Good afternoon, everyone. My name is Adrian Gottschalk. I'm the CEO of Foghorn Therapeutics. Delighted to be here with you in London. True to course, London is delivering rain, so we're, I think, right on track for what the weather should be. I'm going to do about 5 to 10 minutes of a quick introduction to the company, and then Kelly and I are going to sit down and do some Q&A, I think, with her. But feel free to interrupt me as well. Delighted to take questions on Foghorn. What I'm going to cover, though, will only be about 10 slides of our investor presentation, but delighted to take questions after the meeting as well. Our usual forward-looking statement, disclosures, and we'll jump into it, which is the basis for Foghorn really is predicated on the interesting area and science of the chromatin regulatory system.
The company was founded about eight or nine years ago on the premise that this was an underserved, underappreciated area for drug therapeutics as well as novel targets, and we believe that going after this chromatin regulatory system in cancer is a particularly opportunistic area for novel therapeutics and development. The science here, as I like to sort of analogize, is to one of the architect and blueprints, and so if you think about the chromatin regulatory system as the master architect orchestrating gene expression, the blueprints are obviously the genes, and you can imagine that if your architect decides to put the toilet in the middle of the kitchen, you have problems, and that's sort of what happens in cancer and other disease areas. The wrong genes are opened or accessible for transcription at the wrong time in the wrong types of cells.
We're particularly focused on chromatin remodeling complexes and transcription factors, but we also are interested in other helicases that are important and relevant in the regulation of gene expression. What's unique about Foghorn is we've been able to tackle a series of different and relatively difficult-to-drug proteins. Top of the list on that is SMARCA2, which I'm sure we'll spend some time in the Q&A on. This has been a target originally identified through work that Novartis did probably a decade or so ago. It's one of the top synthetic lethal relationships in oncology. But you add to that list targets like CBP, EP300, ARID1B. These are all very relatively difficult-to-drug proteins involved in genetic dependencies in cancer. We've done this now not once and not twice, not even thrice, but now multiple times on a range of these different targets where we found very selective chemical matter.
In the case of our first program, which we'll probably touch on as well, this is a dual inhibitor of both SMARCA2 and SMARCA4 that's currently in development in an AML study combination with decitabine. In terms of our platform that underlies and underpins the various things that we've been doing, it really is sort of the intersection of three areas, which is our deep understanding of the underlying biology here, specifically around chromatin regulation, dovetails with a platform that we've built to really study and interrogate these proteins, a whole suite of biophysical, biochemical, and functional-related assays, again, on a complex originally that was about one and a half million molecular weight, so as we've been interrogating aspects of this biology, we've really had to develop a whole suite of assays that allows us to study very, very large proteins or very difficult-to-make proteins.
And then lastly, we tie that and integrate that with our chemistry. We become very adept at protein degradation because the vast majority of these targets are non-enzymatic in nature. So it's really the intersection of these three areas that is the basis for the platform. And very quickly, what that has led to then, again, is the ability to deal with very complex and very difficult-to-make proteins, illustrated by the example on the left-hand side, and then protein degradation, which is obviously applicable to things outside of chromatin and chromatin regulation. Really, three chapters in brief on the company. The first area, if you will, was in validating that we could actually drug these targets, find chemical matter, build out our platform. The second phase was getting some external validation. That was through a deal we did with Lilly back at the end of December, end of 2021.
That was a $380 million deal, $300 million in cash, $80 million equity for five targets. One of those, which is disclosed, which is the selective SMARCA2 program that we'll spend some time on in the Q&A, and then the third chapter, if you will, is really about proving ourselves out in the clinic, which is sort of the current phase and area that we're in today. In terms of the pipeline, I like to think about this as a sort of little big pharma, as you will. We're obviously a smaller biotech, but we've got a very rich pipeline, about 10 or so different programs that we're prosecuting. 286, which is in the clinic, which is due for a data readout before the end of this year.
Our selective SMARCA2 program that's in collaboration with Lilly, where we just started dosing last month, and then a suite of other things that are coming up behind that. The proprietary part of that being CBP, EP300, and ARID1B. Again, time permitting, we'll talk a bit about that part of the pipeline. In terms of near-term catalysts and what we're looking at over the coming 12- 18 or so months, we will have, again, top-line data on our 286 study in the AML combination setting. 909, we're looking forward to some updates next year. We anticipate some disclosures related to some additional preclinical work that we've been doing in combination there. No official guidance right now in terms of time to the Phase I data readout for that particular study. We also have our selective SMARCA2 degrader. That's also obviously partnered with Lilly.
We look forward to hopefully putting that into the clinic in the coming years. And then our proprietary pipeline, as I mentioned, selective CBP degrader, selective EP300 degrader, and then ARID1B. So we'll have some other updates preclinically and some transitions towards the clinic over the course of the next 12- 18 months. Last quick comment for me before I sit down with Kelly here. Everything we try and work on, we want to be meaningful from a patient unmet medical need, but that obviously translates into what is the commercial opportunity. So as we prioritize the types of targets we look at and the areas that we go into, we want to make sure that these are meaningful revenue opportunities. The cost of running a Phase I for a patient population that could impact 20,000 patients as opposed to 500 is roughly the same.
So all things being equal, we want to make sure we're having the biggest effect that we can. I'll stop there because I know we're going to get into a lot in the Q&A, so we can transition from the slides to the discussion.
It is a pretty comprehensive intro in the short 10 minutes. So maybe let's stay focused on SMARCA2 program. So in terms of biology, it's not like we know very little, even though in the drug development, it has been quite challenging. Maybe first share your insights for inhibitor, not a degrader, because that's a relatively new modality. What has been the difficulties to develop an inhibitor for this protein?
Sure. So maybe just to take a step back, the 50,000-foot view of this. So SMARCA2 and SMARCA4 are highly related proteins. They're paralogs, meaning they came from the same genetic lineage. If you look at the primary amino acid sequence of these proteins, they're about 90% homologous. That homology probably goes up if you actually look at the ATPase binding pocket. Each of those proteins is actually part of this BAF or SWI/SNF remodeling complex, which is opening and closing chromatin. So the historical challenge when this target was first identified, as you can imagine, given the high homology of the proteins, was actually finding selective chemical matter to inhibit SMARCA2 over SMARCA4. Novartis, back in the day, had a program on this. I think it went for, but it was basically a dual inhibitor, similar actually to the SMARCA2/4 program that we have with FHD-286.
So the challenge has been, how do you find really selective chemical matter that inhibits preferentially SMARCA2 over SMARCA4? Based on the platform, and I won't go into all the details of exactly how we did it, but the short version is if you look at the polypeptide at SMARCA2 alone, you will find different chemical matter than if you screen the full remodeling complex because there is allosteric and it exposes or it reveals with certain assays much more selective chemical matter. So that was the basis for how we came to our 909 program. Again, when we did the deal with Eli Lilly back in 2021, we were actually in lead optimization at that time point. But I think that chemical matter and the selectivity was very differentiating relative to what others had at the time. Degradation is a whole different modality we can talk about.
Again, to our knowledge, there's no other company that has delivered a selective enzymatic inhibitor for this target.
Okay, fantastic. And besides non-small cell lung cancer, what other tumor types also has SMARCA4 mutant background where you see like 909 actually has a role there?
Yeah. So if you refer to our investor deck, there's a nice slide in there. It actually comes from the Memorial Sloan Kettering, the MSK-IMPACT study. It sort of shows that about 5% of solid tumors have a mutation in SMARCA4. Lung cancer is about 10% of lung has a SMARCA4 mutation. Now, not all those mutations are going to be relevant because you need those mutations have to confer a loss of function of SMARCA4 for the synthetic lethality of SMARCA2 to be applicable. Obviously, non-small cells at the top. You have cutaneous melanoma. You have the cancer of unknown origin, which means they can't trace it back, obviously, to the histology. There's cutaneous melanoma. So there's a range of different tumor types there.
We, at present, we'll let Lilly speak for themselves, but we're most interested at this point in non-small cell lung, in part because 10% of that patient population is a very large number. I think it's about 23 or so thousand patients in the United States alone. You can probably double that or a little bit more if you include Europe and certainly not even including any populations in Asia. So we're really interested in that. We know from some competitor data that esophageal cancer may be relevant as well. And again, I think that's the exciting part is figuring out which other tumor types might be relevant as we get into the Phase I and beyond.
Got it. So the focus now is non-small cell lung cancer, but for the dose escalation trial you just guided, the first patient that has been dosed, does it limit to non-small cell lung cancer?
Yeah. So the Phase I study design is a classic 3 plus 3 dose escalation. We're going to take all histologies, but the patients, as part of the inclusion criteria, they must have a mutation in SMARCA4. I think as that study progresses, just based on the epidemiology of SMARCA4 mutations, I think you'll see a natural enrichment for some non-small cell lung cancer patients. There is the ability to backfill in some cohorts. So the collaboration may decide to add in some more non-small cell patients in that setting. At the conclusion of dose escalation, though, we've, as we stated in our investor presentation, we're going to look to have a pure cohort in an expansion setting for non-small cell, and then we'll have another cohort for some of the other tumor types, and then potentially some combination therapies as well.
Okay, great. And under the Lilly's collaborative effort, you also have SMARCA2 targeting degrader moving forward. So curious, across these two different modalities, what kind of expectation we should have like they do similar and also differently to tackle different tumor indications?
Yeah. So it's probably premature to try and figure out exactly which direction we'll take the degrader. What I can say, though, is because of the importance of this target, we wanted to be, I would say, agnostic. I recognize it's all small molecule, but we wanted to be agnostic as to the approach. You can imagine, and I should say that we were binding to different places on the protein between our inhibitor, which is an allosteric inhibitor of the enzymatic activity, and then binding to a different domain for the protein degrader. So you can imagine a world where resistance will arise. Unfortunately, as far as I know, that happens with almost every drug in the cancer setting.
So you can imagine that you might want to sequence an inhibitor and then a degrader or vice versa, or you might even think about combining different agents and trying to hit it hard to sort of delay or stop any resistance from arising. In terms of indication prioritization, I think time will sort of tell as to whether there's some differential effect there. Oftentimes, with protein degraders, you're looking at hitting targets where there's additional scaffolding potential. That's not something, at least from an empiric basis, we've observed as we've studied this SWI/SNF complex. But I think the intention at this point is obviously we're in the clinic with 909, and the goal is to get the degrader in the clinic. I think it's going to be a significant enough patient population and evolution of understanding of the biology there that makes sense to have this two-pronged approach.
I see. And as SMARCA2 is a chromatin composite protein, so it has a very prevalent existence. Curious just to compare inhibitor versus degrader, could we speculate a very different tolerability profile?
You know, it's an interesting question. I think that's going to depend on what we see in the clinic. Our inhibitor, as we showed at AACR earlier this year, has about a 33-fold selectivity profile. That's measured based off the median IC50 across a range of different cell lines, which we think is an appropriate way to do it in an unbiased view. Our protein degrader, we don't have much more to say beyond what we've said prior to our collaboration for collaboration purposes, is you have almost infinite selectivity with the protein degrader. So there is a potential that if you're really able to get the selectivity window to be even wider, that maybe that will minimize some tolerability-related issues. But again, that's to be determined.
We're very confident that what we've got with the 909 molecule, which is, again, a 33-fold selectivity, that we're covering the target at the right IC level that we want without meaningfully hitting the SMARCA4 protein. That, with some of the PK parameters, suggests that we've got a really nice window there for that therapy. And again, obviously, that's been demonstrated preclinically. That's what we've now got to show in the clinical setting.
Okay, very informative. And also, how established is the SMARCA4 mutation screening at the study centers?
Yeah. So based on what my understanding, you know, it's part of the Foundation Medicine panel. It certainly seems to be, at least in the major academic centers as of now, something that patients will get sequenced for. It's interesting, actually, if you look at the literature, these patients who have SMARCA4 mutations with non-small cell tend to be less responsive to immune checkpoint inhibitor therapy. There's a nice Kaplan-Meier curve, I think, actually in our investor deck, where their prognosis is far worse, unfortunately, than those patients who are wild type for SMARCA4. So it's certainly being tracked at present. Patients can get sequenced. Unfortunately, there's no differential therapy available to treat those patients at this time.
Okay, great. And also curious, do you have a sight on the development plan for the SMARCA2 degrader? Do you expect it's going to be like running in parallel next to inhibitor, or it's more like sequential in terms of?
I think just pragmatically at this point, we're more in the serial nature of this. That 909 is obviously in the clinic. I don't have any official guidance to give on when the degrader will transition to Lilly and be in the clinic, but it's obviously a little bit behind where 909 is, so I think from that perspective, it will be in a serial fashion. We'll obviously have learnings from what we're doing with the 909 study, so that's sort of where we are with that.
Okay, great. And looking into the landscape, we have a recent data drop from another SMARCA2 targeting agent. Curious, what are the key learnings you can leverage?
Yeah, so obviously, I think you're referring to our colleagues at Prelude, and I think they're still in the midst of dose escalation. They shared some data at ESMO and the Triple Meeting that took place, ironically, both in Barcelona. I think the good news story there, at least as it relates to our interpretation, is validating of the target. They saw PRs both in esophageal cancer, actually, as well as in non-small cell, and I think from our perspective, we're really curious to see how they continue to dose escalate there.
Our point of view has been that you need to cover this target, whether it's with an inhibitor or with a degrader, you need to be constantly covering this target, whether it's constant inhibition at, for example, an IC90 level or degradation at sort of call it 90+% . So I think that still has to be played out with that data set. Whether their molecule can do that or not, that's, I guess, will be determined through the clinical study. But we see that as actually very compelling for validating this target and the importance of it. And I would say, again, in what are relatively difficult to treat patients who have exhausted other therapies, I think coming out, even with the PR rate that they have, I think bodes well for what we're doing.
Okay, fantastic. And also, it's still very early days, but curious, have you thought about like a combo regimen for targeting SMARCA2 and PD-1, probably an obvious one, but what other combo partners you can think of based on the mechanistic rationale?
Yeah. So I think obviously dealing with non-small cell lung cancer, most patients are receiving a checkpoint inhibitor and chemo upfront. When you fail that, unfortunately, the best that I think people continue to eke out is probably a 15%-20% response rate with docetaxel. We know, again, looking at sequencing of patients, that there's a meaningful overlap with KRAS. So I think those are three areas one could think about combining. The collaboration and Lilly specifically has done actually quite a bit of preclinical work. So hopefully we'll have more to say on that as we get into 2025. And I think it's reasonable to expect that there'll be some combination studies down the road once we've established safety and hopefully some efficacy for 909.
Okay, terrific. And moving to 286. So you're going to have a data update in relapsed AML settings. Maybe help us to understand what should we focus on for this data update?
Yeah, sure. So this will basically be at the conclusion of the dose escalation study. And maybe just again to take a step back and set context on this. So 286 is now a dual inhibitor of both SMARCA2 and SMARCA4. This is a program we'd originally studied in uveal melanoma as a monotherapy and then AML as a monotherapy. And we observed some clinical benefit in the uveal melanoma case. We had a PR that lasted about 16-17 months. We had a whole bunch of stable disease. We saw reductions similar to actually what I think Immunocore with Kimmtrak and ctDNA levels. But the short version is we didn't proceed further. We would have needed to take that forward in combination studies. We felt the competition there was stronger than would warrant us going it alone.
The monotherapy AML study. We saw a lot of circulating blast as well as marrow blast reductions, but not enough to get to the international working group criteria for a CR. So we've gone into the combination with a hypomethylating agent, in this case, decitabine. These are all relapsed refractory patients, the vast majority of whom will have had prior Vidaza exposure. Average overall survival here is about two and a half to three months for these patients. And unfortunately, they're relatively sick individuals. So what we expect then to put out here before the end of the year will be the top-line efficacy-related data, as well as obviously any comments on safety, tolerability, and whether or not we're going to proceed with the study. So we've set the bar that's a threshold. There's about 20% for a CR rate.
We're going to be very disciplined, I think, as we have been in the past. If we get the right threshold to move forward and we've got the capital to do it, which would probably require financing in this case, we would contemplate going it alone. We've obviously got a very rich pipeline and portfolio, so we want to make sure we're fully funded everything with the 909 program and degrader we just talked about. But that's basically where we'll find ourselves before the end of the year.
Okay, looking forward to it. AML is a quickly evolving landscape. We see these new therapies, especially for the targeted therapies, actually driven by IDH1, FLT3, and then Menin actually targeting strategy. As 286, it has more like a broad or like a general function. Do you see like a combination opportunities for this molecule?
Yeah. So again, what we observed in our Phase I monotherapy was sort of a broader-based differentiation effect irrespective of the specific genetic mutations and frankly, in patients who had relatively adverse cytogenetics. So we've generated some preclinical data. Interestingly, in combination with a Menin inhibitor, we think that certainly could be an opportunity. There's certainly the reason to believe you could combine the agent with other chemotherapeutics. We're obviously running one with a hypomethylating agent. And I think so there could be some interesting areas to take this forward in. Again, whether we do it or we do it through ISTs or depending on where our data go, we've had actually several ISTs already interested in studying with different regimens in the context of AML. So there's definitely that opportunity. And there may be opportunities outside of AML in some of the solid tumor settings.
There's been actually a lot of publications, for example, in small cell lung cancer where this mechanism of action could be really relevant.
Okay, fantastic. Maybe lastly, you also have a panel of chromatin proteins in the early pipeline and to target CBP and P300 and also ARID1B. Curious, what kind of a genetic, human genetic evidence actually support to pursue these targets?
Right. So we predominantly looked at some of the dependency data that's come out of either the Novartis DRIVE effort or the Broad with the Achilles where they CRISPRed out genes and looked for dependencies. So that's been the basis for a lot of the work. Obviously, we've then translated that in the case of CBP and EP300 into actual animal models, various cell-derived xenografts where we can actually see that we get tumor regressions in the case of CBP in some cancers. So we're pretty excited by both CBP and EP300. ARID1B is actually a very similar story in some ways to the SMARCA2 program. It's part of that same remodeling complex. It's actually amongst the most mutated, or ARID1A, the paralog is amongst the most mutated targets in cancer. It's at the very top of some of those synthetic lethal dependencies.
Also a target that folks have tried a drug, but unfortunately been unsuccessful to date on that. So we're really excited by all three of those programs, slightly different in the types of cancers. Some of them have additional frank dependency, as is the case for EP300, where it looks like prostate cancer may be relevant, even though there's no reciprocal genetic lesion in that paralog. So we're excited by all three of those programs. They're all degraders. We'll hopefully have more to say about that in 2025 as well.
Great. So the keywords here are not only chromatin protein, but also synthetic lethality as a theme.
Yeah, synthetic lethality. And then last thing I'll say just as we embark in, as we focus more and more on protein degradation, I think you can expect that there'll be other things that we'll do with that part of the platform, potentially in cancer, but potentially outside of that realm as well.
Right. Also protein degrader. Thank you so much for this very insightful discussion, and thanks to everyone for attending. We'll wrap up here.
Great. Thank you. Thanks.