Great. I'm Brad Canino, Senior Analyst at Stifel. Thanks again for joining the Stifel Oncology Days virtual event we're holding today and tomorrow. Happy to be joined on the next fireside with C4 Therapeutics. We've got Andrew Hirsch, CEO, and Len Reyno, CMO. Thanks so much for joining us. Maybe to Andrew, can you just start off with an overview of C4 and the priorities for the remainder of the year at the company? Yeah. Thanks, Brad, and thanks for having us. So, for those of you not familiar with the company, you know, C4 is one of the targeted protein degradation companies. We were founded early in, or sort of late in 2015, coming out of Dana-Farber. You know, we actually the assets we took out of Dana-Farber, we're no longer pursuing. The platform that we built internally is really everything wholly owned, and all the assets that we've developed through that platform and put into the clinic are all developed here. So, you know, with our powerful TORPEDO platform. You know, I think as we think about the priorities for this year, it's important to set the context on kind of, you know, what we did last year, which I think was an important year. You know, we took a number of important steps, as we, you know, put a number of, you know, you know, 3 molecules into the clinic and started to generate data. And so the first thing we did was we prioritized the pipeline based on that data to really focus on the two programs that we're advancing ourselves, you know, CFT7455, which is our IKZF1/3 degrader for multiple myeloma and NHL, and CFT1946, which is our BRAF V600X degrader, for melanoma, lung cancer and colorectal cancer. I'm sure we'll talk much more about those, through the discussion today. We also made the decision to partner our 3rd program, or actually our 4th program, CFT8919, which is our EGFR L858R degrader, with Betta Pharmaceuticals, who has Greater China rights. So they're responsible for the phase I dose escalation study. We retain ex-China rights. So, you know, that as that trial and data unfold, we have the decision and option to decide to do kind of ex-China development, and we own those rights. So working closely with Betta to get that program into the clinic. We also streamlined our discovery portfolio, when we're focused on very high value, important oncology targets. Then we also announced 2 important collaborations, one with Merck in the US to develop degrader antibody conjugates. We did that, and then last month we announced a collaboration with Merck KGaA in Germany, Darmstadt, Germany, to discover 2 targeted degraders against what we think are critical oncogenic proteins that have progressed from our internal pipeline. And then so we put all that together, as well as some funding from our ATM and from Betta. That's also extended a runway to execute against our plan into 2027. And so in January we announced key priorities for the year, and I'll I'll I'll touch on some highlights. The first is a more complete data set for CFT7455 plus Dexamethasone and multiple myeloma. In December, if you recall, we presented the completed monotherapy cohort from that program, and then initial data in combination with Dex from the first 2 cohorts, where we saw actually responses in 2 of 3 efficacy-evaluable patients at a lower dose, 37.5 micrograms. So as that arm continues to enroll patients, and we continue to dose escalate, you know, we expect in the second half of the year to present a more complete data set from that cohort. In addition, we continue to escalate in CFT1946. That's in the phase I dose escalation study, enrolling patients with CRC, melanoma, and lung cancer, and then other cancers that harbor the V600X mutation. We're pretty excited about this program. Not that we're not excited about the other ones, but because the degrader approach addresses the liabilities of treating these cancers with inhibitors. You know, we've had some preclinical data last week at AACR, which really showed that CFT1946, both as a single agent and in combination with some standard combination partners, had superior activity to the inhibitors, standard of care combinations in those settings. And so we look forward to sharing the first data from that program in the second half of the year. We did share in January some early PKPD data showing the drug is behaving as we expected from a PK perspective, and that we are degrading the target, obviously not enough, at those first two dose levels. And so we're excited to share that data. So those are the big ones coming up. We have a number of other milestones, but I think, as in terms of the investor attention, I think the two clinical readouts is where, you know, are key priorities for the year. Yeah, great. Maybe we'll start with a basic question on CFT7455 within the myeloma treatment paradigm, because you're enrolling these patients who've received this mechanism twice or more before with lenalidomide, pomalidomide, many other therapies. I guess, what about the properties of the drug? Patients' cancers, maybe. Should that you should expect activity in this heavily pretreated refractory population. Yeah. So it's a great question. I think, if you recall, and many people don't, because it's been a while, when lenalidomide and pomalidomide were initially developed, nobody knew they were degraders, right? And so as a result, they weren't really optimized degraders, you know, based on today's standards. Actually, they're quite poor degraders when you think about the potency and catalytic activity, and that's an important aspect. This catalytic nature of degraders, the fact that they don't. They actually just catalyze the reaction between an E3 ligase and a target protein. And then, once they do that, they can go back and do it again and again. And what we've seen is that degraders with high catalytic activity, so that can degrade the most number of target proteins per minute, we think, can lead to sort of differential biology. And the IMiDs provide a great example there, where lenalidomide doesn't really lead to apoptosis. It leads to sort of stasis. And then pomalidomide's an improvement on potency and catalytic activity. And you do see that start to lead to apoptosis. When we designed CFT7455, our goal was to be more potent than pom. And in fact, in vitro, it's about 1,000-fold more potent from a catalytic activity. And so why that matters is one of the common resistance mechanisms to this class of medicines is downregulation of cereblon. The E3 ligase that induces degradation of IKZF1 and 3. And so the more potent a degrader is, the less cereblon you need to degrade the target. So in settings where cereblon's been downregulated, the fact that we have higher potency should lead to the fact that, you know, should lead to sort of better degradation, with lower levels of cereblon. Also, the quicker you degrade the target internally, the quicker you lead to apoptosis. And so we think that that confers an advantage. The other thing, too, that was important, as we thought about designing the drug, is that the clearance mechanism, we wanted to avoid a dependency on the renal system. Len and pom are both cleared renally. And so, a lot of these patients have, you know, renal insufficiency. And so it makes it challenging for patients with multiple myeloma to take these medicines. And so, by avoiding renal clearance, this is, we think, a good option for those patients as well and addresses some of those liabilities. So, taken together, you know, we really think that this should have activity in these late line multi-refractory patients. And in fact, based on the early read from the data we shared in December, we actually do see that activity, and not just in patients who are refractory to the sort of common treatments, but also to newer, BCMA-based therapies. We have seen a number of responses, you know. Our best responses, in fact, have been in those patients. So, you know, taken together, we think this is a really nice product profile for patients in this line setting. Now, that's not the only line we expect it to take the product into. We think it can move to earlier lines of therapy. That's obviously where we're starting. Yeah, and now you mentioned the activity in these late-line patients. You also had one that was a stringent CR. I guess, can you define what that is? And why is that such a strong anecdote? Right? You've only had a couple patients at the combo. But why is that such a strong anecdote for the future potential efficacy profile of CFT7455, in your opinion? Sure. Len, do you want to touch on that? Sure. So, you know, that it's really an important clue to the potential, essentially scope of the efficacy of the agent. So, first of all, that sCR occurred in a patient treated at 37.5 plus Dex. And we would be the first to say we don't think that 37.5 Dex is necessarily the optimal dose for 7455 plus Dex. So that's the first thing is occurring early in the combination with Dex dose escalation. The second thing is, who is it occurring in terms of a patient? This is a patient that is actually exposed to multiple lines of therapy, including bispecifics earlier in their treatment course. So this is a patient that actually, from an anecdotal or n-of-one, actually represents the unmet need in a U.S.-based population at this time. So we think it's a highly relevant patient to study. In terms of thinking about a stringent CR, obviously, it means that you've lost measurement of the peripheral biomarkers for myeloma. But more importantly, when you do a bone marrow examination, the myeloma cells have disappeared. And I think if you think about depth of response, stringency reflects a really profound anti-myeloma effect occurring at a dose that we're not claiming is optimal. And we would hope that would be a harbinger for broader effects across other patient populations. The other thing about that patient is how that patient presents as a stringent CR is they evolved over several cycles to that state. And mapping it back to what Andrew just told you about the reason for the drug itself. That maps to our hypothesis, how the drug's gonna work in that it's a catalytic drug. The drug has been designed to favor bone marrow and tissue distribution. So, in fact, if you think about how that patient presented, and who that patient was, we think it's a really important anecdote that points to the promise of the drug in the current contemporaneously recruited population. And I'm mapping back to that, because, you know, we have to treat the patients as they are. And this is a U.S.-only study that we're doing currently. So we're actually seeing patients who have come through at academic centers who've really been exposed to the standard of care, including more recent introduction of bispecifics and even CAR-T. So, you know, we continue to recruit in that group as we optimize the dose in the plus Dex cohorts. Yeah. Now, how does that Stringent Complete Response achievement so early in the study at an unoptimized dose, like you said, compare to the mezigdomide experience, which is Bristol Myers claimed most potent pipeline degrader of IKZF1/3? Yeah, I don't want to quote their data flippantly. I think they may have had one CR in their expansion cohort in the New England Journal experience. But I think it's fair to say that the appearance of a CR in their databases was a rare event. Again, we need to see what our data looks like with more patients. But we look at their data with interest, and certainly are impressed by it, that it is a more potent drug, and their data would suggest that associated with the response rate they quoted in their 100-patient New England Journal expansion cohorts. So we follow that with interest. and we're cautiously optimistic that, based on what we know about the pharmacologic differences and how our drug is actually more optimal, that we may see a similar, if not better, effects moving forward. Yeah, I think it's just hard to compare. You know, a dose escalation patient population, right, with an expansion patient population. And so I think it's important just to, you know, we're not. We don't want to jump to conclusions based on a handful of patients versus 100 patients. But, you know, to Len's point, I think their response rate was really driven by PRs and not CR. Yeah, I think the other way to think about it, or the way I think about it, when you're in early drug development, as we technically still are here. We're looking for clues that the data, as it's emerging, is mapping to the promise of the reason we put the drug in clinic. So the other thing to think about in the plus Dex experience is also to map it back to the monotherapy experience, which we shared in December. And in that regard, we did see evidence of the dose responsiveness in terms of anti-myeloma effects, in that 75 micrograms per kilogram was better than 50 and looked better than doses below that. So the fact that we're seeing this type of activity plus Dex is really important for two reasons. Pragmatic reason is that docs give these drugs with Dex, but also because the preclinical data supports the notion that there'll be a potential synergy with Dexamethasone in this class of drugs. So the fact that we see that early on in the dose escalation really starts to connect more dots that we're starting to fulfill the promise of why the drug was put in clinic in the first place, which was a very, you know, the very good premise of your original question, considering that, you know, the approval basis of prior drugs. Yeah. And now you did move to the 14-day on 14-day off schedule as a means to mitigate neutropenia, which is the on-target toxicity, given the potency of your drug. I guess, how do you gauge that neutropenia has been sufficiently mitigated to a degree that is going to be manageable for physicians who treat myeloma? You know, how do you interpret this? If you're in my seat as an investor analyst in terms of rates, grades, sequelae, dose management, etc. I think, as you think about neutropenia in this class of drugs and in this status of development, you have to separate the neutropenia signal that's defined in the dose finding or the safety determination phase from the neutropenia signal in practice. So let's take those and break it apart into two parts. So far we've been presenting the dose escalation experience for the drug, both with and without Dexamethasone. And in the dose escalation, when you increase the dose level at each dose level in cycle one, you need to define the kinetics of the neutrophil reduction, as well as a neutrophil recovery without growth factor. So that leads to a fairly artificial construct, because in clinical practice, as patients are exposed to this class of drugs in cycle one, they're monitored by their clinician. If the duration of the neutropenia looks like it may be too prolonged, growth factor is introduced to rescue the patient. So in cycle 1 for dose finding, we don't do that. So you'll get a neutropenic rate, and you'll expect that. In fact, many several patients will get grade 3 or grade 4 neutropenia in that cycle. In subsequent cycles, you can then give growth factor. So you can actually rescue a patient during their nadir from prolonged neutropenia by introducing growth factor in the absence of a clinical reason. So if you look at our data to date, what we've seen is we've had a predictable incidence of neutropenia that is dose related as we go through the dose levels. But what we've not seen is a significant incidence of neutropenic complications. And it's the neutropenic complication rate that actually is the problem in clinic, not the incidence of neutropenia. So we're cautiously optimistic, based on what we've seen to date, that when we can give the drugs with growth factor, not just in cycle 2 and beyond, but in cycle 1 and beyond, that we actually will have a very, manageable neutropenic complication risk. And that's the most important thing for investors to think about. The 1st clue is the neutropenia to help you understand the PKPD relationships of the drug from a pure point of view to just understand to see what you're seeing. But it's actually the big picture of how the drug is used, with growth factor that's more important in the long run. I think it's important. I think some investors may be confused by the driver of neutropenia. Right? The drug isn't killing neutrophils. Right? What it's doing is by degrading IKZF1 and IKZF3. Right? You're effectively blocking neutrophil maturation in the bone marrow. And so, you know, when you see neutropenia, what you're seeing is just as the neutrophils in the blood die off their normal cell cycle, they're not being replenished. And so actually, neutropenia. Also, their baseline is an important factor whether you're gonna see neutropenia. And that's why all these drugs that were given with a break, because you need to have a break to replenish. And so the break, as Len said, is exactly related to the unique PK of the drug. And so that's our PK suggests that the 14-day on and the 14-day off is the right one. Given the half-life compared to others in the class, there's nothing special about their 21-7 schedule. It's just related to the PK of the drug. Got it. Okay. And now, can you overview the additional dose escalation that has been ongoing in 2024? And at what doses? Because you mentioned 37.5 is likely suboptimal. And what will continue until the expected update later this year? So, as we shared, if you recall back in December, if you look at that deck, we noted in December we had already moved on to a 62.5 plus Dexamethasone that we were recruiting as a safety cohort. Again, as a reminder, in terms of, it's a Bayesian logistic regression model design, which means that we recruit typically between four and six patients in each cohort to declare the safety. Again, that's a cohort where you don't use growth factor in cycle one. So that's what we've shared. And after that, we will make data-driven decisions. So the other part. Sorry. We were also adding patients at 37.5 to fully characterize the signal there. So those are the two dose levels we shared. We are evaluating it in the context of phase I design, meaning, after we evaluate 62.5, we'll look at the opportunity for further dose escalation. We'll also ask the question whether there's interim dose levels that we should explore. But taken together, I think what people can expect in the second half of the year is a more complete disclosure of the dose escalation experience with Dexamethasone, as well as the addition of additional subjects at safe doses to fully characterize the multi-cycle safety, as well as the early signs of efficacy. And now, what's been the cadence of recruitment into the trial? Will that change over time as you clear some of the safety questions for some of the cohorts? I mean, ultimately, this is a question of what's a reasonable sample size to expect on the next update at these therapeutic doses starting at 37.5 in combo with Dex. So again, if you go back to the design itself, you can expect to see 4 to 6 patients in the safety phase before we move on to another dose level, as well as some backfill expansion cohort patients that will bring those sample sizes, potentially as big as 10 per dose level. Now, what is a good outcome for the next update of CFT7455 plus Dex in the second half of this year? I think, you know, what we're expecting and hoping to see is we will see continued evidence of the effectiveness of the drug emerging, as well as clues to what the optimal dose truly should be for a later stage development. I think the one cautionary note we'd make is we know everybody's gonna do a calculation of response rate, and it's human nature, but these are not cohorts that are recruited in a phase II type population. So I think a good outcome will be to see a reproducible and predictable measures of efficacy, as well as safety, and including durability of the anti-myeloma effect. So again, the longer patients are on study, it's not just response rate, but it's actually duration of response, and or even something lesser than a response. So taken together, I think we would hope to be able to make further the case that the drug has meaningful, anti-myeloma effects at safe and easy doses that are easy to deliver. Right. Now, you also have data for your BRAF V600X degrader this year. Andrew, you opened the call suggesting that this was the right modality to use in these patients. Can you speak a bit more about that? Yeah. So I think, you know, the currently approved inhibitors that are selective for BRAF V600X all have the same sort of liability, either what's called primary or acquired resistance. And that's generally mediated by something we call paradoxical activation. Right? And what happens there is that, as a result of inhibition, the monomer forms a dimer. And then that leads to continuing signaling through the MAPK pathway and uncontrolled cell growth. And so, that happens with a lot of these. And we've tried to design a lot of, as an industry, different ways to address this. And in fact, current standard of care, they're used in combination with either a MEK inhibitor for the acquired paradoxical activation, or a EGFR antibody for the intrinsic resistance. And that's actually one of the most common forms of resistance. But by degrading the mutant protein, we just actually remove it. So it can't actually incorporate into the dimer and lead to that signaling. And so that's why I think this is such an elegant solution to the problem of paradoxical activation, the resistance you see with inhibition of this target. In addition, we did design CFT1946 to have a dimer-breaking motif on the targeting warhead, to also avoid any further paradoxical activation and downstream effects, because it does actually work in both ways. The primary mechanism is degradation. But there is some inhibitory activity from the targeting ligand. And so we wanted to make sure we did that didn't lead to paradoxical activation. So we just think it's a very elegant way to solve this problem of the monomer still being present and incorporating it into a dimer. Yeah. Now, what types of patients are being enrolled into the phase I trial? And how does that influence the data? And And that could be expected to be seen around any early signs of anti-cancer activity from a phase I. Yeah. You wanna talk about? Yeah. So this is a phase I study. This is actually a study that's more global than our other studies. So of note, we're doing this study both in the U.S. and in Western Europe. And for the first part of the study, the phase I portion, we are recruiting patients who have a V600 mutation and have been treated with a BRAF inhibitor. By its nature, that leads three groups of patients that we get predominantly on the study. So we're getting patients with melanoma, non-small cell lung cancer, and colorectal cancer. Now, they may or may not have had a BRAF inhibitor based regimen as their most recent regimen, but they definitely had a BRAF inhibitor regimen from which they have progressed. It's a safety study. So it's also being governed by a BLRM, Bayesian logistic regression model, in terms of how many patients we recruit. So each dose level for the safety determination will tend to have four to six patients, before we can declare that dose level safe. It's a traditional dose escalation study. We're trying to get to an optimal dose and get through as many dose levels as possible. So when you look at the J.P. Morgan presentation, I think we showed that we, at that point, had gone on to dose level three, and we're continuing to fill out that monotherapy experience. Another important part of the protocol, however, in addition to recruiting those patients for safety, once we've declared a dose level safe, we're actually adding additional patients so that we can further characterize the PD of the drug. And again, you saw some examples of that at Andrew's presentation and J.P. Morgan, where we're doing actual pre- and post-biopsies. We're able to then measure the drug effect in tissue to look for evidence of degradation, as well as downstream effects of that you'd expect with that degradation. And this is a really important tool, because we want to be able to do is select a dose for further development that is not just based on purely and simply a safety measure and PK, but is actually associated with evidence of the drug effect that we think we need to optimize in clinic. So that's the work that we're doing now. The plan is to share the monotherapy dose escalation in the second half of the year. Once we're finished that work, or that work will begin to consider combination partners for the drug, almost logical ones being cetuximab in colorectal cancer, or trametinib in the other indications. We haven't guided to when we'll share that data, but it's a natural progression of the protocol to be able to then start to characterize safety and early clues to efficacy. I think the one thing I would emphasize is notwithstanding that we'll have a fair number of patients, they won't be from a single tumor type. So the idea that we'd have a number of patients at a single tumor type at a dose of truly of interest, to start to map to projections of efficacy, etc., I think that would be an expectation that exceeds the reality of the design. Yep. And this is where PD, the PD, becomes really important, because we know that we have to get to at least 80% degradation based on preclinical models. And so a lot of our dose work is gonna be guided by that PK PD, to understand. And because we know what inhibiting BRAF does. And so we know that if we take the protein out, right, that leads to the downstream impact. So the fact that it's a validated target where there's a clear liability to inhibition will help us connect the dots, when we see that degradation PD data. I think it, you know, we've been very pleased with the level of engagement and the type of investigators we have on this program, although it's been a crowded space. We're the only people actually evaluating the degrader mechanism of action. And that provides a clear rationale for clinicians to actually direct their patients to this study. So we've been really pleased with the reception of the study itself and look forward to being able to share the first data in the second half of the year. Yeah. Now, what type of genomic analysis is being done within this study? And is there something beyond just paradoxical activation, right? When we think about resistance to the prior BRAF inhibitor that they had that might predict efficacy and lead to certain development steps with a biomarker? Yeah. So we have a very rich biomarker program. And really, one of the things that we're always asking ourselves is, is this a drug that is gonna benefit from an additional precision medicine approach, if you will? It's very early in the collection of that data. So we're not prejudging what the outcome of those conversations will be. But we're collecting the data so that we can really take a look at that question. The other thing that we want to also map back to is to try to understand, are there predictors in patients who've had primary resistance to inhibitors? So they showed up, and they were already resistant to the mechanism versus people who progressed after a period of response. But again, early on, the numbers are small. It's gonna be hard to make a really robust conclusion. In fact, it would be inappropriate. What I will say is that we're really heavily invested in ensuring we get the data so that we can begin those conversations both internally and externally with thought leaders, and ultimately, as necessary, with the agency. Okay. All right. Well, unfortunately, we've run out of time. But Andrew, Len, thanks so much for joining us. Really appreciate it, and look forward to the data updates this year. Great. Thanks.