compound without changing the drug itself, the API.

Yes, great. Alfonso?

And as far as clinical development, I'm sure you noticed that the entire presentation revolved around multiple myeloma, which is -- and that's because we're thinking very seriously about advancing the compound in that indication. For a couple of reasons.

One is preclinically, we've seen almost universal sensitivity across cell lines, multiple myeloma cell lines to the agent. So there's a special sensitivity of the indication to this approach. But then there's a second element, which is the derisking that has been provided by dual CBP/EP300 inhibition in the clinic. So having that element of derisking already in place is very important to us. That element is not present in AML. It's not present in DLBCL. Those are indications that we are seriously also contemplating as targets for potential clinical development. But the main indication right now is multiple myeloma.

And on combination testing since a lot of the therapies in myeloma, whether it's CD38 or Revlimid or Pomalyst, what have you, are typically in combination. Can you comment on any combination testing you've done preclinically?

Yes, that's all ongoing, and we hope to report out in the future.

Yes. Certainly very important there, Paul, that is pending.

Our next question comes from Robert Driscoll at Wedbush.

Congrats on all the progress here, real kind of -- saw the progress on ARID1A and the other targets here. Just wondering if you've done any work or maybe others have characterized ARID1A mutations and the effect on function expression and so on? And then maybe kind of looking forward, I know it's early, but how you're thinking about selecting patients in the clinic there?

Yes. Thanks, Robert. Good question. So maybe Steve sort of ARID1A effect on function and expression and then patient selection in the clinic. Alfonso, if you want to speak to that? Steve, to you first.

Yes. So the ARID1A mutation status is definitely something that we're digging deep into currently. And basically, yes, that's incredibly important. We've learned that across other programs, and we are in the process of characterizing the effect of each particular mutation.

And in terms of patient selection, we have one advantage -- one great advantage, which is the fact that ARID1A is customarily being tested in the FDA-approved NGS platform. So if you look at the FoundationOne panel, you would find ARID1A. So we will be able to find and identify patients with ARID1A alterations. I think there's still some characterization to do in terms of Class I, Class II mutations and the functional importance of each one of these, specifically in ARID1A. For the purpose of patient identification, I think will be relatively easy.

Got it. Maybe sneak one more in. Just how potent do you need that ARID1B degrader to be? I mean it probably depends on the cell lines and so on, but just wondering if you have any thoughts there in terms of the level of degradation required?

Great question. That's something we're currently investigating exactly how much degradation we need for optimal efficacy. So I won't speculate, those experiments are ongoing. And of course, they're helped as we move the program forward as our tools get better and better, those questions get more and more relevant.

Our next question comes from Yuan Zhi at B. Riley.

Thank you for putting out this important presentation. We've got 2 questions. Maybe we can start with, can you talk about the dynamics of degradation and the recovery of ARID1B at DC50? How long does it take to show growth inhibition and cell killing?

Steve, do you want to take that question?

Yes. We're still characterizing exactly the dynamics of the cell killing with our degrader molecules. We're still in process of fully understanding that phenomenon.

Got it. And for the CBP mutation, is that mutation homogeneous in multiple myeloma patients or it has some heterogeneous expression? How will you select patients based on that?

For the EP300 program.

Well, for EP300, it's a lineage dependency. So we're not relying on the presence of the CBP mutations. We've seen sensitivity to the agent across a vast array of cell lines regardless of CBP mutation status. So again, it's a lineage dependency. We won't have to screen for CBP mutation.

Our next question comes from Silvan Tuerkcan at Citizens Bank JMP.

Thank you for all these updates here. One question, thinking about all these large indications that you have coming your way in terms of development and thinking with some IND enabling it to be starting next year across the board here, can you just lay out maybe a loose plan around partnerships or your thinking around partnerships or which of these assets you may want to take forward alone to fund these trials and think about breast cancer here in multiple myeloma that are a little bit larger and heavier lifts?

Yes. Thanks, Silvan. I'll address that question. So very generally, I would say we're very cognizant that going to very large tumor types is probably best done in a partnership. And I think it's always a question of when. We've been very privileged, and I just say I'm incredibly pleased and highly complementary of our colleagues at Lilly. They've done a fantastic job in the SMARCA2 program and specifically as you think about non-small cell. So just to make it specific, I think there's certainly appetite on our end to go into Phase I dose escalation and expansion studies, obviously subject to availability of capital and our cost of capital.

But I think as we think about registrational type activities down the road, I think having a partner who can execute on clinical studies on a global basis as we think about the various combination agents that are required, certainly, if one goes into ER-positive breast multiple myeloma and elsewhere, I think those are going to become critical.

I tend to be pretty economic sort of minded on the switches. There's no emotional attachment per se. I think we've got 3 really great programs. They're obviously at slightly different points in time. And so we'll just have to see how the story evolves over the next 6 to 18 months. And obviously, we want to be very, very disciplined with our capital allocation and just to be specific about that where we're prioritizing and ensuring that we're very well resourced to engage with our collaboration partner, Lilly, on the SMARCA2 program. So as we've guided to publicly, we're progressing these programs to IND and then we'll have to determine whether we partner or able to get adequate capital to finance a Phase I study. So more to come on that.

Great. And then maybe could you share some feedback from the presentation at the conference, given I think there's a lot of excitement around ARID1B and you finally be able to develop a degrader here? Was there any feedback?

Sure. I'll turn it over to Steve, who was -- who obviously presented yesterday. And Steve, if there's any high-level comments. I know, generally, we received a lot of interesting commentary from colleagues in the industry and other folks who were there with -- given the seminal accomplishment because as far as we know, no one else has been able to achieve this. But Steve, maybe you have a few more specific items or comments you can add.

It's quite gratifying that the feedback was quite positive across -- from a number of different people who attended the seminar. People were very curious how we were able to achieve both selective binding as well as selective degradation. And so they asked questions about the nature of the chemical matter and the specific screens that we ran in order to get the chemical matter. So obviously, we couldn't give a whole lot of clarity there. But I think there's a lot of curiosity about how we were able to achieve what I think a lot of companies have tried and haven't made much progress. So that was also very gratifying.

Great. So that concludes today's Q&A session and also today's call. The replay and corresponding slides from today's presentation are available under the Investors section of Foghorn's website. Thank you, and enjoy the rest of your day. You may now disconnect.