Good afternoon, ladies and gentlemen. Thank you very much for coming out to the TD Cowen 46th Annual Healthcare Conference. My name is Steven Einhorn on the Biotech team, here joining me is the management of Foghorn Therapeutics. With presenting today is Dr. Adrian Gottschalk, President and CEO, who will give a presentation and might have a few questions afterwards. Dr. Gottschalk, take it away.
Great. Thank you, Steven. You're nice to see you. Thank you to the TD Cowen folks for having us here. I have two younger brothers who are upper extremity orthopedic surgeons. Unlike them, I don't actually have an M.D. or Ph.D. Steven just flattered me immensely. My mom is somewhere extremely excited that her son is now a physician. It's a pleasure to be here with you today, and I'm excited to talk to you about Foghorn Therapeutics and the progress that we're making within our partner pipeline with Eli Lilly, but also our proprietary pipeline. I know we've got about 30 minutes.
I'll try and make sure we get through everything. In case there are some questions in the last few minutes, I can take some time to address them. Foghorn's a clinical stage biotech company. We've been predominantly focused in the area of oncology. We've been working in this biological system called the chromatin regulatory system. This is an area of biology that for a very long time was thought to be playing a housekeeping role, a housekeeping role as it related to cells and tissues and not really as relevant in the disease setting. The truth as has been sort of uncovered over the last decade and a half is that's the furthest thing from the truth.
Mutations in this system are prevalent across a range of different tumors, and there's also evidence that this biology plays a role in other disease areas, particularly in the areas of autoimmunity, as well as neurodegeneration. The challenge has been how do you drug the system, and how do you drug it selectively? That is something that we at Foghorn have been working on for the better part now of over 9 years. As I'll show you over the course of the presentation, and a number of different targets, that we've actually been able to achieve what many in pharma had attempted but unfortunately had not been successful, which is selectively drugging of some of these very important components of this system.
As we've built the company, we started off predominantly as a small molecule, classical sort of enzymatic inhibitor type approach. As you'll see, within the pipeline, we've actually developed pretty exquisite capabilities in the realm of protein degradation. In fact, most of our more advanced proprietary programs are actually protein degraders. The biology, as I mentioned, is in the chromatin regulatory system. The oversimplification of a lot of literature, science, and work, is that the system is responsible for opening and closing chromatin, which has the effect of turning on and off genes, effectively exposing double-stranded DNA to transcriptional machinery. Obviously, that turns it on, and when it's compacted, the genes are not accessible for transcription.
The platform that we've built here is really the intersection, as I like to think of it, as a three-legged stool. Deep focus on biology, incredible capabilities that we have built in, biophysical, biochemical, functional-related assays that allow us to actually find the selective chemical matter. Then, of course, the underlying chemistry, which is a mix now of both, protein degradation, excuse me, enzymatic inhibitors. More recently, we've embarked on sort of the broader umbrella of induced proximity. Not the subject for today's conversation, but stuff that's starting to percolate up from our platform that you'll probably hear about over the coming years. The pipeline that's resulted from these efforts, I'm showing here, obviously at the top of the list is our FHD-909 program that I'll talk about in a few moments.
This is partnered 50/50 with Eli Lilly and Company, and there are several other targets on here that Lilly has the rights to. The proprietary pipeline that I'll talk about as well today, our selective CBP program, our selective EP300 program, and our selective ARID1B degrader programs. You know, we're on track to have IND-enabling studies later this year, we believe for both CBP and EP300, and ARID1B is a little bit further off. We're looking for in vivo proof of concept this year. A program that I won't spend any time on other than what I'm about to say, is an I&I program that we have. This is a small molecule, non-degrader program, very, very novel target that we don't believe others are working on.
We believe if chemistry continues to play out, and the biology continues to validate, that we'll have an IND on that program sometime in 2027. For competitive reasons, we're staying quiet at the time. Just as a quick reminder before I jump into the assets, the deal that we did with Eli Lilly back in December 2021, you know, this was a significant strategic arrangement, 50/50 rights on the SMARCA2 program that I'll talk about shortly. Significant amount of cash and equity at the time for what I believe is still the largest preclinical oncology deal. As you can see, there are some other milestones or royalties that apply to some other assets that again, we're not gonna talk about at present today.
Jumping into our SMARCA2 program, I'm actually gonna start with where we are in the clinic. We continue to dose escalate. We have not yet hit our maximum tolerated dose in this program. Eli Lilly is responsible for all the day-to-day operations of this program. We have sites open in the United States, Japan, and as of the last couple of months, you know, the collaboration has opened sites in France, Germany, Spain, and South Korea. That's, that's to finish out the dose escalation portion and some of the backfilling, and in potential anticipation of a decision to move to dose expansion. Again, this is just good practice by our partner, Lilly, to ensure that we've got all the right sites and that they're planning for success.
You know, the decision was made to start backfilling cohorts in the Q4 timeframe. That was on the basis of achieving one or both of the next two things, which is either achieving sufficient exposures where we believed were in the IC90 range of target coverage and/or observation of clinical activity. We've not commented on whether it was one or both of those things that have triggered the backfill portion. I think it's important to note in the pure escalation portion, we're taking any solid tumor histology with any type of SMARCA4 mutation. In the backfilling that is ongoing, the collaboration is enriching for non-small cell lung cancer patients and specifically for those patients who have a class one or a strong loss of function SMARCA4 mutation.
When I take a step back and I look at the Gantt charts and how the study's enrolling, which again, Lilly is doing a fantastic job with, I believe, and this is my guidance, not Lilly's guidance, I believe that we're gonna be tracking to a decision sometime in the middle part of the year that could come a couple months early, it could come a few months later. It just depends on how the phase 1 continues to unfold. We have not yet hit our maximum tolerated dose. We're still dose escalating even though we are now backfilling some of the cohorts. The right-hand side of the chart is obviously where we hope to be sometime later this year. This would be the dose expansion component.
It would include both a mix of monotherapy likely as well as combination type cohorts. I wanna set now the sorta context for why anyone should care about this study now that I've told you what the study is. I think everyone probably in this room is familiar with how non-small cell lung cancer is treated, certainly once you get into the metastatic setting. In this case, we're focused less on driver mutations. These are patients who would get a checkpoint inhibitor plus or minus a chemotherapy and then progress, unfortunately, on towards receiving other chemotherapies. In some cases, they may have a KRAS mutation and so on and so forth. So this is sort of the schema first through third line.
The patients that we are actually treating in non-small cell in the study, in this dose escalation study, are actually fourth or fifth line patients. Keep that in mind when I show you the next couple of slides. In this case, we're now looking at how these patients perform as compared to patients who are wild type for SMARCA4. That's the chart on the left-hand side. This is first-line or frontline metastatic chemotherapy patients. As you can see, and I'll oversimplify as you go from the left chart, left bars to the right bars, you basically cut the efficacy on all parameters roughly in half from response rate to median PFS to median OS, when you go from a wild type patient to a patient who unfortunately has a SMARCA4 mutation.
Again, this is in the first-line setting. You're seeing a median PFS of 2.7 months, overall survival 8 months. The patients that we are seeing in the fourth or fifth line setting, in most cases, you can measure their survival in weeks. Another way of saying this is the bar is very low, the unmet need is excessively high. The Kaplan-Meier curve here now is just a representation of what I just showed on the bar chart. Nothing really new on the left-hand side. On the right-hand side here, you can see that these patients, who have these SMARCA4 mutations, each little sliver is a patient that has been sequenced, is relatively non-overlapping with most of the actual mutations, with the exception of KRAS mutations.
The story there for those patients who are unfortunate to have both a SMARCA4 as well as a KRAS mutation is pretty abysmal. When the survival, the Kaplan-Meier curves here, are vertical, you know you have a problem. That's indeed what you're seeing here, certainly on the PFS and the OS front. Again, this is in the front-line, sorta setting. Response rate here, at least in this study, was zero. We know that this is of interest to the collaboration. Lilly obviously has their own stable of KRAS molecules. If and when this moves into expansion, I would anticipate at some point that you would see combinations with one or more KRAS molecules. I'll shift now to our proprietary pipeline.
I'm gonna talk about some of the selective protein degraders that we've developed. You know, just to set context before I get into both CBP and EP300, these are very, very similar proteins. They are histone acetyltransferases. They are responsible for depositing acetyl marks on various different proteins within the genome and regulating gene expression. The challenge in drugging these targets is they are very, very similar. Historically, the approach that we've seen from peers is to have a small molecule inhibitor that binds to the bromodomain on both of these proteins. The consequences of that, unfortunately, that we've observed pre-clinically, and I think that have been demonstrated with one of our peer companies, is that you end up with myelosuppression.
You end up with some cytopenias that we believe long-term are limiting as you think about combination therapies in different settings. I'll first talk to you about CBP. We have our lead molecule that I would probably classify as a pre-development candidate, FHT-171. This program has progressed through non-GLP tox. We've completed the in-life portion in both rat and dog for FHT-171. We're in the process of obviously getting all the various tissue and detailed analyses back as well as the toxicokinetics. The exciting part to me for this program are some data that we put out right around J.P. Morgan, which is the understanding that this could actually be relevant not only in the synthetic lethal context where EP300 is mutated, but also in ER+ breast.
The data I'm gonna show now in ER+ breast and where I'll focus this conversation or is in the ER+ setting. Here's some of the in vitro data when we actually inhibit, sorry, or degrade CBP. In these MCF7 cell lines, we see that we downregulate and reduce expression of the estrogen receptor, but we also impact the downstream regulated genes of the estrogen receptor. You can see here as a monotherapy, you know, in increasing concentrations of the degrader and what it does to the colony formation. Obviously, what we're interested in is getting into human beings.
The next step here are some data that we generated with a single dose, as you can see, daily subcutaneous, 10 milligrams per kilo in a cell-derived xenograft model in a ESR1 mutant, and then two PDXs, one ESR1 mutant, one ESR1 wild type. I think these compare very, very favorably if you're looking at, for example, the KAT6 inhibitors, excuse me, that have gone into the clinic. We are now in the process of actually running additional monotherapy models, exploring different doses as well as combinations that you could obviously think of CDK4/6, various SERDs and whatnot.
Now that we actually are on the precipice of having all the initial safety data, we need to correlate that back to the types of dosages, project what we think the human doses are, and assuming that all goes well over the next several months, the next destination for this program will be GLP toxicology, thereafter the clinic. As I mentioned, the challenge has been that dual inhibition of both CBP and EP300 is a myelosuppressive effect. Here we are showing some data comparing our degrader FHT-171 to two dual bromodomain inhibitors, one from Genentech that never went into the clinic, and one from our colleagues at CellCentric, which is inobrodib.
Here we see again that we don't have this impact on platelets, and obviously, we don't have an impact therefore on the megakaryocytes in any meaningful way. Just a little bit then on the technical parameters here. You can see this is a 30 picomolar degrader for its DC50 relatively rapid kinetics here, and achieves a Dmax of roughly 97%. Very selective over the sister protein EP300. As you can see from the proteomic volcano plot here, an exquisite selectivity profile over not only EP300 but other bromodomain-containing proteins. Importantly, you know, this is a VHL-based degrader, so it's not suitable to oral formulation.
We've spent a lot of time as a company working on long-acting injectable formulation technology that will allow us to de-deliver VHL-based degraders, ideally no more frequently than once a week subcutaneously. That's indeed what we have here with FHT- 171. And you can see here compared to daily subcutaneous dosing versus our long-acting formulation, we achieve equally impressive efficacy in this particular gastric model. That's our CBP degrader, pardon me. I'm going to shift gears now to our EP300 degrader. This is a really exciting program, and we're appreciative of our colleagues at CellCentric who have sort of been plowing the way, as it were, in the space of multiple myeloma.
I think they've demonstrated that this particular mechanism is very relevant in the heme setting, specifically in multiple myeloma, where they've shown impressive efficacy in fourth, fifth line relapse refractory multiple myeloma. Again, albeit from our perspective, with some potential limiting tolerability issues by virtue of the fact that they're hitting both CBP and EP300. Here I'm showing you where we think this could be potentially relevant across a range of different hematological malignancies from multiple myeloma to follicular lymphoma all the way on the right and everything in between. Obviously, you can see here why multiple myeloma is being of interest. It's sort of impressive that pretty much any cell line that we've tried, we have an impact on that lineage.
About 60% of diffuse large B-cell, somewhere in the same range for AML, et cetera. We've tested some earlier compounds in various models here that we're showing that are generally well-tolerated. In multiple myeloma, diffuse large B-cell, as well as prostate cancer, by the way. We think there's an opportunity longer term in the AR+ prostate world. Again, these were sort of earlier degraders. We've taken these degraders also into some of the models, and we've compared ourselves to the inobrodib compound here in this parental model of multiple myeloma, where we were actually dosing seven days on for inobrodib. I'd remind you that in the clinic, the molecule's dosed four on, three off.
We see sort of impressive efficacy here, where we're basically getting regression even over the course of the no treatment period. Again, we're not impacting platelets in the same way that dual bromodomain inhibition is. You know, we do this pretty frequently on any of the molecules. This is not even our most advanced, but we can see in this sort of CBC panel, we're not having any impact on white blood cells, red blood cells, platelets, or neutrophils for that matter. We've also looked in the IMiD-resistant setting. Here, you can see sort of the parental models in treated with in this case, Pomalidomide, Lenalidomide for the top three series and at the bottom for the forthcoming Mezigdomide and Iberdomide from our colleagues at BMS.
You can again see in the resistant setting in the middle and extreme right, that this degrader still has pretty impressive activity. We've taken a step forward then into a CDX here. This is now a Pomalidomide-resistant multiple myeloma model. You can see there the vehicle and the green line are roughly overlapping, the green line being Pomalidomide. Again, we compare to the inobrodib molecule here, dosed seven days on, which is the dark gray line, and then the four on, three off, to mimic what's done in the clinic. You can see that's in the light gray line. Then the degrader here in our case, is the dark blue line. Again, double O seven is not yet our pre-development candidate.
We actually have more advanced molecules that are more potent and are more amenable to the long-acting injectable formulation. Again, the goal here is to get this to a once-a-week subcutaneous delivery. I should mention just by the way that oftentimes people ask, "Okay, why not develop a Cereblon-based degrader?" Well, we have a Cereblon-based degrader. The problem, as people probably appreciate, in the IMiD setting, they are Cereblon-based molecules. You either get mutation Cereblon that render the IMiDs less effective, and/or you're competing with the IMiDs from the Cereblon ligase engagement. That doesn't lead to a productive interaction from an efficacy perspective. Here you're seeing one of the more advanced degraders here at double O seven.
You can see again very rapid kinetics, almost complete degradation, and very high selectivity. We're very excited by this program. We're continuing to push this forward. We actually also have an oral molecular glue that is targeting EP300 that is slightly behind where the VHL degrader is, both sort of as a backup option, but also lifecycle management, given the route of delivery here. In the last few minutes before I take some questions or open up to the floor, our ARID1B degrader. This is a target that I think has resisted all drugging and selectivity for many, many years.
When we've chatted with some of our colleagues in the large pharma setting, the one quote I would use is, folks have been banging their head against the wall trying to figure out how to actually selectively drug this target. The challenge is in part that this is a very, very large protein. It's also part of the BAF chromatin remodeling complex. It has no enzymatic function, and it's very, very similar to its sister protein, ARID1A. You know, what we set out to do was initially find selective binders using our platform. We've done that, and we've subsequently converted these binders into degraders. We think this is relevant across a range of different solid tumor malignancies here.
Here we're just sort of showing some of the more prevalent ones, again, setting up a synthetic lethal relationship where ARID1A is mutated, and therefore one would want to drug ARID1B. Here we're showing some of the progress that we've made. We have both the Cereblon as well as the VHL degrader. We've actually made even more progress on Cereblon. We're now north of what we're showing here. This is old data where we're showing 60%. We've actually crossed the threshold of 80%+ with our Cereblon degrader. We think there's a potential to take, you know, at least one if not both of these forward. We'll have more to say as we continue to make progress both in the potency as well as the degradation here.
Again, just showing that this is not just a one-off case where we're seeing sort of removal of the protein across bladder and some colorectal lines here. Lastly, you know, still a little bit more work to do on the volcano plot here of the protein. You know, I'd like this to look a little bit more like our CBP degrader. We're still a little bit early days for the ARID1B degrader, but nonetheless making some nice progress. The goal for 2026 with ARID1B is to get this to in vivo proof of concept. That's an important milestone for us for the coming several 6+ months.
The nice thing here is we've also actually generated some in vitro data. If you look at some shRNA knockdowns of relevant genes under the control of ARID, it correlates very nicely with what happens when we use our tool compound, which is on the right-hand side of this chart. Excited by this program. A little bit further behind where we are with CBP and EP300, nonetheless an important target and one that we think has significant potential in oncology. You know, I'll close by just saying, you know, the pipeline that we have is sort of rich. We're excited to get through the 909 dose escalation and the backfilling.
Our colleagues at Lilly, as I mentioned, I believe will have sufficient data sometime by the middle part of the year, plus or minus a few months around that, to make a decision as to whether we go into a dose expansion. There's a few other things that right now are still confidential with the Lilly program. Obviously, we have our proprietary degrader programs, an I&I asset that I mentioned that, you know, we'll be trying to progress over the course of this year. Then our platform that underlies all of this, there's some very interesting work we're doing in induced proximity that, you know, over the course of this year and probably next, we'll probably have some more things to say about. The company at this point is well-funded.
We recently completed a registered direct offering back in January. It was a $50 million offering that was led by our friends and colleagues at BVF. We just went to our top four institutional investors, we priced that at a premium, a 30% premium to where we were trading the day that we did the offering. Was 50% warrant coverage at 2 x that premium price and 50% warrant coverage at 3 x that price. I think that's a vote of confidence, not only obviously in what we're potentially doing with 909 in the collaboration, but also the broader pipeline we have.
The way to think about that is that gave us our coverage at our current burn rate roughly about two-quarters of spend. I think we've got about five minutes left to run, happy to take questions. If not, we'll give people some time back. Thanks, thanks again for listening, everyone, happy to take questions. Mike's coming. I think Ramon's got a question in the back as well. You wanna take it? Yeah. You wanna take the question in the back first? Sorry, Yaron.
It's okay. Just a quick reminder, in the non-small cell lung cancer case, the SMARCA4 mutations and the RAS mutations, are they linked at all? You know, are they physically next to each other? Are they just, are they sort of completely independent?
You know, it's a very good question. I actually don't know the answer to that question. What I do know is that for every 10 SMARCA4 patients, roughly three of those 10 will have a concomitant KRAS mutation. In terms of proximity on the genome or chromosome as to where they sit, we can email you as a follow-up. I'll ask our CSO and CMO that. I just don't know the answer to that, though.
For 909, it looks like you're backfilling and you haven't reached an MTD.
That's right.
It suggests that you're backfilling lower cohorts and you're not even. You continue to dose escalate at the same time.
That's right.
Usually if you begin to backfill it for Project Optimus, potentially, right? It means that you're beginning to kinda think about the lowest effective dose or, why backfill while you continue to dose escalate?
Right. I think it serves a dual purpose on that, Yaron. Which is one, is sort of figure out where is your lowest efficacious dose, right, for Project Optimus. The way it's working pragmatically, right? I'll just be arbitrary and say dose A, B, and C. Let's say we're escalating at A, we've cleared B and cleared C, so we're backfilling a bit at B. If we clear A, we'll stop some of the backfilling at B, and then we'll start backfilling at A as we keep going up. Part of this again, what triggered the backfilling was either or both of believing that we're into the appropriate exposure ranges, which for us was, you know, predicting where our IC90 target coverage is.
That's what we've seen pre-clinically that leads to the regressions in the various animal models. Obviously, we've projected that out to human dosage and/or seeing actual clinical activity. It, it serves the purpose of what's actually our lowest effective dose, but equally importantly, searching for that efficacy signal. Qualitatively, what I've said so far is that we've been pleased with the safety and tolerability of the molecule. We haven't hit the MTD as of yet. The important part is to actually be enriching for these non-small cell lung cancer patients with the relevant SMARCA4 mutations. It's a bit of an iterative process on this.
I imagine you're opening sites, so these patients, it takes a little time to find them and enroll them.
Actually, enrollment has not been an issue so far. I think in part because when the study was set up with, roughly, I think it's 15 or 16 sites in the U.S., five in Japan, and then, I'll probably be off by a couple here, but call it two or three in Spain, two or three in France, two or three in Germany, two or three in South Korea. Those extra sites were opened in anticipation of some of the backfilling just to help speed that up. Also candidly, which I think is a, you know, classic, large pharma appropriate move of if you know, you don't wanna sit there and say, "Oh, now I'm going to expansion, but I got to wait six months to go open sites." You wanna move seamlessly from one to the next.
I'm not trying to infer anything on that. I think we still got to see how the study plays out.
Are you seeing responses already?
We have not commented on the clinical activity at this point.
'Cause everything that's going on based on the slides that are going on, talking about what the next plans are, the poster Lilly presented as to where they would wanna expand and how to, how to do combo, opening new sites, backfilling, it all suggests that this is not consistent with a company that is planning on returning rights to you midyear.
Yeah. I can't speak to. I can't comment on as to what Lilly will decide or not decide to do at this point. I think it's good planning overall, we haven't commented on activity of the asset. The only thing I've said qualitatively is so far the safety and tolerability has been pretty good, and we haven't hit our maximum tolerated dose.
Are you expecting single-agent activity?
I certainly will expect it. Again, I'm not the final decision-maker on this. It's, it's my colleagues at Lilly, based on how the collaboration is structured. There's some joint discussion, but ultimately, when you go through all the contractual details.
Yeah
my colleague and friend Jake paid us a lot of money to have the final decision on this. I expect if I were the sole decision-maker, I'd want to see some single-agent activity. Again, we're in the 4th, 5th line setting. I showed that data, Yaron, where we're showing, you know, 2.7 months of median PFS in the first line. You know, if I were the sole decision-maker, if I'm seeing, you know, a few PRs in non-small cell, with some duration of 3-4+ months in the fourth, fifth line setting, I'm gonna be pretty darn excited. Again, the game plan isn't to do this as a monotherapy in fourth, fifth line patients.
It's go straight into that front line setting because we see how those Kaplan-Meier curves diverge.
Maybe final question. If Lilly decides not to advance to dose expansion, would you do that yourself?
I think it would be context dependent. If we're seeing efficacy, as I just mentioned, and we believe this is an exciting molecule that has meaningful commercial opportunity, we could contemplate that. I think Lilly would have to decide not to work on SMARCA2 at all, right? We do have a life cycle or backup, if you will, in the SMARCA2 degrader. I think if they're not going forward, it's a question of why. If, you know, my presumption is if this looks interesting and there's good safety, tolerability, and efficacy that, knock on wood, this will proceed into dose expansion.
Right. Fantastic. Adrian, thank you.
Awesome.
Thanks for coming.
Yeah.
Appreciate it.
Thanks for having us. Thank you.