Good morning, everyone. Welcome to Barclays' 28th Annual Global Healthcare Conference. I'm Etzer Darout, a Senior Biotech Analyst at Barclays. It's my pleasure to have C4 Therapeutics with us this morning to kick us off. I have Andrew Hirsch, CEO, Leonard Reyno, Chief Medical Officer, from C4 Therapeutics. Andrew, maybe you can just get us going with just an overview- Sure. of C4 Therapeutics and then the upcoming milestones that you think are key and are worth noting to investors. Absolutely, and thanks for having us. It's great to be here. For those of you not familiar with C4 is a targeted protein degradation company, and we use our degradation platform with the goal of developing medicines in areas of high unmet need. We have two programs currently in the clinic. Our most advanced is cemsidomide, and I'm sure we'll spend some time talking about that today. That is an IKZF1/3 degrader that's targeting. We're in development for multiple myeloma. Last year, we completed a Phase one study, and we've now started the next phase of development. We started a Phase two study called MOMENTUM. We started dosing patients last month, and that's underway and enrolling. We expect to start in Q2 a Phase 1B study in combination with elranatamab, which is the BiTE from Pfizer, and we're excited to get that underway. That forms the basis of what we think is an exciting and differentiated registrational path. The other program we have in the clinic is CFT8919. That's an EGFR L858R degrader for non-small cell lung cancer. That's in a Phase one study in China, run by our partner, Betta Pharmaceuticals. We expect to have data this month that will enable us to make a decision on the path forward for that program. In addition, we have a robust discovery effort that combines both internal programs as well as collaboration programs. Our internal programs are really focused now on an area sort of outside oncology. We're focused on inflammation, neuroinflammation, and neurodegeneration. We call that INN, and we're excited that really leverages some of the key elements of our platform as well as 10 years of learnings of degraders and what degraders can and can't do. In addition, we have collaboration partners. We're working with Roche, with Merck KGaA, and with Biogen on developing degraders against targets of interest for them. Most recently, Biogen has two molecules in Phase 1 that we've delivered as part of that collaboration. We have a strong balance sheet at the end of the year with just under $300 million, which provides us runway through the end of 2028, which should get us through a number of important milestones, including an early look at data from the MOMENTUM study, which will be in the second half of 2027. You know, through the Phase 1B and startup of a potential Phase three with the BiTE combination. Lots of exciting milestones coming up. This is really a key year of execution as we get these studies underway and launch the cemsidomide development plan, as well as pursuing our discovery targets. Great. No, thank you for that. Lots going on in multiple myeloma, obviously. Even yesterday, we saw an update SUCCESSOR-2 trial from Bristol Myers Squibb. Just maybe give us some perspective in terms of what cemsidomide could deliver to sort of the multiple myeloma disease armamentarium, and what you believe is achievable with that molecule, and maybe highlight as well some of the data that you've generated to date there as well. Yeah. Maybe I'll start at a quick high level and then. Yeah, yeah. We can get into some of the data. Look, I think the IKZF1/3 pathway for multiple myeloma is foundational. I think that's lost on a lot of people because, you know, these are targets that have been drugged through the IMiD class, which we've had for a long time. If you remember, the IMiD class are not optimized degraders. In fact, when they were discovered, we didn't know that they were degraders, and now that we've learned that they were degraders, we're able to develop an optimized degrader. We think that cemsidomide has a potential best-in-class profile based on the data that we shared last year, and that's based on the fact that we've really optimized both the catalytic activity as well as the selectivity and PK of the molecule. I think it gets lost on people that we're dosing in micrograms. People seem to forget that, which is incredible to me, that we're able to do that. I don't know if you want to. Yeah. I don't know if I could build on that because, you know, obviously, people are interested in the evolution of the myeloma space and it's undergone a fundamental disruption with the advent and the penetration of immune-based strategies. It's a really important but, just to map back to what Andrew just said, IKZF1/3 degradation remains a fundamental mechanism of action, and it's really important to think about what that actually means in practice. In that regard, our first-in-human study is incredibly informative because what we showed in that study where we had patients who had a median of seven lines of prior therapy, in fact, 75% who had been exposed either to CAR-Ts or T-cell engagers or both, we showed that at our highest exposure, we still had a 53% response rate. Why does that matter? It matters because what it tells you is notwithstanding all the other things the patient has been through, there remains a foundational role for targeting these transcription factors and that's exactly IKZF4. That's sort of the top-line summary of the trial, but why are we positioned for success is, I think, really important to both patients and investors. What's unique about our dataset is that we were able to show really very elegantly that at every dose level we tested with dexamethasone, we had meaningful anti-myeloma responses with a very manageable and class-leading potentially safety profile. Why? Maps back to what Andrew just said. We were able to optimize the PK/PD relationships. We're differentiated in the class because we have a 48-hour half-life. That 48-hour half-life with the potency, we're the most potent drug in the class, more potent pre-clinically than mezigdomide, is with that 48-hour half-life, we're able to achieve anti-myeloma effects across a range of doses, clearly goes up as you increase exposure, but we're able to release the brake in time to allow for neutrophil recovery. Taken together, you know, we have a data set that I would refer to as a broad permission slip, that cemsidomide can be developed really in the future in any line of myeloma care. Our plan moving forward is a very efficient plan to address two parts of that spectrum, with MOMENTUM, late line, fourth line plus, and with the BiTE anticipating further development in the Phase three, earlier lines of therapy, pivoting on the move to immune-based strategies. Right. Great. Maybe with that, just talk a little bit more about momentum of the trial, maybe the trial design there. Maybe some of the nuances too relative to the Phase one too, right in a highly refractory. Sure. population, if you can kind of talk through those. In some respects, the MOMENTUM trial mirrors almost exactly what we did in the Phase one first-in-human study with some important changes. One is simply operationally. Now, that's going to be a study that we conduct both in the U.S. and Western Europe. That increases our because obviously in the end, cemsidomide should be and will be a global asset. That will affect the population we recruit. I told you a few minutes ago that we had seven prior lines of therapy. The eligibility criteria is fourth line plus. What that will map because of the two continents is that probably in the U.S., there'll be relatively more prior lines of therapy with more patients who have actually progressed after T-cell-directed therapy. Mm-hmm. In Western Europe, we anticipate they may have had relatively fewer lines of therapy. That's an important, you know, premise because in fact, one of the things that we don't want to do is pigeonhole that patients have to have failed everything and anything to get value. Patients don't take, you know, nth line therapy that's approved for various reasons, including access. It will Mm-hmm. will be the same kind of trial on the high level, but I don't anticipate at the end that the median prior lines of therapy will necessarily still be seven. The other thing, of course, that's different is now we've really understood how to give the drug, and so we can manage the drug in terms of dosing and decision-making vis-a-vis optimizing safety and opportunity for efficacy in a programmatic way consistent with driving the drug forward for potential accelerated approval. Mm-hmm. That's the other difference, is the trial will be conducted with what I would describe as regulatory intent. Really, the main issue is, you know, we always follow the protocol, but we will follow the protocol and in addition, have the indices of safety and efficacy reviewed by an independent committee. Mm-hmm. That will, you know, increase the potential rigor of the data set that we anticipate will support, ideally an accelerated approval discussion. Yeah. Great. I guess with that, can you talk about what you view as sort of a hurdle rate for response rate for that, you know, again, highly refractory population? Yeah. Also maybe sort of coming to some sort of agreement with the FDA around what that bar, if you will, could be for success. Yeah. I think the FDA is always very cautious in trying to and giving an arbitrary bar for what success will be, especially if you are having a discussion regarding accelerated approval. Mm-hmm. Contextually, it's always how does the data look in the context of what else is happening in the space at the time you present the data? Right. That said, there are some principles that I think are reliable. Mm-hmm. that we can think about. One, as we know from experience, most accelerated approval drugs are gonna have to have a meaningful response rate with meaningful duration and also safety that's acceptable, manifested in particular by not having patients come off drug. Mm-hmm. -for safety issues. We've modeled the study that with 100 patients, we can reliably detect a response rate of 40% or greater. Mm-hmm. We anticipate that the duration of that response benefit will be at least six months, more being better. We're higher than that in our- Yeah. in this presentation, and that the drug will be safe. There again, we're really proud of and happy about from the first in human study, we have almost no discontinuations of cemsidomide for any safety-related events. That's the sort of context of the study. You know, historically, it's compared against what the background rate of an effect might be, and we know that non off-label use of IMiDs in various lines is active. Typically, we've statistically modeled that signal wouldn't be greater than about 25%. With 100 patients, we can distinguish between those two. Got it. Great. I guess with the increasing use of anti-BCMA therapy, maybe you can also speak to how important is that post-BCMA activity we're observing with cemsidomide, especially put in the context where the comparator IKZF1 three degraders really didn't have that sort of Yeah. that hurdle that you guys have. No. Yeah. No. Yeah. with the anti-BCMA therapy. Can you speak to that as well? It's a great question and important observation. Yeah. that, you know, people obviously are always making comparisons with us in terms of emerging, you know, the class of BMS is calling CELMoDs, which are essentially optimized degraders. Okay. I think it's a really important distinction. Right. CELMoDs are nothing different in their mechanism of action than cemsidomide. What they are are potent optimized degraders. The difference is that when people talk about what folks have seen with those drugs, those drugs were developed. It's not a question of they didn't offer to include those patients. Those patients didn't exist. Right. In fact, when I joined the company three years ago, I had initial conversations with some investors saying, "You know, does this MOA even matter anymore?" What our data just resoundingly shows that it does matter, that patients who get state-of-the-art care still progress, and they still show up seeking disease-modifying care. We are the only drug in the class that has actually articulated and defined a really impressive response rate with that exposure history. Yeah. I think that patient population is growing because as the CAR-T and the BiTEs move into earlier lines of treatment, what happens is patients are living longer, but they're still progressing. So if you look at the Carvykti data, I think two-thirds of patients, you know, kind of relapse like around five, you know, within the five-year mark. So for one-third of patients, it's close to a functional cure. But there are still two-thirds of patients who now have a great treatment option that can prolong keeping their disease in check. Mm-hmm. But they will progress too. Mm-hmm. That just expands the number of patients available in this late-line setting as we see that migration of these newer therapies to earlier, more immunocompetent patients. Got it. Great. Between now and when you sort of get to the, you know, response rate, duration of response endpoint, are there any interim updates that you could provide on that trial before we get to that or is it just sort of heads down, if you will, until we get to that response rate? Yeah. I mean, as Len said, we're conducting them for regulatory intent and, you know, we're blinded to the data. That's why we have the independent safety data monitoring committee. We're trying to be as, you know, clean as possible. We don't wanna bias the outcome of the study. Not at all, and so we're not gonna see anything, so we won't really be able to provide an update until, as I mentioned, really that second half of 2027 where we'll be able to share an investigator-assessed response rate. Yeah. The regulatory endpoint will be that centrally assessed as well as some indices of durability, and that really won't happen until about mid-2028 when we'll have that data set. Got it. The first look that we'll be able to see and potentially share would be that second half of 2027. Got it. Great. Maybe we can shift to the second line plus setting in combination with T-cell engagers. If we've obviously seen data from Bristol there, from iberdomide as well as mezigdomide. Maybe first just your thoughts around where cemsidomide could differentiate from those combinations. You know, I guess relative to what we've already seen. I think it's easy. It's gonna differentiate by being more effective. What you really wanna know is what's the evidence for that. I think, you know, what's pretty important to think about, well, why are you doing the combination in the first place? You're doing the combination in the first place because we know that a BiTE-directed therapy suffers from T-cell exhaustion, as well as lack of, you know, optimized T-cell effect that does two things. It contributes to relapse, but it also reduces the depth of the response. If you think about the data we presented in our first-in-human study, there are two buckets of that data that are important. One, we already talked about, and that is that we have the most active compound of the class. And then the second piece that we didn't spend any time on yet is that we also know from our translational data in that study that at every dose level we study, we have a beneficial effect on the T-cell population and a concomitant and related effect on cytokines that are associated with immune activity. Taken together, the promise of that combination is the following, that because we have at every dose level, and every dose level that we have has anti-myeloma effects as well. We're hoping that we can both augment the anti-myeloma effect, which will appear very early in the first two to four cycles of therapy. Mm-hmm. That would manifest with hopefully higher quality, i.e., more CRs, deeper CRs, more MRD negative CRs. Then at the end, that will also manifest as prolonged progression-free survival and ultimately survival. Some unique differences from the data that's already been presented for us. If you look at the data that was presented at ASH for iberdomide combination with elranatamab, which is our combination partner, we benefit from that data because when that trial was started, the sponsor, Pfizer, was still figuring out how to give a BiTE with the combination and dose and schedule, as well as how to define the safety events and the response to the safety events. We have the luxury of learning from that and actually making sure that as we incorporate our combination strategy, that we're only really focused on the dose of cemsidomide, and that we have appropriate indices of both safety and efficacy, and in addition, that we have optimized the supportive care. Because as you know, with BiTEs, there is a you know, a very real issue. The good news is it's manageable but it needs to be optimally managed. We benefit from that data. Another key difference, though, is when I talked about the data that we had from our first-in-human study, that signature with the immune enhancement is with dexamethasone. If you look at the iberdomide data from ASH, that was not with dexamethasone. I think partly that's simply because the data in. You know, to generate that hypothesis was lacking. That's another key difference because we know dexamethasone does have augmented anti-myeloma effect. It will also reduce the side effects risk of CRS. It also has an augmented safety benefit in terms of supporting neutrophil counts, especially in the first two cycles. There's a lot of key differences. We're excited about the data that was presented, though, because the data that was presented, notwithstanding we think it's not the optimal combo. Mm-hmm. It did show a beneficial effect on a higher response rate. Right. It really is a very small study and really doesn't have the ability to drill down into quality of CRs, et cetera. As an out-of-the-gate data set, really supportive of our hypothesis and the design we have. We're super excited about it and it really enables us, I think, to move quickly. Because obviously, you know, we need to be agile, and we need to move fast to get these trials done, to get the data to the environment we need to get ultimately to design a Phase three in this instance. Yeah. I think some people sort of looked at that data and said, "Well, like, the bar is higher for C4." Actually, to Len's point, it sort of de-risked our hypothesis around can these classes of drugs be combined in managed safety, and the answer was yes. You saw the increased ORR that really put it on par with CAR-Ts. What it didn't do is increase the sort of CR and greater rate to be able to put that. That's really the name of the game in myeloma today. It's not necessarily ORR, because we think with these new combinations and these novel immune-directed agents, you can get close to 100% response rate. Mm-hmm. It's really how do you drive that MRD negative depth of response, and that's the opportunity for cemsidomide, which is, you know, again, we think, best in class in terms of both potency and tolerability. We think that the potency of cemsidomide can actually drive that CR plus rate. Mm-hmm Higher and maybe you know, we haven't seen the MRD negative rate for that study. I don't know if they're gonna present it at some point, but then hopefully have quality MRD negativity as well. That's really the opportunity that data set opened for us. Yeah. As you think about the Phase 1b study that you're gonna be this year, is it really more around sort of the safety of the combination, or are you gonna sort of embed the ability to look at sort of the deepening of response? So, so- The durability within that study? Yeah. Of course it, you know, by definition it's safety, but obviously it's gotta be efficacious. Mm-hmm. It's not gonna be statistically powered to actually have a reportedly reliable response rate. We will obviously look at and share the quality of response, the depth of response. We'll be looking at that data and making decisions vis-à-vis how to design a Phase three trial. Mm-hmm. You know, we anticipate that the regimen will be safe because we think we have the optimized drug vis-à-vis safety. It will be clearly very active. We won't be in a position, you know, to have 100 patients at a dose of interest quickly, but we will get data as quickly as possible at relevant doses. In that regard, I think what's really important to note, we're starting with our starting dose of 75 micrograms of cemsidomide. Mm-hmm. A great question is why. That reflects our confidence in the safety signal. We know the drug is safe across a range of doses. If we look at the data from our first in-human study, we have a modest side effect signal at 75, purely manageable. When we look at the effect on neutrophils as well as the supportive care that would be administered with a BiTE, we're cautiously optimistic that that dose will clear a safety hurdle. That will do two things based on the design of our trial. It will allow us to go higher. You know, we have to define whether 100 is the right dose when you're using a combo partner that's not just dex. Right. Will also allow us to expand the 75 level and, if need be and of interest, to look at 50. Again, you know, our job is to obviously do right by patients and to do safe regimens, but our job is also to bring efficacy to patients as fast as possible, and then therefore to bring data to who we need, which is our investor audience. Mm-hmm ... to give confidence that our plan is working and on a timeline that's efficient to get the drug to market. Yeah. Great. I think one point that's sort of maybe missed on folks too is sort of the innovation around the 14 days on, 14 days off that you ended up implementing for that. Yeah ... versus sort of the legacy 21-7. Is that a moat, you think, in terms of for this molecule, for this program? Is this something others can try to replicate? Mm-hmm do you think that it's really the quality of the molecule? They. that has allowed you to do that? They can. Yeah. for a drug with a 24-hour half-life. Right you can give sort of a lower thing. The question I think I would frame back is our 14-day on, 14-day off schedule is pharmacologically optimized for this drug. Right. For a drug with a 24-hour half-life, anything less than the 21/7, if you're looking for the anti-myeloma effect, is not gonna be an optimal regimen. It'll likely be safe and tolerable, but if you ask a different question, would it likely optimize the anti-myeloma effect, I think the answer would be doesn't make sense, it wouldn't, based on the understanding of how the drug actually works. Right. Great. Maybe lastly on CFT8919 Yep Just your lung cancer program. Just, you know, the opportunity there, and you know, maybe the progress that the program is making currently. Yeah. When we set out with this program, you know, I think that we observed that, you know, when you look at osimertinib, which is a fantastic drug, there was really a gap in efficacy from DEL19 versus L858R patients. Mm-hmm. You know, we thought making a degrader against selectively against the L858R segment was gonna lead to improved outcomes for patients with that L858R driver mutation. That was the goal of the program, and we started a Phase one study in China with our partner Betta. You know, we'll have the data, some of the data from that Phase one study this quarter, and that'll enable us to look at what does that mean and then kinda plug that back into you know, are our market assumptions the same. There's been certainly some advances in that space that has shrunken the gap between the osimertinib data and the in terms of DEL19 versus L858R. We will also, as we always do, evaluate what the development path looks like to really capture the opportunity. The bulk of the opportunity, we believe, is in the frontline setting. That will go into the calculus of what that looks like, how complex is that, and is that a study for us to do, assuming the data supports it, or is that something that may be better suited for a partner. We'll put all that together and make a decision internally this month, you know, and we'll communicate it at the right time. We're on track for that. Great. We're up on our time. Andrew, Len, thank you so much for this discussion. We'll be back with our next session. Thank you. Great. Thanks. Thank you. Thank you.