FOGHORN THERAPEUTICS INC. (FHTX) - FOGHORN THERAPEUTICS INC

All right, so welcome to this next Fireside Chat with Foghorn Therapeutics. With us today we have Adrian Gottschalk, President and CEO. Adrian, welcome. Thanks for joining us. Thank you for having me. So, Adrian, after the FHD 909 decision, how would you describe Fogorn's strategy and priorities today? Sure. So, obviously, unfortunately, we had to, along with our colleagues at Lilly, we made the decision not to proceed forward with our SMARCA2 program, the FHD909 program. I think the first iteration, if you will, of what we've been working on was predominantly chromatin-related, the BAF complex, obviously, which we were targeting a subunit of that with the 909 program, as well as in the context of synthetic lethality. So I sort of think about that as the first chapter, if you will, of the company. And post, obviously, this clinical study, along with other data that we had generated over several years with other molecules that we had targeted some of this biology with, we sort of turned that page. So we were moving away or have moved away from targeting the BAF complex. We've moved away from synthetic lethality, and the pipeline on which we're presently focused is looking at where there's just clear and frank dependency in oncology, but also where we're able to use our platform to selectively drug challenging targets, which has sort of resulted in this novel INI program that we've subsequently disclosed where we are going into the area of inflammatory bowel disease, so ulcerative colitis and Crohn's, and then more broadly using the platform, which I'll distill and oversimplify to say we're really good at working with complex and difficult-to-make proteins coupled with very extensive chemistry, including degradation but now induced proximity, where we're going to harness some novel biology within the endoplasmic reticulum to effectively go after and get rid of secreted protein cytokines and transmembrane proteins, but it's not just limited to those types of proteins. So that's effectively sort of the evolution, if you will, of the company, harnessing the platform capabilities that we built to go after chromatin remodeling complexes, but now evolving into areas beyond that and beyond synthetic lethality. I don't want to spend too much time on 909, but just any insights gained from the study as it pertains to SMARCA2 as a target, would you see that as being validated or perhaps not a useful target in itself? Yeah, so from our perspective, I believe, and obviously in concert with Lily, we developed an excellent molecule in 909, generally very selective. It was overall, as we dose escalated through that study, it was generally safe and well tolerated. We were able to escalate, obviously, multiple times, and at the end of the day, the view that we have is that what was very exciting preclinical data, data that, frankly, the industry as a whole at one point was excited about, or folks in the oncology area, the biology just didn't translate, and so from my vantage point, it wasn't a function of could we have gotten a better molecule. We, I think, ran a really great clinical study, or I should say Lilly in collaboration with us did. And so from my perspective, there's something unfortunately flawed with our understanding of the biology, and hence the synthetic lethality. And so at least in the context of how we went after it, you know, that is not an area of biology that we should sort of be exploring further. So would you agree that it's pretty unlikely for other industry programs that address market to perhaps, you know, have a similar outcome at the end of the day? Yeah, I mean, I'm not an absolutist. I think that's dangerous. But if I were allocating capital, given now that we've got evidence from obviously our colleagues at Prelude, they took a degrader approach with some limitations potentially there. we've taken an approach with an inhibitor. We had a degrader also in development with Lilly. In our hands, you had to get north of 95 plus percent degradation to even equal what we were able to do with the inhibitor, and so I personally would be skeptical, but I mean, that's why people run clinical trials. Hope springs eternal in the biotech industry, as you know. If I were sitting on a board and working on that target, I'd be very skeptical about allocating for the capital. Okay, helpful. And then where do you stand with the EP300 and CBP programs? Sure. So these are parallel proteins, very, very similar. So we've got two separate and distinct efforts ongoing after those targets. We're very excited by our EP300 program. This is looking at hematological malignancies, namely multiple myeloma and potentially diffuse large B-cell lymphoma and potential some others to come along. That program is on track to an IND by the end of 2027. We have a once-a-week subcutaneous formulated drug. We have some backup efforts also that might lend itself to oral delivery of a selective EP300 drug. And we're particularly excited by the data that's being generated preclinically, but importantly also from our colleagues at Cellcentric. They've done an excellent job of profiling their molecule in Obradib, which has shown, in our opinion, very compelling efficacy in multiple myeloma. I know they're scheduled to have a presentation or a poster, I believe, at ASH highlighting combination data with an anti-BCMA. They've already shown combination data with a fixed background of pomalidomide and dexamethasone. And so we see this as an orthogonal mechanism. I think the rate-limiting issue, at least from our perspective, is their drug hits both CBP and EP300, whereas if you're able to dial out the CBP portion just hit ep300 you eliminate some of the thrombocytopenia and the platelet impacts that come with that so particularly excited by that program again that's that's moving along along with some some life cycle management activity there our cbp program again separate and distinct that's targeting er positive breast cancer unfortunately we took a bit of a delay with that program as we announced back in august the the cro with whom we were working you know in the the May timeframe unfortunately lost their entire animal facility so we've had to go back to the drawing board as it were with a bunch of other in vivo models with some other CROs so we're basically redoing a bunch of that work we need to get to human dose projections and we need to do some combination work with CDK4-6 and SIRDs before we'll push that forward but that's basically sitting there almost ready to go it's a once a week long-acting injectable formulation that's already gone through through the dose range finding studies at this point okay and so on ep300 um how could that fit into the myeloma landscape and do you need patient selection for that uh target or is it for all comers yeah so we don't as of yet have a specific biomarker to indicate that you would at least in multiple myelom uh subset out of population there's um some some interesting hints uh that there could be some rationale there, but more clear for diffuse large B-cell lymphoma. You know, I was talking to people about this earlier and been doing a lot of reading about the multiple myeloma landscape. And I think fundamentally, you're still dealing with four primary mechanisms or types of drugs, whether it's a CD38, a BCMA, an IMID, or a proteasome inhibitor. And the sequencing thereof is really dependent on the staging of the patient and some of the cytogenetic as well as genomic alterations. But ultimately, that's what the physicians are sequencing and cycling through. And so even though we've seen really brilliant data out of J&J from their majestic studies, I think there's still an opportunity because unfortunately patients by and large still do relapse. And it's become more of a chronic disease, which means the patient population is going to continue to expand. Thankfully, it's become more chronic, still not cured in everyone. So I think an orthogonal mechanism like targeting EP300, targeting that access, still has plenty of room to play. Obviously, probably not immediately in the first-line setting, probably in the second, third, potentially fourth-line settings as you think about combinations. So hence why, from, again, from our perspective, eliminating some of the cytopenic type effects that come with dual targeting will be important because you are combining with other mechanisms that can be cytopenia as well. Yeah. Any additional insights from peer programs as they, you know, read out data in coming years that could further help validate this target in myeloma? Well, again I mentioned South Centric, there's obviously other folks who are also working on a dual CBP-EP300 access. And I think that's just fueling, in my opinion, the interest in this area because it is validating. And again, tremendous credit goes to South Centic for doing that. I think they do have a drug in that. Although we'll see how the data continue to evolve, the BCMA combination data that's coming at ASH will certainly be of interest as well. And how much more selective with your program and how were you able to achieve that right so um the degraders we have range from 100 fold to a thousand or even ten thousand fold selective over cbp um and so as we've been you know trying to figure out which exactly development candidate we want to uh or candidate we want to nominate to go forward uh we're trying to figured out what that right threshold is and It may be that 100 is more than enough selectivity. The exact way that we've gone about deriving that selectivity, candidly, is a mix of the chemistry against the actual binding portion of the protein, as well as some of the engineering that we put into the molecule by virtue of making it into a degrader. So we find, specifically with Protex anyway, that as you're dealing with that geometry, you can actually engineer some additional selectivity into the molecule. Right. And I think you maybe commented on partnering this. Can you speak about your plans here as you prepare for clinical studies in the future? Yeah. So I think my own personal philosophy when it comes to oncology for these larger indications or the more competitive spaces are, is that in areas like breast and prostate, lung, and I would include multiple myeloma into that. I think at some point you want a strategic partner given, you know, the myriad number of combinations one is going to need to run. In the ideal setting, you know we might find ourselves in a position where partnering this before we go into the clinic would make a lot of sense. Obviously that always depends on the economics, what we think would be in the best interest of value creation. But I think one could also envisage running a dose escalation with some cohort expansion as well. So I think we're very open-minded about that. And I think as folks are watching the space and observing what happens with a dual CBP-EP300 type program, I think, we potentially have the better mousetrap here. That could be very interesting for some of the strategics. Okay. And then curious to learn more about your INI program. So what can you tell us about, I think you mentioned IBD, but anything else you can tell us about that molecule and where it could go? Right. So this is, we just disclosed actually, I guess, a day ago that we were focusing in the area of inflammatory bowel disease, so ulcerative colitis and Crohn's disease. So we've come across a target that, at least to our knowledge, based on what's in the public domain, we don't see anyone else actually working on this target in the INI setting. We were able to come up with some very selective chemical matter that hits this target, and we've explored it a little bit in some other models. There's some activity in psoriasis, but the really striking effect, at least from our vantage point, was in these IBD models. So we looked at it in a T-cell transfer colitis model. We've looked at in this IL-10 knockout model, and we've put these data into our current investor presentation. And it compares very favorably. It looks pretty much equivalent to the murine version of an IL-1223P40 antibody. And so we've been able to see nice disease activity control in the T cell transfer colitis model. Obviously, you look at the one measures looking at colon weight to length ratios to show that it's sort of normalized. That looks really good in the IL-10 knockout. We have other data we've generated. We'll hold off on sharing all the cool cytokine impact and stuff for some time, probably in the first half of the year. This program is tracking to start non-GLP tox studies here in December. We'll do rat and dog, two-week sort of evaluation. Touch wood, that will go well. And then we'll be positioned to do GLP tox and get ready to put that into the clinic. That is tracking for start first in human studies before the end of 27. Okay, great. And then, yeah, you did mention work around secreted proteins as well, or cytokines. Yeah, so can you talk about how you're applying the platform to that particular area? Yeah,so, you know, if I just back up a second, what we had to become really good at when we were dealing with chromatin remodeling complexes was how to make really difficult to produce proteins, deal with complexes of proteins coming together. And then obviously we've built out the chemistry component of protein degraders and whatnot. And so over the course of now almost nine, nine and a half, ten years, we've also been able to start getting into this area of induced proximity, right? sort of the broader umbrella, if you will, for protein degradation, and, you know, completely orthogonal, quite frankly, to all our efforts in chromatin. This is nothing to do, per se, with our prior biology efforts, but we sort of, as we were doing some thought exercises to where do we take our capabilities from a strategic perspective, we came across some potential to leverage the endoplasmic reticulum, specifically areas of biology within the ER, to go after secreted and transmembrane proteins. So we've been working. We initially started off by doing some genetic alterations where we were fusing tags to a target of interest, and some of this machinery then used a small molecule to induce those interactions between the tags. And we can show, or we have shown through genomic alteration, or through genetic alteration pardon me, that we can degrade IL-12, IL-23, IL 17, TNF-alpha, PD-L1, EGFR. We've got a long laundry list of other things we can do. recently we've actually been screening this machinery and some proteins of interest both for molecular glues which i think is ultimately the direction we're going to take this but also for binders to this machinery so um you know we're in the process of validating a lot of that chemistry um i think we'll have hopefully some some news to report on that by the time we get into the first half of next year this is an area that albeit it's early but we see as a very much open for partnering. It's something that we've had conversations with several pharmaceutical companies on. I think once we have the actual chemical matter that demonstrates that we can drug this, I think you'll see some more activity from us there. So it's a potentially very exciting part of what we're doing, albeit, again, a little bit on the earlier side. Great, and so from an investor perspective, what are the things they should be paying attention to over the next 12 to, let's say, 24 months? Sure. So, you know, I'll just start sort of roughly from the top, right? So for our EP300 program, it's tracking, again, the IND end of next year, roughly. I think there we would look again to find a strategic partner or, you know, if appropriate, we'll look to finance putting that into the clinic. I think secondarily then is the INI program, look for an update, you know, first half of the year after we get through our initial safety studies, further disclosure on the data that we've generated with the development candidate, additional safety information, cytokines, et cetera. And then that, again, you now, the goal there would be to put that into the clinic before the end of 27, with the goal of generating the SADMAD package, and ideally some disease patient information by, let's call it, the second half of 2028 Q3 timeframe, perhaps, if things go our way. As it relates to the induced proximity efforts that I just mentioned, we're not obviously going to disclose the chemical matter we're generating, But I think we'd like to show that in vitro proof of concept, showing that we can actually degrade some of these targets, show that we combine to some of this machinery. Again, I'm not one to promise business development, but ideally we'll be in a situation where there's some business development activity around that in 2027. And then for our CBP program, I'd look for, you know, sort of go, no go from us. Probably in the first half of next year, we've got to get through some of the ongoing in vivo pharmacology to determine what our human dose projections will be. And, you Know, are we excited enough by what we do as both a monotherapy and ideally also in combination? So those are sort of the that's the setup. Our cash runway right now, just to be clear, is into the second half of 2029. this is post our restructuring and some of the things that we did back at the beginning of October. That funds us through to the other side of the SAT-MAD with about a full year of cash behind that. It funds the EP300 program to IND, it funds us with the induced proximity to get the chemical matter and start thinking about some partnerships and moving stuff forward there, and funds our cbp efforts also the in vivo part of that sounds good well great thank you so much adrian uh appreciate all the updates and walking us through the story absolutely thanks for having me good to see you thank you