Hello everyone, welcome to the BofA Precision Oncology Conference. My name is Chi Fong, one of the biotech VPs here at BofA. I'm joined by my colleague Jason Gerberry, Senior Biotech Analyst. Here with us for the next fireside chat is C4 Therapeutics. For those who don't know, C4 is a clinical stage biotech company focused on developing protein degraders for the treatment of cancers. I'm pleased to introduce Andrew Hirsch, CEO, and Adam Crystal, CMO from C4 Therapeutics. Andrew and Adam, thanks so much for joining us at our fireside chat today. Great. Thanks for having us. Andrew, maybe to start off, can you talk about the company's broader philosophy on designing protein degraders? What are some of the key considerations for selecting a target to pursue in development? I'll sort of take those in chunks. I'll first talk about our philosophy on how we design degraders, and then we'll get into how we apply that in the oncology space, you know, kind of separately. You know, it's really an interesting field and, you know, one of the key things that we focus on really when we design a degrader for any therapeutic area is maximizing the efficiency of the catalytic cycle, rather than any single step in the process of degradation. For those of you who aren't familiar with degraders and how they're different from inhibitors, I'll give you sort of a quick introduction of what I mean. They're different from inhibitors in that their role is really just to connect an E3 ligase to a target protein, so that it can be tagged for destruction. In effect, it's catalyzing the destruction of that target protein by kind of tricking the body's natural protein recycling system to recycle a protein it wouldn't otherwise recycle. A key feature there is that once that target molecule is tagged for destruction, a degrader molecule can go back and make that connection again and again. It can connect another target protein, an E3 ligase. We call that the catalytic cycle. We know that can happen anywhere from, I would say, 300 to 3,000 times per minute. We believe that optimal degraders do this toward the 3,000 times per minute in that range. That results both in maximal efficiency of that cycle, but also very differentiated biology. The best example we have of that are the IMID class of medicines. If you go look at like thalidomide or lenalidomide, those are fairly weak degraders, and they really only lead to sort of tumor stasis. As we increase the catalytic efficiency with pomalidomide, with CC-92480 and of course with CFT7455 we see that those medicines actually induce apoptosis. We really see different biological outcomes, the more catalytically efficient and potent a degrader is. Our entire approach to protein degradation is focused on this. It's really a fundamental principle for how we think about creating degrader medicines, and our whole platform is really built around that. I would say the other important component is very early on, we made a strategic choice to focus on cereblon, which is one of the body's E3 ligases. That's for really two reasons. One, it's widely expressed in all tissues and compartments, so it gives us kind of wide latitude in terms of target selection, but it's also the only clinically validated ligase that's out there, as it's the ligase, right, that's used in the IMID class of medicines. We believe that reduces clinical risk. In addition, when working with over 45 targets, we have, you know, about a 95% success rate using cereblon to degrade those targets. We don't feel the need to go beyond that. One of the really important components is that what we've learned is that really subtle changes in the cereblon binding component of a degrader can have pretty big impacts on the catalytic efficiency of a degrader. As a result, you know, we've really made a deep investment in cereblon binders. We have at least 15 distinct chemical series of cereblon binders, you know, which we call our kind of cereblon toolkit. Also that library enables us to have the capability to develop both molecular glues, which we call MonoDAC, or heterobifunctional degraders, which we call BiDAC, to deliver candidates, and that gives us latitude in terms of the different types of target selection. As you mentioned, our focus for our own internal pipeline is on oncology, and I think we're focusing on targets where there's a clear genetic link to cancer and there's a, I would say, a clear degrader rationale for why a degrader against that target. Great. You mentioned that, you know, there's certain features that make it perhaps more preferable to design a protein degrader compared to, say, an inhibitor. Can you elaborate what are some of these perhaps special features that make it attractive from a target perspective to design a degrader over an inhibitor? Yeah, sure. Adam, you wanna tackle that one? Yeah, absolutely. I think it's an interesting question from a lot of perspectives, but it's worth sort of noting upfront that when you look across the myriad of targeted protein degrader companies now, right? There are a long list of targets, not everyone is pursuing the same targets. I think this speaks to the fact that the technology is appropriate against a wide variety of targets, as opposed to some new technologies where it really lends itself best to a select few. But that doesn't mean that we don't have very clearly defined criteria for how we think about the targets we prioritize. I think it's worth saying that our criteria have changed. When we first approached this years ago, we put an emphasis on limiting biologic risk, and you can see this in our lead programs like AZF 13, BRAF, EGFR. These are programs that the world knows, and we know that there are that good drugs work. Now, it hits the other criteria, but it's also worth noting that as we approach what you could call Pipeline 2.0, we've begun to accept more biological risk, believing that many of the technical risks have already been addressed. How do we approach target selection, right? To identify those targets where we think TPD is an excellent modality. The first is really not specific for targeted protein degradation, but worth emphasizing nonetheless. We wanna emphasize targets where we believe that hitting them well would be transformative for patients, where we think it can apply to patients in areas of unmet medical need and be a great advantage to those patients, as well as providing commercial opportunity. Andrew mentioned. In oncology, we like to focus on bona fide oncogenic drivers in spaces where we believe that hitting that target will result in bona fide tumor regressions, as single agent. I think the remaining considerations we think about a lot are specific for the targeted protein degradation space. Andrew spoke to this a little bit, but we must have what we refer to as a degrader rationale, meaning a reason to believe that a degrader can do something against that target that other modalities, for example, small molecule inhibitors, can't. Scaffolding function is an easy one to point to, and BRD9 provides an example of this. Inhibitors are ineffective, whereas if we eliminate the protein with the degrader, we recapitulate the genetic effect of ablating the target. Second, we think about places where we need to maximize selectivity. Andrew spoke about this a little bit as well, the confirmation of the ternary complex formation, which really does allow exquisite selectivity. With the targeted protein degrader, you can achieve selectivity against isoforms of the same family or against mutant versus wild-type that are more challenging to do with other modalities. I think finally, we think about targets where there is a reason to believe both data and rationale that hitting that target will be tolerable. There are certainly many, many targets where taking it down will kill both the tumor cell as well as normal cells. Those are not targets we are interested in pursuing upfront. Things that allow us to have this, there are a few to point to. One is mutant selectivity, so BRAF, it's only expressed in the mutant tumor. You spare normal cells because you don't degrade wild-type BRAF. Synthetic lethality, where the only cells who care about it are those with the particular mutation, like the tumor. There are also examples of targets that aren't widely expressed in the adult human, right, but are in development or in cancers. So those are some of the filters we put through as we prioritize, and I think the one that's not on it, and it's worth highlighting, is traditional drug ability, right? I think we are confident that if we are interested in a target by either a BiDAC or MonoDAC approaches, we can probably make a degrader for it. I think one of the things that is so exciting is that we do not have that as one of our criteria. Great. The company is cooking at degraders, developing degraders for several established oncogenic drivers. You've touched upon that already a little bit, but can you elaborate on the potential therapeutic advantage you may get with a degrader over an inhibitor, say in the BRAF or EGFR space? And conversely, what would be some of the theoretical drawbacks with a degrader approach? Sure. Adam, you wanna tackle that, and I can come at the end and talk about those sort of drawbacks, potentially? Absolutely. There are examples where it's really clean cut, right? Neither EGFR or BRAF are necessarily those examples, because they are kinases and small molecule inhibitors do turn off those kinase activities. I think that even with these molecules, we are entirely reliant on our belief, data supported, that a degrader can do something which an inhibitor cannot. BRAF is a great example of that when you think about the fact that wild type BRAF is an obligate dimer, right? It is part of a complex signaling cascade, which includes dimerization of BRAF as well as MEK downstream of that. There is a liability of the three approved RAF inhibitors against that dimer. They do a great job of, for example, inhibiting the V600 mutant protein, which signals as a monomer, but does not do a particularly good job of inhibiting the dimer. In fact, it can hyperactivate the dimer through a process called paradoxical activation. We think a lot about the role of dimerization and how a degrader can potentially overcome that. Said simply, when we degrade our target, the V600 mutant protein, it cannot incorporate into the dimer, and paradoxical activation cannot be problematic. It provides a very strong rationale to go after mutant BRAF, which can be accomplished with a degrader and not with an inhibitor. I think that there are other aspects of degraders that provide advantages in precision oncology. You know, we've spoken to some of them as well. I don't wanna belabor them, but obviously, we think that we can make a degrader against anything that we have a ligand starting point, right? This is not the case with, for example, inhibitors, where you can start with a weak inhibitor or a weak binder, and it's really impossible to develop enough potency to make a molecule against it. We're more confident that with the degrader, we can start with a very weak binder and emerge with a molecule with drug-like properties. I think the other clear advantage of degraders is the catalytic activity of them, meaning they are fast. These molecules can take down proteins in vivo, you know, within two hours to maximal levels, and this provides a clear advantage to other modalities where maximizing the effect on target can take more time. Some proteins or rather some malignancies, some cells fail to adapt when you take out the protein driver that quickly and they commit to apoptosis, whereas if you have a slower mechanism, the cells can learn to adapt and they don't apoptosis, but might growth arrest instead. I think you also asked, you know, what challenges there may be in this space, and I think it's interesting, a lot of them have already been addressed in large part. The ones that were the biggest specters in the field were can we make molecules with drug-like properties? Can they administer it orally? Do they get in? Do they hit target? And are they tolerable? I think that the field has already demonstrated that with the entrance of some BiDACs into the field that the answers to all those questions are yes. Yeah. I mean, I would just add, I think it comes back to what we said earlier, that target selection is really important understanding a degrader rationale. I think sort of the risk is you don't really have a strong degrader rationale for going after a target, and you spend a lot of, you know, chemistry effort to sort of develop a degrader that ends up sort of being not differentiated. You know, I think one of the things I love about this field is all the benefits we just talked about. But at the end of the day, it's small molecule chemistry, right? It's not. This isn't anything new kind of biologically. It's not, you know, sort of that. It's no more complex than small molecules in terms of, you know, manufacturing, et cetera, you know, other risks. You have all the normal risks you have with small molecule chemistry, right? They're no different, and there's nothing really incremental to a degrader. It's just a different mode of action to sort of taking, you know, stopping signaling that's driving cancer. Okay, great. I think a question for you, Adam. I think we've talked in the past a little bit about this. With bifunctional degrader, you know, we have observed hook effect in preclinical setting. How do you optimize drugs in clinical setting to avoid the so-called hook effect? Sure. I think it's a super important question, and just for the audience, I'll sort of explain how I think about hook effect so that we're on the same page. With these bifunctional degraders, you can have maximal degradation in a sweet spot, but at the concentrations of your drug become higher, you see the molecule becomes less effective at degrading target. The way I think about this is that when you flood the system with too much molecule, some of it binds to target on one side of the molecule, some of it binds to E3 ligase cereblon on the other side of the molecule, and so the critical approximation doesn't happen because there's too much drug there. You know, I actually think the most important step in avoiding this becoming a clinical problem is a preclinical step. Meaning we want that sweet spot not to be a threefold range or a tenfold range, but more like a hundredfold or a thousandfold range in which the molecule does not demonstrate a decay in its activity, going from maximal over, you know, a thousandfold range. We tend to see that with our later stage molecules, that we have a wide range during which we see maximal activity. When we see a hundredfold or a thousandfold range, it actually makes it really easy to think about how to manage that clinically. You know, I think that in the phase I space, investigators and other clinicians spend all of their time thinking about how to get enough drug on board safely, right? That's the challenge, right? Very, very rarely is it the case that we're getting 10 or 100 or 1,000 times the concentrations we need from the maximal effect. Simply stated, I don't think it's gonna be a problem with most of our molecules 'cause the struggle will be getting to the maximal effect, not too far beyond it. That said, we'll monitor by PD to ensure that we're getting maximal degradation and don't see a decay in it as we go up in the dose level, but I don't anticipate it'll be a problem. The other thing I would say is that very simply, as you dose, you know, it might be the case that at Cmax you're a little bit into that hook, but, you know, as that concentration comes down, you're gonna have maximal degradation. I prefer not to be in a hook effect for any of the 24-hour dosing period, but if you're in there for an hour or two, I think the overall effect would be trivial. Okay. We have seen resistance, treatment resistance from practically pretty much all the targeted oncology drugs approved to date. You know, with degraders, what would be some of the theoretical resistance mechanisms you might expect? Granted, we really have limited clinical experience to interrogate the resistance problem with protein degrader. Curious, what have you learned about resistance in the preclinical setting? Sure. I actually think that there is a useful set of clinical data to point to where we might see resistance with targeted protein degraders, and it's the experience with the IMiD molecules, which are, of course, degraders. What emerges and what has been widely published in the literature are really two mechanisms of resistance or two buckets of mechanisms of resistance with IMiDs. Both of which could translate to the BiDAC space or the PROTAC hetero-bifunctional degrader space rather than the glue degraders like the IMiDs. The first is that in cells or in vivo models or in patients, what is observed with chronic treatment with IKZF1/3 degraders, and I'm speaking specifically of lenalidomide and pomalidomide, is downregulation of cereblon. Now this makes sense, right? The cells are being killed by a molecule which harnesses cereblon to degrade target which kills it so effectively by selection, the cells learn to down-regulate cereblon, resulting in less degradation of target and better survival. The literature is a little bit all over the place, but effectively, half of patients who are treated in this way have a 50% or greater downregulation of cereblon. What this translates to in experimental models is resistance. When you have less cereblon, you degrade less targeting, you survive better. It's worth saying that with molecules like our CFT-7455, because it is so fast and because it is so potent, it retains activity in the setting of lenalidomide or pomalidomide resistance, which is engineered by this mechanism. The other published mechanisms of resistance in patients are really mutations in cereblon, and there are three classes of mutation that effectively result in some degree of loss of function. Such mutations are rarely present at baseline, meaning before treatment with Len or Pom, you know, something like 0.2% of patients have it at baseline. After Len, it approaches 15%. After Pom, it approaches 30%. There's some retrospective data that says some of these mutations correlate with poorer prognosis when you get Pom. For example, if you get Len, you have one of these mutations, and then you get Pom, you tend to do less well. I don't think it's binary, right? I don't think you are resistant or sensitive, but I think it does cause a relative resistance. We're looking forward and looking at these mechanisms as we go forward and accrue more patients to our studies. I think it's important to emphasize that despite the setting, the presence of these two known sets of resistance, the hypothesis that a super fast and potent degrader will be active has effectively already been proven, right? CFT7455 with dexamethasone has an overall response rate in the 50% range after Len and Pom. The hypothesis that such a molecule, and I think our molecule is such a molecule, can overcome resistance, has a lot of data to support it. Great. For bifunctional degrader, given modular nature of that from a drug discovery perspective, can you talk about what knowledge transfer you can leverage from one bifunctional degrader to another? Yeah, sure. You know, basically what we've sort of seen to date in working, you know, with these is that degrader optimization is generally specialized to the individual target, you know, even down to the individual ligand that we're working with in terms of bifunctionals. 'Cause remember, what we're doing is we're essentially tricking a ligase to tag a protein for destruction it doesn't normally tag. What's really important here is getting the physical conformation, right, of the target protein relation to the ligase right. That really ends up being very, very different across different target proteins. You know, there are some learnings, for sure. I'm not gonna share those 'cause some of those are proprietary and a little bit of our secret sauce. I would say it's maybe not as modular as people may think, since you really end up having a fairly unique structure for the target protein of interest. You know, one of the things we found is that, the cereblon binder toolkit I mentioned earlier, which really has a high level of chemical diversity, you know, and range and binding potency, that's really important for our success 'cause it gives us the ability to utilize a modular approach at that cereblon binder to move quickly to find good starting points for rapid but specific optimization of degrader activity and drug properties. You know, as I mentioned earlier too, it's that, you know, those binders differ in very subtle changes in sort of exit trajectory, you know, from cereblon, for example. We find that has some pretty big differences in terms of catalytic efficiency. So there are some learnings, I would say, but you know, we think our platform and our toolkit you know really lets us customize you know kind of the BiDAC for kind of each unique target that we work with and ligand, if we do in the BiDAC space. We have a targeted protein degrader summit coming up later this month. Does C4 have any planned presentation at the summit? Yeah, no, we do, and we're actually really excited about it. We're not planning to present any clinical data on our programs at the upcoming summit, but I think this will be the first time our team's gonna present on our MonoDAC platform. You know, it's gonna highlight our ability to rationally design efficient MonoDAC degraders, you know, through our diverse chemical library, you know, combined with a bunch of sort of unique screening approaches that we use. You know, I think a lot of the focus has early on been on our BiDAC platform. But we're excited to share what we're doing in the MonoDAC space, and we look forward to doing that at the conference in October or this month, I guess. Great. Looking forward to it. Great. Why don't we transition into CFT8634, company's first bifunctional degrader in clinical trial. Can you give us a quick overview of the program and where it's at in development? Yeah, sure. As you mentioned, CFT8634 is our orally bioavailable BiDAC. It targets BRD9 for the treatment of cancers that have a dependency on BRD9, which right now includes synovial sarcoma and SMARCB1-null cancers. This has been, as we talked about earlier, considered an undruggable target, because bromodomain inhibitors can't treat these. Some of the oncogenicity is driven by some subdomains. Unlike inhibition, you know, we're able to show effect 'cause we can take out the whole protein in kind of preclinical models of synovial sarcoma. You know, we announced in May that we started dosing the first patient in our phase I/2 clinical trial, and that, as you mentioned, is our first BiDAC degrader kind of in the clinic. You know, it's a traditional sort of phase I dose escalation, looking at kind of safety, tolerability, and antitumor activity. In kind of both SMARCB1-null tumors as well as synovial sarcoma, you know, once we establish a recommended phase II dose, you know, that the goal would be to sort of break out into individual cohorts, one in synovial sarcoma and one in SMARCB1-null tumors. When can we expect to see initial clinical data from that trial? We haven't guided to that yet. You know, as is generally our practice in a phase I dose escalation study, you know, you never sort of really know how many escalation cohorts you're going to need. What I can say is it's been going well, you know, so far since the first cohort we started in May. As we get closer to getting line of sight to when we think we're gonna hit that recommended phase II dose, we'll provide some guidance then. Mechanistically speaking, I guess what makes BRD9 an attractive target for synovial sarcoma and SMARCB1 deleted tumors? You know, can you talk a little bit about the mechanism and what therapeutic roles does depleting BRD9 play in these genetically defined tumors? Sure. Adam, you wanna tackle that one? Absolutely. BRD9 is certainly a protein that most folks are less familiar with as a target, and the underlying biology is pretty complex but can be ironed out to thinking about it this way. BRD9 is a member of something called the BAF complex or SWI/SNF complex, and what this complex is responsible for is chromatin remodeling. In normal cells, the dominant species of the BAF complex is referred to as the canonical BAF complex. BRD9 is not a member of that. In certain malignancies, really, for example, synovial sarcoma, what happens is that the translocation or fusion protein that defines synovial sarcoma results in the ejection of SMARCB1 from that canonical BAF complex, which is called a perturbed BAF complex. It doesn't work anymore. Those synovial sarcoma cells become dependent on this lesser species called the non-canonical BAF complex, of which BRD9 is an essential member. When you degrade BRD9, you shut down the non-canonical BAF complex that the synovial sarcoma cells are uniquely dependent on and hopefully kill those synovial sarcoma cells while sparing normal cells. That underlying biology is seen in synovial sarcoma, as well as SMARCB1 deleted tumors, right? Very similar biology. You're just messing up that canonical BAF complex by deleting rather than ejecting that SMARCB1 protein from the canonical BAF complex. Complex but simple once you understand you degrade the target and only the cancer cells matter, and it's genetically defined. Why is it an attractive target besides the underlying mechanism? Really, there are three things. One, I already spoke to, genetically defined, right? We know that in synovial sarcoma and SMARCB1 there are all likely to respond because the disease is defined by the mechanism that results in BRD9 dependency. The second is that synovial sarcoma, for example, is truly an area of unmet medical need. These patients do quite poorly in the metastatic setting. First-line treatment is Adriamycin and ifosfamide. Patients tend to respond, but the median DFS is not good. It's less than a year. In the second-line setting, patients get really dealer's choice, not so good agent. There's a wide variety of agents which docs use for. They're all different because none of them work particularly well. The bar for an accelerated approval in that second-line setting is quite low and defined by the approvals of drugs like pazopanib and tazemetostat and similar indications that got approvals with overall response rates in the 10% range. Durability of response is something that may be important. Really, the third reason we love degraders in this space is simple. It's that inhibitors don't work. You can put an inhibitor of BRD9 on synovial sarcoma cells, and they simply don't care. It does not affect their viability. When you degrade BRD9, the cells are affected, and the drug is active. This is a space where the target is uniquely tailored to degraders, and we're excited to have the molecule in the clinic. Great. In your ongoing phase I, is there any adverse events of interest you are prospectively monitoring based on either the on-target mechanism or GLP tox profile? Yeah. I think that there's a tremendous need to demonstrate effectively proof of mechanism, right? I think it's fair to say that there's no particular concern that we're focused on from a tox perspective. But from a mechanism and efficacy perspective, I place great emphasis on demonstrating engagement and degradation of target. Obviously paired biopsies can do this, but those are challenging. There are some peripheral biomarkers which may serve in blood samples to demonstrate degradation of target, and we're looking forward to seeing that data when it becomes available. Okay, great. You have another degrader, CFT1946, a BRAF degrader that was recently cleared for phase I initiation. Can you give us a quick overview of the program? Yeah. Adam, you wanna do that one too? Sure. CFT1946 is an orally bioavailable degrader of class one BRAF mutants, right? Class one BRAF mutants are the V600s we're familiar with, because there are three approved RAF inhibitors across them. To keep it at a high level, as I said before, we believe that degrading the BRAF mutant provides an advantage over inhibiting. What this translated to in our preclinical models were two things that are critically important as we think about how to develop this molecule. One is that models of upfront therapy, meaning models where there is no resistance to BRAF inhibitor, but V600E-driven models, CFT1946 results in a deeper and more durable regression than comparator standard of care BRAF inhibitors. Similarly, and perhaps more importantly, is that in models of the resistance setting, in one example of this, we knocked in NRAS Q61K to a V600E-driven melanoma cell line. That's a clinically bona fide mechanism of resistance to BRAF inhibitors. Our molecule maintains activity against this model, whereas BRAF inhibitors are almost by definition dead inactive. We're excited to begin the study in the near future. As you know, we got the Study May Proceed late last week. Initially we'll be looking at as single agent, we'll be looking at BRAF driven tumors in the indications where there are full approval, so melanoma, non-small cell, colorectal and anaplastic thyroid after exposure to prior BRAF inhibitor, the resistant setting. We'll also be looking at patients who have BRAF-driven tumors and rare indications without approvals, who are naive to BRAF inhibitor. We also look forward to combining with trametinib within the first human study and then expanding to populations of non-small cell, melanoma, with both single agent and the combination. Building off of that, what key questions are you aiming to interrogate with the phase I trial, with this different bucket of the phase I design? You know, curious, how was the phase I design, you know, in such a way that help you address those questions individually? Yeah, it's a super important question. There's really maybe two or three things I would point to. Well, I should say upfront, right? Obviously the usual, right? Safety, PK, PD, and efficacy will all be assessed. I think that the things of great focus for us, again, are mechanism, right? We need to demonstrate activity and ideally, we need to demonstrate degradation of target. With this protein, it's expressed only in the tumor, right? There is not the opportunity to assess the target anywhere but that tumor that provides a challenge. We'll be looking at peripheral markers. You can think of cell-free DNA, where we could see measures of efficacy peripherally, but with biomarkers, though not necessarily directly observed target degradation. I think the other thing we want to see here is efficacy at achievable levels, right? How much efficacy is important. Well, initially, most of the patients we look at are going to be resistant patients. In that setting, as is often the case in oncology development, any response is potentially very informative. We're going to look deeply at that, because there are mechanisms of resistance which are understood, and we'll look retrospectively to see which mechanisms of resistance might predict responsiveness. We are not prospectively screening for mechanisms of resistance for two reasons. One is that they're not well enough understood that we can have great confidence that we could appropriately select the right patients. The second is that there are logistic barriers to prospective screening that would create challenges for the trial, and we think we're better off effectively taking all comers BRAF, who have seen BRAF inhibitor and looking retrospectively to learn about why they might be responding. You mentioned that the mutations is specific to the tumor cells. Would you be able to look at target degradation, you know, at a serum level, or you would have to do a tumor biopsy to interrogate that question? Yeah. I think to see target degradation, we'll need to look at tumor. It's really the only place that there is mutant protein. In serum, you can look at things that measure activity of the molecule, right? For example, we should see downregulation of V600 allele and ct cell-free DNA. That's a measure of activity of the drug, but a step removed from degradation. I know it's really early, but how should we think about the evolution of the program? You know, when might we see initial clinical data from the phase I trial? Let us start the study first. I'm sure I'm getting way ahead, right? Yeah. We have a goal to start the study before the end of the year. That's where we're focused on that. Kinda like I mentioned, as we get into enrollment, we'll see how the pace of enrollment goes, how many cohorts we need, we'll provide guidance then. Okay. Cool. I do want to touch on CFT7455, even though that's not, you know, within the precision oncology realm, but it is an important asset for the program. Could you give us a status update on the program? When can we hear the next, you know, data update with it? Sure. Yeah. I mean, there's not much new that we're sharing since our last update kind of for, you know, for our Q2 results. Look, we continue to enroll patients in the dose escalation portion of the study. You know, if you recall our goal in changing the schedule and going to 25 micrograms, two weeks on, two weeks off, was to establish a safe dose and schedule that we can then escalate from, you know. We've been enrolling those patients since kind of before we shared the data from cohort A at AACR. We continue to do so. Again, as we get closer to a more precise guidance for when we'll share data, you know, we'll provide that. But for now, we're not providing any data guidance at this point. Got it. I think the two, single agent, those escalation cohorts are open for enrollment right now. That's right. You have a combination cohort or cohort B to, you know, plan as well. Has that opened for enrollment? If not, what's the gating factor for that part? Yeah. What you're referring to is the dexamethasone combination cohort. That is not yet open for enrollment. I think, what's important is, you know, FDA required that the starting dose for that dex combination be a dose level lower than an observed safe dose in the single-agent cohort. At this point, we're able to open that cohort at our discretion. Right now we're focused on getting to the correct recommended phase II dose of the single agent, as well as dexamethasone as quickly as possible. We'll open that cohort when we think it'll accomplish that goal. Great. We have a couple of minutes left. Maybe if you can touch upon a little bit about the EGFR degrader program. Where is it at? What's the latest status, and when can we hear the next update on that program? Yeah. I think our guidance and our goal for this year has been to complete our IND-enabling activities this year. We're on track to largely do that with a goal of an IND submission and clinical trial start in 2023. You know, I would say the other thing we've discussed with that program is given the high prevalence of patients with these mutations in Asia and China. You know, our goal would be to have a partner to help us execute that clinical study in that region. Obviously that's also part of the plan. As those plans come together, you know, timing may change as we get to a collaboration point and, you know, align on a development plan. We are on track, you know, to sort of complete most of the IND-enabling activities this year as a positioning for an IND submission and clinical trial start in 2023. Great. We are almost up against our time. Thank you so much, Andrew and Adam, for joining us today. I hope everyone have a good rest of your day as well. Great. Thank you. Thanks, Chi. Thanks for having us. Thank you.