Yo. Why don't we get going with the Q&A? Well, first of all, welcome. Great. Thanks for having us. A pleasure to be hosting you. Thanks a lot. Why don't we talk about C4's development strategy a little bit. You guys tend to go into indications that have proven targets, but these indications are very crowded. When I look at it's basically de-risk from a science or biology perspective, but very high bar for success commercially. Is that a fair statement? Well, I think what you're seeing is, you know, sort of the strategy play out that the company started with, which is a very classic strategy for a new platform company where you don't wanna add biology risk onto platform risk. The goal early on was to go after validated targets where we know that some sort of perturbation of those targets is gonna, you know, lead to activity and clinical benefit and really demonstrate from a platform perspective that we can make these degraders both BiDAC and MonoDAC degraders, and make them with drug-like properties, get them into the clinic. I think the important thing, though, is even though they are validated targets, well, except for BRD9, we'll talk about that in a second. You know, they all have, and every target we work on, frankly, has to have a degrader rationale, right? Why does the world need a degrader against this target, versus an inhibitor or versus the other existing therapies that are out there? The obvious place to start was our lead program, CFT7455, IKZF1/3 degrader. You know, those are the same mechanism, the IMiD class of medicines. As we all know, those were designed accidentally. We call them accidental degraders. Nobody knew they were degraders when they were discovered, so they're actually fairly inefficient degraders. What better way to prove a platform than to try and design the most effective degrader of those targets? That was sort of the first program. The second was our BRD9 program. That's actually a classically undruggable target. That was the rationale for a degrader there. The next two programs are BRAF V600 inhibitor. You know, there's known liabilities of inhibiting BRAF, and so we believe degraders can overcome those. Same thing with the EGFR degrader. Every program, while validated target, there's a commercial opportunity. We also have to prove that clinically, but I think we've got strong rationale for why a degrader needs to be developed against those targets. Now, as we start to think about our next wave of targets, we've proven the platform and we can start to think now about more novel targets, classically undruggable targets, where we think that a degrader is the only way to go, and can really hopefully benefit patients. That's. You'll see the evolution of our story as we move into the earlier preclinical pipeline. We're not actually ready to share those targets, but that's really the approach. I see. Got it. Your focus has been exclusively on Cereblon E3 ligase compared to other companies that have a much broader focus. When you look at that, do you think the strategy is gonna keep C4 relevant in the future? Absolutely. You know, I think that was a strategic decision the company made very early on, and I'm glad they did. You know, it was obviously the two key drivers of that decision were, one, Cereblon is expressed in all tissues and compartments in the body, and so it gives you the widest latitude for target selection. You know that, you know, if you're gonna go out for a certain target, that Cereblon's gonna be there to do the degradation work that you need. The second was that it's clinically validated, right? It's the E3 ligase that the IMiDs use, and we know that it works and works relatively safely in the clinic. You know, we've certainly investigated other ligases biochemically and have gotten them to work, but frankly, we haven't found the need, because Cereblon is successful with about over 95% of the targets that we've worked with. We've been able to make a degrader with Cereblon. You know, I think that's not to say we wouldn't go after new ligases, but I think we would have to be driven there by a target that required it. You know, I think it's an excellent exercise to go through for the industry. Certainly exploring what the function of these other ligases are, what they do and how they can be used is great. We've not chosen right now to allocate capital to that effort because, again, as I said, we're focused on making medicines, and we think Cereblon works. Interestingly, there was, I think, almost a seminal paper that came out. I think it was last month from Christina Woo's lab at Harvard that really talked about what's the role, what's Cereblon's day job, what does it actually do? It was really informative because, you know, what it uncovered is that Cereblon is actually sort of the body's garbage collector, effectively. It has no other sort of regulatory role in cell processing. It's expressed in, you know, at moderate to high levels in all tissues, which makes it really nice for a degrader. I think if we were gonna go after a new ligase, we would wanna make sure that we knew that it had similar properties to Cereblon. For instance, we wouldn't wanna use a ligase that had some sort of regulatory function in the cell because we'd be concerned about off-target effects. You know, was it not doing the work, co-opting it to degrade a disease-causing protein? That's how we think about it. Again, we think that Cereblon is a great ligase to use. We've made a deep investment in at least 15 distinct chemical series of Cereblon binders, because we know that very subtle changes in the exit vector of the Cereblon binder have pretty meaningful changes in the catalytic efficiency of a degrader. We think we've got a nice IP coverage of that. That's gonna keep us relevant, you know, frankly, as long as the target gets degraded. So, doesn’t really matter which ligase you use. Right. Sure. Yeah. When you think about the market environment and then when you guys are advancing a lot of assets into the clinic, can you speak about your burn rate and the need for capital? You know, we reported last week our Q3. We had $366 million in capital. We're burning about $25 million-$30 million a quarter, so that gives us runway, you know, through the end of 2024. I think we're very comfortable with our cash position today that it gives us runway kind of through and beyond sort of meaningful readouts of across a number of our programs. Obviously, to continue, you know, we plan to continue the company beyond 2024. We will need to, you know, do additional capital, but we're gonna be mindful of how we do that as we think about, you know, equity versus other non-dilutive capital. One of the things I really like about true platform companies like C4 is, you know, protein degradation has broad applicability across a wide range of therapeutic areas. Even in oncology, where we're focused, we can't possibly do all the targets, and that provides us the ability to work with collaborators and bring in non-dilutive capital to do degraders in other therapeutic areas or for other targets that we're not gonna pursue. We have that flexibility. I see. Got it. Okay. I asked the same question in the last session as well. There's now about 50 targeted protein degradation companies out there, and this list is growing pretty rapidly. How do you see C4 staying ahead of that competition? And how would you continue to differentiate yourself with the newer degradation companies? You know, Well, first of all, I think at the end of the day, targeted degradation is an incredibly important modality, if you will, or approach to drugging targets. I don't think one company is gonna own the space. You know, one company doesn't own the inhibitor space. One company doesn't own the antibody space. I think there's actually room for plenty, and I think the innovation that's going on is fantastic to see. I think we need to continue to innovate our platform too. We can't just continue to sit on what we're doing. Ultimately, you know, I think we've built our platform in a way, you know, where I think the key principles focusing on the catalytic efficiency of a degrader, right. Being able to model and predict that, focusing on Cereblon, being able to do both monoDAC or molecular glue in the generic term or BiDAC or heterobifunctional pairs. I think that keeps us there. I mean, I think it's, you know. I wanna say it's easy to make a degrader, but you can see by the number of academic papers, you know, they take VHL, they put a linker, they put a targeting ligand, a VHL linker, and they've got a degrader. But that's not a drug, right? Yeah. I mean, I think it's, you know, six years ago, right, the real challenge was can you get degraders with oral bioavailability, permeability, and have drug-like properties. I think, you know, we and all the other peer companies have answered that as a yes, but that's not an easy thing to do. It's not trivial. I think the experience that we have and the data that we have through the seven years we've been at this will continue to keep us in the front of the field. I see. Got it. Okay, why don't we move on to CFT7455. What do you think exactly went wrong with the dose-limiting toxicity with neutropenia? Well, before we talk about that, can we talk about what went right with 7455? Okay, sure. You know, I think we were, you know, the goal with that program was to develop the most potent degrader of these targets. I think we were actually pleased and pleasantly surprised to see that in our first dose at 50 mcg dosed three weeks on, you know, one week off. We saw fairly meaningful reductions in the difference in serum free light chains. Yeah. You know, in the 48%-78% range. That difference was not seen with mezigdomide, which was the BMS most potent medicine until they hit 600 mcg. Right? That sort of was very exciting for us because we played out that potency. Now what was surprising and where we ran into some trouble is we had predicted that the half-life of the drug would be in the 24-hour range. That with a number of our clinical pharmacology modeling made us comfortable that a dosing schedule of three weeks on, one week off was gonna be the right schedule. We were surprised to see that our half-life was actually 48 hours. That resulted in an unacceptable level of Grade 4 neutropenia. In fact, DLTs at our first dose. What's important about any of this class of medicines is that they have to be given with a break in dosing because we know that from all the work that was done by Celgene and BMS, that degrading IKZF1 leads to a downregulation of a transcription factor called PU.1. What that does is block neutrophils in the bone marrow and doesn't let them repopulate the periphery. The neutropenia you see is not killing neutrophils in the periphery, it's actually just the regular blocking the turnover of healthy. As the ones in the periphery die off, you're not getting replenishment of new neutrophils. Based on that, you need to dose with a break. They can come back and repopulate the periphery. That wasn't happening 'cause one week was just too short. I see. Got it. This new study design with two weeks on, two weeks off, you basically increase the dosing holiday by 100%, you decrease the drug treatment period cycle by 33%. What's gonna keep you confident that this is the right dosing regimen going forward? Yeah. I'll take that. I think we're confident in the schedule. I think one of the big misconceptions coming out of AACR was that we thought that 25 mcg was the dose, that’s not the case. We never sort of said that or thought that, because we saw DLTs at 50 mcg. Per protocol, we had to go down in dose, and establish a safe dose that we could then escalate from. That's the reason for the 25 mcg. In fact, you know, based on the data from AACR, we know we need to be above 50 mcg because while we saw promising signs of activity, we didn't have any responses at 50 mcg, three weeks on, one week off. I think, you know, I'm not confident that 25 mcg is the right regimen because we know we need to be above that. What gives me confidence that the two week on, two week off schedule, is really based on a whole host of data. You know, first, when you look at the neutrophil curves from our cohort at AACR. You can see that at day 14, there's really nothing even, you know, maybe grade 3, but nothing close to it. We know from a safety perspective that we probably, you know, will be okay, from that perspective. We also know from other drugs, BMS has another IKZF1 degrader called, I think it's CC-99282. They're developing that for non-Hodgkin's lymphoma. That has a half-life closer to 7455. Their phase I dose exploration resulted in a two-week on, two-week off schedule as well. We also know that from our modeling that, you know, while we have a longer half-life, our two-week off holiday allows the target to come back up to levels that the BMS one-week does with their shorter half-life. All that sort of hangs together that we think we'll be able to ameliorate what we saw. I think, the question you might say is, "Well, of course, if you give less drug you're gonna have less side effects”. Yeah. What's gonna happen with efficacy? Right. Right? I mean, I think that's the natural question. I think what we're you know comforted there is the mechanism of efficacy is apoptosis, right? We know that dead cells don't come back. Based on all the data that we have, we feel strongly that two weeks of dosing, with the potency we have with our medicine, is gonna be enough to continue to have that efficacy. You know, we're looking forward to, you know, hopefully sharing that data when we get there. I see. Okay. That makes sense. Have you explored other dosing regimen, like, say, two weeks on, one week off, or something like that? Clinically, no. Obviously, we did lots of modeling and we did modeling wise. I think, the one week off is just too short a holiday given the half-life of the drug. We don't think one week off is in any scenario— whether it's preceded by three weeks or one or two weeks of dosing— is the right way to go. You know, people have said, "Oh, what about, you know, 18 days on? You know, you either get too close to 21 or too close to 14? Yeah. It doesn't really make any sense. You know, we certainly are enabled to do it if we need to in the protocol if we wanted to change the schedule. But based on all the work, we don't think we will need to. I see. Okay. The ASH abstracts came out, and then we saw some data from Bristol's mezigdomide. What is your impression of the data so far based on what you see? Yeah. I think obviously, you know, an abstract has limited amounts of data. Everything I say will be caveated by we need to see the data at ASH. You know, I think the response rate was consistent. I mean, I think there was some commentary that, "Oh, the response rate came down.” Came down a little bit, yeah. 50% in 11 patients and 40% in 100 and some odd patients is to me the same. I think the confidence intervals probably overlap. I think the Grade 3–4 neutropenia rate went up a little bit to 75%. 70, yeah. I think we'll have to see what the split there is between Grade 3 and 4. I think the thing that drew my attention, and like, most people's attention was the 15% rate of febrile neutropenia. Again, all kinds of caveats. We don't know what the baseline neutrophil counts were, right? This was a heavily pretreated population. Right. If you look at the febrile neutropenia rates of lenalidomide and pomalidomide, they're in like the 3%-5%. Sure. You know, KOLs we've spoken to think 15% may be too high. I think, you know, we'll have to see what the data at ASH says in more specifics. I think that's something that we're watching that, you know, we'll see what that means for how that drug gets developed. I see. Is there any learning from that and bringing it back to your development program? I mean, I don't know. I mean, again, I have to see the data and understand, like, what drove that, right? Certainly, if you looked at our data set, you know, there were patients that had very different levels of baseline neutrophil counts, right? Yeah. We had, like, one patient that was up in the sort of 8,000 or so, and that patient obviously, never ran into trouble, but if a patient starts at a low level, given the mechanism, you know, they might. I think we'll have to look, but it's concerning, I think, in terms of thinking about their strategy of taking iberdomide to replace lenalidomide and taking mezigdomide to replace pomalidomide. We'll just have to see what that means. I see. Okay. What is the status with CFT7455's dose escalation study? How many dose cohorts have you completed so far? When should we see data? Yeah. We're not prepared to provide an update today. Okay. Cool. Cool. There's not much that I can say. You know, what we plan to guide when we can be a little bit more precise in terms of when we think we'll get there, and then how we'll do that, you know, likely we'll provide guidance like we normally do early in the year. Yep. Right now we're not prepared to provide guidance. Right. You could look for that early in 2023. I see. Okay. Guidance that is not data. Sure. I guess it's safe to say that the trial is progressing due to dose escalation cohorts? Yes. We are progressing through escalation, continuing to enroll patients, escalating as needed. Okay. Got it. Obviously, you're not running into dose-limiting toxicity, otherwise, you wouldn't be progressing. We would not be progressing, and we would probably have to make an announcement about the program, if we ran into some more DLTs at a dose where we didn't see, what we want to see. Okay, fantastic. What do you think is the bar for success for CFT7455 in terms of safety and efficacy, given that Bristol already has, like what you said, REVLIMID and POMALYST? Yeah. That, that's a complicated question. I wish I could give you a number and say, "Here, here's what it is." Myeloma is a pretty complicated space. It really depends on what line of therapy you're talking about and what setting. At a high level, the way you sort of asked the question, if you know, our goal, you know, which is one of our goals is to sort of replace, you know, lenalidomide and pomalidomide with CFT7455, then we need to be better than them on overall profile in, you know, different lines of therapy, in every setting. I think, you know we have a two-pronged development strategy. We're developing it initially as a single agent, and I'll get to that in a second. When I say single agent, I don't mean it's the only therapy you'll be on as monotherapy. We're developing as a single agent, and then also at the right time we'll be adding dexamethasone to the regimen as well. That adding dexamethasone is important, as we think about that replacement strategy. You know, again, I think our strategy can be different than BMS. We have one drug, and we are gonna try and move it as early as possible, in lines of therapy. The other important component of our strategy is thinking about some of the newer agents that are out there. We have all the BCMA-targeted agents. We have bispecifics. The important part of the single agent strategy is in some of those settings and combinations, you may not wanna have dexamethasone on board, and so we think it's important to establish single agent efficacy, as we move forward to think about combination regimens with some of the more novel agents. Right. I see. Okay. Why don't we move on to CFT1946, your BRAF degrader? What's the development plan for this asset? Great. Yeah, we're really excited. We got IND clearance in September. We're now moving to get those trial up and running with the goal of hoping to dose a patient by the end of the year. The development strategy is fairly straightforward. We'll start dose escalation in you know the sort of melanoma, lung cancer, colorectal cancer as a single agent. In patients who are resistant to BRAF inhibitors. At some point in the phase I, we'll add a MEK inhibitor, and escalate there. Then once we establish kind of a recommended phase II dose as a single agent, you know, we'll move into an expansion cohort there, in lung cancer and melanoma. You know, kind of to get that, see what that looks like in the resistant population. Within the combination with a MEK inhibitor, the plan would be to look at it both in melanoma and lung cancer in the refractory population, also in lung cancer in the frontline population, all in those three expansion cohorts. I see. Okay. Again, this is a very crowded market. When you look at the bar for success is gonna be very high commercially. What do you think is that bar for you guys? What are you guys trying to achieve, in terms of a product profile? Yeah. I think it's very well described with BRAF inhibition, some of the liabilities of a BRAF inhibitor, right? Inhibitors do a great job of inhibiting the monomer. We know that, you know, that can incorporate into the dimer and lead to, you know, oncogenic signaling. It makes them, you know, PFS is about 15 months with those inhibitors, median PFS. We think we can do better than that. Our preclinical data shows that we can lead to sort of deeper and more durable remissionsN with a degrader, because by taking down the whole protein, we remove that scaffolding function, and obviously the monomer then can't incorporate into the dimer, you completely block signaling. That's the goal for the program. You know, that the bar will be to have much more deeper and durable remissions than you see with an inhibitor. I see. Okay. Got it. We have a couple more minutes for the session, so if the audience have any questions, please raise your hand and we'll get to you. Okay, why don't we move on to CFT8634. What's the development path there, and what's the timeline for solid tumors? Yeah, this is actually fairly straightforward, compared to the other programs. Yeah. You know, CFT8634 is our BRAF degrader. You know, we're developing that in both synovial sarcoma and SMARCB1-deleted tumors. Right now, it's in phase I dose escalation in a mixed pool of both synovial sarcoma and SMARCB1-deleted tumors. The plan is once we establish a recommended phase II dose, we will split out the cohorts into a pure synovial sarcoma cohort, as well as a SMARCB1-deleted tumor cohort. Okay. You know, the goal there, and it'll be in the second-line setting. The goal there would be to try and use that for Accelerated Approval since there really are no, you know, no approved second-line treatments in synovial sarcoma, huge unmet need. You know, the bar that, you know, we've been told by investigators is really the 20%-25% response rate, which is pretty low, but that speaks to the level of unmet need. Right. I see. I think the development path in SMARCB1-deleted tumors is a little bit more complicated. Right. Right. Right. That's really gonna be. It's a collection of rare tumors. That's likely to have to be some sort of tissue-agnostic development, which I think the agency will be open to. We just need to have some data and then figure out how to do that. Okay. Got it. When should we see data from the current phase I/II study? Again, we haven't guided yet. We wanna be able to do that more precisely when we have a sense for when we will reach the recommended phase II dose. Okay. You know, we started dosing in May of this year. You know, I'd say that trial has accrued probably faster than we thought. You know, I think we were a bit concerned initially given the rarity of synovial sarcoma, you know, how fast that trial would enroll. It's actually exceeded our expectations, and we're not providing guidance today. You know, early next year, as with CFT7455, we'll provide guidance on when we'll think we'll have the recommended phase II dose and then subsequently data sharing. I see. Okay. Any questions from the audience? Okay, I have a couple more to end the session. Why do you think C4 is a great stock to invest in? Oh, I mean, how much time do we have? You got three minutes. Well, first of all, you know, we're sort of barely trading above cash, so I think we're not really getting credit for a number of the programs, any of the programs really that we have. I think when I look at our programs, the sort of three we talked about, and then the one we haven't talked about was our EGFR, L858R degrader. I really think there's great opportunity. I think degradation is really sort of the next wave of small molecule drug development. And I think, you know, we're a leader in the field. I think that, you know, the team, you know, can— I almost joke, we can degrade anything. We can't, but, you know. I think we have the right team, the right scientific and platform approach to, you know, really kind of drive the field and have degrade some of these truly undruggable targets and continue to be a leader in the field. I think, you know, on the face of it, the four lead programs alone, I think, you know, if they're successful, you know, the company's way undervalued, and I think we're not getting recognition for those right now. I see. Okay. Last question from me. As we move into 2023 or end of 2022 and then into 2023, what are some of the most impactful events that you think investors should be paying attention to? For C4? For C4, yeah. Yeah. Well, certainly data readouts among our lead programs, which are the big ones. You know, I think we've got, you know, over 2023 and 2024, I would expect to have data readouts, you know, across all four of our lead programs, our IKZF1/3 degrader, the BRD9 degrader, our BRAF degrader, and the EGFR degrader. I think those are important. You know, I think in that timeframe, we'll likely start to be able to articulate what are the next wave of programs that we'll start to work on now that we've sort of proven the platform. I think the other thing that's not talked about much is, you know, we have three collaborations, you know, with Biogen, with Calico, and with Roche, and we're not really allowed to talk about any of those programs. Hopefully, you know, some of those programs will get to the point where our partners will start talking about them. I think that's also gonna be an exciting time as well. Right. I know you can't guide data readout timing, but can you guide when you would be able to guide that? I think we'll do it early next year at an investor conference. Okay. Fantastic. Any final remarks? No, just thanks for having us. That's alright. Excited to be here. All right. Thank you so much, and pleasure to be hosting you. Great. Thank you.