Great. Thanks, everyone, for continuing to join us here at Guggenheim s econd annual healthcare innovation conference. My name is Brad Canino, Senior Analyst here. Very happy to do the next fireside chat with C4 Therapeutics. We've got Andrew Hirsch, President and CEO, Len Reyno, CMO. Thanks so much for joining us. Thanks for having us. It's been a busy year at C4. Maybe just introduce the company and discuss the status of the portfolio today. Yeah, great. Thanks. C4 is a targeted protein degradation company. We're making medicines leveraging this important new modality where instead of inhibiting disease-causing proteins, we're using the body's natural system to destroy them. This is about our 10th anniversary, actually. We've been incorporated for 10 years. Right now, we've got two active programs in the clinic. Our lead program is cemsidomide, IKZF1/3 degrader, in development for multiple myeloma. We recently presented data at IMS, which really demonstrated a best-in-class profile. We're excited about starting the next set of studies in early 2026. I think we'll probably talk a lot about those. The other program we have is in phase with our partner, Betta Pharmaceuticals in China. That's an EGFR L858R degrader that specifically targets the LR mutation. It's an exciting program in that it binds to an allosteric site that's created by the LR mutation, so it creates exquisite selectivity for this mutation. We expect to have data to make a decision on additional development in the first quarter of 2026. Additionally, we have two active collaborations with Roche and with Merck KGaA. We've had a completed collaboration with Biogen, where they've taken two molecules that they'll bring into the clinic. We continue to pursue a discovery portfolio of both oncology and non-oncology targets against really high-value, I would say, novel targets in validated pathways where there's a really strong degrader rationale where a degrader can do something that other modalities can't. With our recent financing, we've got runway through the end of 2028, which allows us to get through the next wave of studies as well as other inflection points across the portfolio. Great. Now, you gave a very comprehensive data package at IMS, several slides to dig into if you want to go on the website. Key takeaways from that, like how do you position cemsidomide with that data amongst the class of IKZF1/3 degraders? Sure. Key takeaways, I'm going to try to be brief, but that really highlights the strength of the asset. Let me just start at the beginning. When C4T built from the ground up, cemsidomide, they built it to be an exquisitely targeted and potent degrader of these two transcription proteins, which we know are responsible for both myeloma and actually lymphoma proliferation. It was built from the ground up, purposely built. It has features from the ground up that make it particularly attractive that's now mirrored in the clinical data. Those features include that the drug has low protein binding. In addition to being potent, circulating drug has a lower proportion bound to protein, which permits a deposit of active drug in the bone marrow. That's a really important distinction. The second, one of the distinctions is that the drug has no renal clearance. We're able to treat patients that may have mild or moderate renal insufficiency. How that manifests, clearly the creatinine clearance for many patients on the trial is 60. We can take patients at 40. We went into clinic with high hopes. It took a while to sort it out because we went into clinic not anticipating that the half-life would be 48 hours. That is a gift. That leads to really those three features that IMS really summarized nicely. The first one is the drug is incredibly safe. All drugs in this class have an effect on neutrophil maturation, so they have to be dosed with a break. It's not pure bone marrow toxicity, but it's simply delayed maturation that requires you to give a break so neutrophils recover. We've shown that separate from neutrophil reductions, the toxicity signal is very mild. We don't have GI side effects as an example. We don't have neuro side effects. We're a really clean drug. That's the first thing that IMS shows resoundingly. The second thing that's important is that IMS shows resoundingly that it works. Safety's great. If your drug doesn't work, then in fact, obviously, you don't have a drug. Why are we excited about IMS? More importantly, why are clinicians excited about the IMS data? Our IMS trial that we presented was cemsidomide + Dex. It was in relapsed refractory patients in a U.S.-only setting. We treated a unique group of patients in that trial. That is that notwithstanding the tremendous progress in the myeloma space, especially centered around immune active strategies, we treated patients and fully 75% of our patients had progressed despite either CAR-Ts or BiTEs or both. Why is it important? When I joined this company two and a half years ago, a lot of questions we got, does anyone even need this class of drugs anymore? Our data resoundingly shows that targeting these transcription factors is important through the entire life history of myeloma, which you would predict from the MOA. The final thing that's really exciting about the nature of the drug works is drilling down to how it worked in terms of cohorts, et cetera. The observation that we made in this relapsed refractory population, that we, regardless of what dose we interrogated with dexamethasone, we started at 37.5 and went as high as 100, that we in fact saw anti-myeloma activity at every dose level. The overall response rate in all comers was around 33%. Super important but, as you increase the exposure of the drug related to dose, what we saw very predictably was an increased response rate such that in the last cohort we enrolled at 100 mg, we have a 53% response rate in late-line refractory patients with a really unequivocally strong safety signal. Taken together, that is what makes it best in class. The final thing, because it's important to where we'll go, I'm sure, a little bit later, is that one of the other features of the class of drugs is when you degrade IKZF1/ 3, you also activate T cells. What we also showed in that data set is that across the range of doses tested, we get T cell activation with dexamethasone consistent with what you'd expect in terms of an augmented immune response. You get more effector cells, but we also can measure cytokines that increase, compatible with the effector cells being more active. Those are the takeaways. Andrew, taken together, we think it's a best-in-class story. It is important because when you think about the myeloma landscape, right, it is a combination treatment regimen. This is a fundamental pathway. You really want the best asset when you think about different combinations to combine. You want a very tolerable safety profile with the optimal efficacy that you can get. We think that is what cemsidomide delivers. Yeah. Len, you mentioned the patient population recruited. I think investors have analyzed the cemsidomide data on their own, but also trying to put them in context of Bristol's development of next-generation drugs that were actually studied a few years ago in phase I. The treatment paradigm in myeloma changes, it seems like, every year. It's really changing now. The difference in the patient populations recruited into the dose escalations as we think about comparing them, why is that important to think about in terms of pulling out differentiation for cemsidomide? Yeah. So it's crucially important for two points. One is that there is ongoing unmet need. So it answers a fundamental question. Is there a need for a late-line treatment that modifies disease? And the answer is a resounding yes, notwithstanding these strategies. The second part is equally and even more important for building values for obviously patients and investors. That is the disruption in the myeloma landscape. What was interesting and I think important at IMS in terms of general teaching sessions was a consensus meeting around how to think about second line and beyond. The message from second line and beyond now is pretty clear that investigators, clinicians, thought leaders really believe that they should introduce their best mechanisms of action as early as possible in the treatment paradigm. This idea that everyone gets the same second and then third-line regimen, that's really going away. People are going to compete for those patients. In that second-line space, and that's important because that's where we're doing a big part of our play with development of cemsidomide, is really a battle between CAR-Ts and BiTEs. CAR-Ts won the response rate battle. I mean, people are pretty consensus thinking it's a very high response rate, really exciting in a drug that's very difficult to give. Only 10% of patients, and this is Bristol's data, get CAR-Ts. You have a lot of patients not getting CAR-Ts. How can you make BiTEs more attractive? BiTEs have a really impressive efficacy signal, somewhat lower response rate than CAR-Ts, and perhaps lower durability. The theory of the case, if you will, is that if you take a drug like cemsidomide and combine it with a BiTE, what you'll do is turbocharge the response, i.e., get a higher response rate and higher quality responses, so MRD- negative CRs, and more duration. There is a lot of interest in doing that. We are well positioned to start asking those questions. That maps to our clinical trial strategy in 2026. Yeah. Maybe we'll expand on that. How has that phase I positioned you to move into these mid and late-stage studies? What regimens and treatment lines are you now prioritizing? Yeah. We had a very productive Type C meeting, if you will, with the FDA back in the summer. It was pretty clear that they were aligned, as we were aligned with the data, that we could really play in any line of therapy with almost any drug partner provided you can show safety. We're a small company. We have to pick our drug partners strategically initially, so balance what we can do with the resources we have to do it. We made the choice that for combination initially, our combination of preference is with a BiTE. We have a supply agreement with Pfizer, so we'll use ELRA. That study's going to start in early 2026. That will be giving ELRA essentially doses according to its label, and then the introduction of cemsidomide once the step-up dosing is complete. That's a phase I- B. We'll interrogate three dose levels that we pull from the first in human. We'll start at 75 mg, and then actually, we'll simultaneously evaluate both 50 and 100. Why is that important? Why are we doing three dose levels? The dose we have in late line when you're only with Dex, we're pretty satisfied that that maps to 100 mg. That's because of the 53% response rate. Obviously, in combinations, you've got to finesse things a little more. That may not be the right dose in a BiTE combination. We want to give all our doses are active. We're starting at 75, but if we need to give 50 for any safety reasons, then that's fine. Small study initially, but with the plan being to use that study with some well-designed expansions of safe doses to be able to pivot and design a phase III study very quickly after that. The phase III study that would follow would be a full approval study. Exciting about that study is that it has an accelerated endpoint built into the design. That is, in a full approval against a BiTE, we could do a pre-specified look at response rate, in particular MRD- negative CRs, and present that to the agency as an argument for accelerated approval for the BiTE combo, and then use a time-to-event endpoint from the same trial to get full approval. Excitingly, that support maps to the second part of our strategy, which is we started out by saying that we've unequivocally shown that the late line patients are important, that they need modification of their disease. In parallel with starting this program, which culminates in a phase III randomized trial, we will start a non-randomized phase II in early 2026 to essentially confirm the durability and the efficacy of the [cemsi] + Dex in a late line population, which we would then plan to present to the data supported for accelerated approval. Two shots on goal for accelerated approval. One trial that we would anticipate could then convert that accelerated approval to full approval for both indications. That is a baseline, kick at the can, if you will. If we had the luxury of more resources, are we saying we're not interested in other combos? Absolutely not. We need to do and be very strategic in terms of how we spend resources and how we focus on what we think will be high PTS on a timeline that can deliver value to patients and therefore investors quickly. That is where we start. As the landscape evolves and as our resource structure may change in terms of funding, we will consider other novel combinations as well as other standard combinations, such as obviously the elephant in the room, CD38. No reason why we would not combine with CD38 and combine well. We have some preclinical data that supports that, but also with a drug like carfilzomib. If you think we are jockeying for position right now with old drugs, or not old, but drugs that have already been approved, it is really BiTEs, CD38s. Carfilzomib still has a role. Obviously, Dex is woven in and out of all those regimens. There'll be novel things to come. Foundationally, cemsidomide is a potential partner for any and all myeloma combinations. The other thing I think the data supports is, and obviously this is something we would not be able to do, is a maintenance indication. Given the tolerability that we have seen, very limited dose reductions, no discontinuations due to safety, that really tees up nicely for either a post-CAR-T or a post-transplant maintenance. That is obviously not a study that we can do at our scale at this point. Can we spend maybe an extra minute on the dose selection? Obviously, you haven't picked a dose yet for the combinations, but you're suggesting you'd be comfortable within a kind of a 50% reduction. Why is that? We would like to give the highest dose that is associated with anti-myeloma activity because we still believe that adding cemsidomide to a BiTE at an exposure level that is associated with direct anti-myeloma activity is useful. We would like to get into that range. The good news is 50 is in that range. That is in that range. Why we would like to go higher is clearly because we really have unequivocal evidence that that anti-myeloma direct effect, plasma cell killing, is higher at higher exposures. We want to go as high as we can, but we also have to recognize that you have to then balance the safety profile of two drugs. They do not have overlapping toxicities except for one thing. That is they both have a risk of neutropenia. Now, when combined with a BiTE, there are no restrictions on growth factor support. It is not as if you cannot give from the get-go, we can give G-CSF. The goal is to limit the amount of time patients would have grade 4 neutropenia because the duration of that puts patients at risk, as you well know. We will choose the highest dose that we can safely give looking at those parameters. The reason 50 is still interesting is what I alluded to earlier. When we look for the immune stimulation signal, for all intents and purposes, that part is not really distinguishable between the doses. They are all very immune stimulatory. I hope that makes sense. Yeah. I guess as you look at some of the combination work that Bristol has done with their next-generation drugs, which are oftentimes coming in at lower doses than their monotherapy or plus Dex, how do you compare the therapeutic windows in terms of the dose range between the two and what's viable? Yeah. So it's a great question because Bristol has a very different shaped response curve at lower doses. Where if you think about it, look at their data in their phase I, yes, they have an impressive 40% response rate at 1 mg. But it's a pretty steep curve, meaning that the responses are there, but it's very flat over the doses. Before you get to one, it starts to pivot at just above 0.6. We know, for example, we're obviously not privy to Bristol's confidential information. But what's been shared publicly, we see doses of mezigdomide often landing at 0.6, for an example, which clearly is a less efficacious dose there. That's one of the things that we know is different. The proof will be in the actual efficacy signals. Yeah. I think at 0.6, they had about a 31% response rate. And then below that, I think it was about 10%. That is a very steep curve where when you look at our data, 53, 40, mid 30s in that range, still quite robust even at our lowest dose. The other exciting feature about the IMS data, which kind of it's in there, but it's buried. It's worth pointing out. While we clearly at 100 have a tendency towards more cemsidomide-related side effects as it relates to infection, that is not driven by a huge increase in grade 4 neutropenia. We just did a poster at the clinical pharmacology meeting in Denver, I guess last month already. In that poster, we showed nicely that over the range of doses tested in our phase I first in human, that grade 4 neutropenia is only slightly correlated with exposure. We actually have a really lovely therapeutic index where we really started to break apart that risk of neutropenia from the benefit of anti-myeloma effects. I'm sure if we gave 200 mg of cemsidomide, we wouldn't be breaking that apart anymore. We're not doing that. In the range we tested, it's really nicely shown. Yeah. Maybe on the positive side for Bristol's drugs, we are starting to see some of the phase IIIs beat out in earlier lines. I think what are you learning about the potential of these next-generation IKZF1/3 degraders with these results coming out? Yeah. The result that I want to learn the most about is their phase III that they did the teaser press release on, I guess it's two months ago, which is iberdomide in second line with daratumumab and dexamethasone. The reason I'm interested in that is that it's a second line study. We're interested in second line with DARA, an important drug. They separately had disclosed that they would be submitting data to the FDA that includes MRD-n egative CR rate in that trial. I'm assuming that they have data that suggests that's associated with a provocative MRD- negative CR rate. I want to know what that number is. The reason I want to know that number is because that's a contemporaneous benchmark for how far a drug like iberdomide can get you in that space. I think it is interesting data, not so much because of what it says about BiTEs, but what it says about what the contemporary benchmark may be for MRD-negative CRs there. I am assuming that will probably be a late-breaking abstract at ASH, but we have not seen that data yet. Once we see that data, that helps us a lot to understand the landscape. The other thing, I think when Bristol did that study, the assumption was that people would just think about second line the way they always thought about second line. That is not how that study is going to enter into the commercial space. It is going to be how does that study compare to what we can achieve with CAR-Ts and BiTEs. It is not necessarily a slam dunk from a study result to commercial uptake. I think there's going to be much more competition for second line than what they perhaps envisioned when this trial was designed. Now, on the BCMA TCE collaboration, I mean, there are several manufacturers with those out there. Andrew, can you talk a little bit about how the collaboration came to be specifically with Pfizer and what the interactions were like for that? Yeah. I mean, as people have been aware of this asset, and Pfizer was probably the leader in recognizing the potential combination opportunity. We're not restricted from doing others. This is just one that we thought the profile was good. Pfizer has been so far a really good collaborator to work with. Obviously, they're providing supply. It's not a co-development agreement, but there is a joint development committee where we are able to leverage their expertise with the BiTEs in the commercial setting, how it's being used, what they're learning, obviously not what they're learning from other combinations they can't share, but really what they know about their drug and how to write a protocol and how to develop it in combination with cemsidomide. That's been a nice partnership there. What updates do you expect to provide investors as that combination trial advances, maybe before a clinical data presentation is available? Yeah. I mean, I think as we've done with phase Is, we're able to, we have the ability to provide updates as we move through initial safety combinations. What are we seeing in different cohorts? Each cohort, dose cohort, can be an update depending on the data being kind of worthy of an update. I think the first thing, as Len said, that we need to answer is what's the dose that we can provide it safely at? Then understanding what does that look like in terms of early reads of efficacy and expansion cohorts. There'll be a number of opportunities to read out throughout the year prior to sort of having the guidance I think we had as mid 2027 as being sort of complete, but that's sort of everything. There's a lot of activity in 2026. Trust me. Maybe last question for me, how do you think about the commercial potential of cemsidomide, both as the Dex combo in fourth line plus myeloma and then separately the BCMA combo potential in second line? There's really two. We talked about the changing landscape, and I think those two things work well to set up for commercial success here. The first is as some of these newer agents, the CAR-Ts and the BiTEs, are moving to earlier lines of treatment, what that does is the higher response rates and the durability are these patients are surviving longer, but they're not cures. The CARVYKTI data, I think 2/3 of patients relapse within five years. That creates a larger pool than exists today in that late line setting. Some people have looked at other drugs that are approved in that late line setting and said this is not really strong performance. It's not a big market. We think there's two things happening. One, drug profile, but two, as the market grows, we think that's going to grow. We think that could be a $1 billion-$1.5 billion opportunity. Then as these agents move into the T cell agents move into second line, both CAR-T and BiTE, we think there is a really growing opportunity there. Again, as Len mentioned earlier, we do think CAR-Ts have kind of class-leading efficacy and durability right now. Given all the challenges, we think a combination with a BiTE could make that combination on par with what we see from a CAR-T and take a share from what people are projecting as CAR-T share. We think together, the two opportunities are about a $2.5 billion-$4 billion opportunity when we see those two dynamics happening in the marketplace. Okay. Great. Andrew, Len, thanks so much for joining us. Thanks everyone for listening in. Great. Thanks for having us.