All right. Good morning, everyone. Ikenna Okafor here, Associate Biotech Analyst at TD Cowen on Tyler Van Buren's team. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a hybrid presentation and Q&A with C4 Therapeutics. It's my pleasure to introduce Andrew Hirsch, the CEO, and Len Reyno, the CMO, who will join us for the Q&A. Andrew and Len, it's a pleasure to have you both here. Thank you very much for joining me. I'll go ahead and hand it over to you, Andrew, to kick off the presentation when you're ready. Great. No, thank you. Thanks for having us. Before I jump in, I'm excited to really share an update on what's happening at C4. Before I do that, though, I'll be making forward-looking statements today, and this is our legal disclaimer on this matter. For those of you not familiar with C4, we are a targeted protein degradation company, focused on building a sustainable pipeline of medicines, with high-value degraders really across the, to achieve our vision of ultimately becoming a fully integrated company. We really have a validated clinical oncology portfolio, which consists of cemsidomide or IKZF1/3 degrader. I'll spend most of my time talking about that today. We have 15 minutes for a short presentation. Certainly in the Q&A, if we want to and we have time, we can get into some of the other clinical assets, which are our EGFR L858R degrader, CFT8919. In addition, we've recently started talking about a new discovery strategy focused on inflammation, neuroinflammation, and neurodegeneration, developing first-in-class drugs against undruggable targets, but in important validated pathways. We also, in October, completed a financing that provides us runway through the end of 2028, through a number of important value inflecting milestones. To that point in January, we announced an ambitious plan through 2028, really key important inflection points across the three years. This year, 2026, we're really laser-focused on starting our next phase of development for cemsidomide. We recently announced that the MOMENTUM phase II study has started enrollment, and we've dosed patients, and we expect next quarter to start the phase Ib in combination with elranatamab, which I'll talk also about. We also expect to make a decision around the 8919 program that's currently in phase I in China, and that data will serve as an important decision point on the next steps in that program. We also, with the discovery portfolio, continue to make progress, and we'll start to refine indication selection as well. 2027 is where we're gonna start to have some new data. As we think about the MOMENTUM study, in the second half, we'll have an early read on the response rate from that study, and we'll have data on the combination with elranatamab, as well as start to advance some of that discovery. In 2028, that's when we'll really have the registrational dataset from the MOMENTUM study, with that supportive, our first NDA, with cemsidomide. A really exciting three years to really think build value. Also in 2028, you know, potential for three INDs coming out of the discovery portfolio. That results in the pipeline that you see here. Again, I'm gonna focus the bulk of the presentation today on cemsidomide. That's really where we are laser-focused right now, and we can certainly talk about the other aspects of the company in Q&A. In addition to our internal pipeline, we do have three active collaborations, or two actually active discovery collaborations with Roche, where, you know, we've got two ongoing programs with Merck KGaA around the KRAS family. Biogen recently has taken a second degrader that we delivered to them into the clinic. This year, we expect to deliver another development candidate to one of our collaboration partners. Those have been incredibly productive. We're excited to see the progress that Biogen's making with the two programs. That's an RAC4 degrader and a BTK degrader for autoimmune diseases. For cemsidomide, I think the key takeaways that, you know, if you walk away from this presentation to understand are, first, you know, despite the incredible advances in multiple myeloma with immune-directed agents, IKZF1/3 degradation continues to be based on the biology central to the development and progression of the disease. IKZF1/3 degraders, we think, will remain relevant across multiple lines of therapy and in combinations. I think you've seen that from some of the existing data that came out at ASH recently. In addition, cemsidomide has a best-in-class profile among other IKZF1/3 degraders, both approved and in development, including the CELMoD portfolio from BMS. That's a large and growing myeloma market, and it's clinically validated in a commercially de-risked MOA. Lastly, you'll see an efficient development plan, with the potential for two accelerated approvals, and it's differentiated from others' development of this class in that we think that we're developing it where the landscape is evolving. To the first point, many of you were not around initially when IMiDs were developed by Celgene. Cemsidomide has the same MOA as lenalidomide, pomalidomide, and iberdomide and mezigdomide, which are the next generation, from BMS. What's important is there's two mechanisms. In the left or the middle panel, this really impacts hematopoietic stem cell differentiation, which is the root cause of myeloma, the sort of aberrant creation of plasma cells. By degrading IKZF1/3, you fundamentally stop that differentiation, and that's why it's relevant across all lines of treatment. The second mechanism is T-cell activation. IKZF1/3 regulate IL-2 production, and by degrading that will increase T-cell activation, which is becoming increasingly important in the current age of immune-directed therapies, where the liability that most of them suffer from is T-cell exhaustion. By combining, and you'll see that in our development plan, we think we can address that liability and improve the outcomes, which are already impressive but still have room for improvement of these new therapies. I mentioned best in class and I'll caveat. All the caveats are on cross-trial comparisons. Starting with the right-hand panel, you can see this is the response rate of the cemsidomide phase I data that was presented at IMS compared to the appropriate phase I data from the BMS portfolio, iberdomide, and mezigdomide. You can see the left set of columns is across all doses in the phase I study, and the right is at the highest dose. You can see a very, very competitive efficacy profile. Where the differentiation also comes in is in terms of patient population. On the left side in the green box, you can see that this is a more contemporaneous patient population that we studied. The iberdomide study and the mezigdomide phase I study didn't have high levels of BCMA or CAR T treatment as prior treatment for these patients. In our study, 75% of the patients had seen these agents in addition to 100% of them being triple-class exposed and 100% seeing prior CD38, which is really a contemporary patient population. The number of prior lines is not on here is seven median prior lines from three to 22. A very late line patient population, but very representative of what we see today in the late line. Where we really see differentiation, this is critical as we think about myeloma and combination therapies on the safety and tolerability profile. We didn't see any dose discontinuations due to cemsidomide toxicities and the grade 3/4 neutropenia rate, which is a consequence of IKZF1/3 degradation, so on target, was manageable. Importantly, we only saw 6% of dose reductions across the study from treatment-related emergent adverse events compared to about a quarter of the patients in those studies. That's critical as patients need to stay on an efficacious dose, and they need to continue and not come off therapy for tolerability. We really think when you combine the safety and the efficacy profile, we think this is a best-in-class asset in a very critical pathway. That leads to the development plan that we've outlined. You can see kind of highlighted in the first two boxes, in green and dark blue are the studies that we're working on getting up and running. In the dark blue, that's the MOMENTUM study. That's a phase II single-arm study of about 100 patients in the same patient population that we studied in the phase I, and we think that trial has the potential to lead to an Accelerated Approval. In addition, in the green box, we're gonna start in the second quarter, a combination with elranatamab, which is the Pfizer BCMA BiTE, and we think there's an incredible opportunity there that I'll walk through to really improve the performance and outcome of the BiTEs which again, as I mentioned, are already impressive in impacting patients. That study will serve as a foundation for a phase III pivotal study, which will serve both as the confirmatory study for that phase II MOMENTUM study, the single-arm study, but also has a second opportunity for Accelerated Approval in that an early look at response rate and particularly MRD-negative CR rate has the potential to serve as an Accelerated Approval endpoint for that combination in second-line or later patients within a time-to-event endpoint at the end, being that confirmatory study for the Accelerated Approval label. We think these are really exciting development paths and really are important in terms of where the landscape is going. Why is that? In the fourth line setting, we think that setting there's a large number of patients, about 22,000, U.S. and EU, and we think that's growing because as some of these newer agents move into earlier lines of treatment, we expect to see a real increase in the patients that are living longer. Two-thirds of patients on CARVYKTI progress by five years. There still is an opportunity for improvement. In the late line setting, the current agents that are approved all don't have great uptake 'cause of really modest efficacy and tolerability challenges. It's a validated pathway, and we've outlined an efficient development path. In terms of the combination with a BiTE, what I'm showing here is the opportunity to really bring BiTE efficacy on par with what we see with CAR T, which really serves today to be best in class. What you see here just in the graph is BiTEs alone, and this is data that was presented at ASH this past year, from others IKZF1/3 degraders. What you can see here is on a response rate data, the combination of an IKZF1/3 degrader, plus a BiTE really brings the response rate on par with CAR T, but with a much, much less potent degrader, really you don't see any meaningful improvement in the CR rate or better. We think with cemsidomide's profile in combination, there's an opportunity to increase that. That's really the foundation and foundational rationale for that study. This will be in the second-line or later patient population. When we look across both of those indications in a really growing market, we estimate about $46 billion by 2030. peak revenue for these two indications is about $2.5 billion-$4 billion. A really meaningful opportunity across both of those lines of treatment. You know, taken together, we think its best-in-class profile, efficient regulatory path, and large opportunity creates a really exciting opportunity for patients and for C4. I'll touch briefly on the discovery strategy. When we hired our new CSO a little over a year and a half ago, we sort of stepped back and looked at what have we learned in the 10 years we've been in the degrader business? What is our platform good at? What have we learned about degraders, and how is the right way to apply that going forward? The Two things we really anchored on were the ability to drive blood-brain barrier penetration, with what was a fairly large small molecules that initially no one really expected. The high catalytic activity that the degraders have, so while you can get BBB penetration, you also don't need a lot because they're very highly catalytic and highly potent. The last is our platform's ability to highly fine-tune degrader kinetics. We can design a degrader that can only degrade 50% of the protein if you're trying to, for instance, tone down an immune reaction, and that can lead to a lot better outcomes. We've looked at with that benefit, what are the key targets that might go after where there's a clear target to disease link? Where is there a strong degrader rationale? How do our expanded capabilities leveraging DEL technologies improve development? We've highlighted, as I mentioned earlier, focus on inflammation, neuroinflammation and neurodegeneration, we call INN, and we've identified three validated pathways, but there are five novel targets across these three pathways that are undruggable that we have started work on, and we're very excited about the potential for these. You can see the indications that they may be relevant in the right panel and how they map to the pathways. The important thing too about the number of these is there are what I would call sentinel indications, where, you know, you'll see Alzheimer's disease on the list. That's not something we would jump into as a small company. There are smaller indications that can de-risk the therapeutic hypothesis for Alzheimer's that we may be able to, we are able to develop early and de-risk the pathway as we advance. We're excited to share more. We're purposely not sharing the targets or anything more about that until we make further progression, largely for competitive reasons. I know, in closing, just reiterate our key upcoming milestones, as we've laid out the next three years. We're really excited to get the phase Ib combination study started, and then move these programs forward through the next three years, where we expect to have our first NDA, and then three potential INDs from the discovery pipeline by 2028. Thank you, and I think we're gonna jump into some Q&A in the fireside chat. Yes. Thank you, Andrew, for that wonderful presentation. Before we get started, the Q&A, for the audience, feel free to chime in or raise your hand if you have a question. I guess you're right, [Ben]? Thanks so much. Just wanted to go back to the slide. You showed the slide with the incremental benefit combining your drug, with BCMA x CD3 versus CAR T or BiTE alone. Mm-hmm. It looked like there was a significant difference in the benefit in ORR versus CR, and I was just wondering if you can explain that? That's not our data. That's data with another competitor, another competitive IKZF1/3 degrader that is meaningfully less potent. The point I was just making there is that while it improved the overall response rate, we didn't see the improvement in the depth of response. We think that serves as proof of concept for combining our degrader with a BiTE, which is much more potent than the one from the data that was seen here. We think with the potency, that CR rate can go higher because of the potency differentiation between the data that I shared there with the competitor drug and ours. Does that make sense? Thanks. Yeah. All right. Thank you for that. Okay, let's take a step back, start out with cemsidomide, of course. Looking back at the phase I data set, you know, what most clearly differentiates cemsidomide from the other CELMoDs, iberdomide, mezigdomide, that are currently in development? As dose optimization evolved in phase I, what stood out most in terms of balancing efficacy and tolerability, and how did those things, how did those learnings directly inform the dosing regimen you chose to take forward into MOMENTUM? Sure. You want to tackle that one? Yeah. Why don't I tackle that? There's a lot there. Really great question. If you think about what we showed in our first in-human study, it's really a very robust proof of concept. What is that? What are the components of that? The first component is the drug was active and had anti-myeloma activity at all the doses we studied. The overall response rate of all the doses combined was 36%. There, that tells you with optimizing dose, you have a developable drug. We also showed nicely, though, that not with that standing as a baseline, that you got more responses at a higher dose, and at our top response, our top response rate is 53% at 100. That becomes an anchor to really what we shoot for. Response has to be always interpreted with respect to safety. What we showed, which is a really unique characteristics of cemsidomide, is we're able to break apart response from safety to some degree. Now, we know because of the class effect that this class of drugs will always be associated with transient neutropenia, and we got that. We got it at a rate that's lower than CELMoDs. Why is that important? In fact, because we had low rates of neutropenia, relatively speaking, we also had relatively low G-CSF use. Importantly, what it manifested was, which Andrew had in his presentation, is that we had very few dose reductions, and we had very few patients, almost zero, coming off with side effects related to the drug. Taken together, we're able to make the case that the drug is very active in late-line refractory patients, and that we should give more drug as opposed to less, and that the even if we give drug and eventually need a dose reduction, that we'll be dose reducing to active doses. It's differentiated from, for example, the CELMoD that we get compared to the most is mezigdomide. How is it differentiated? There they have a much tighter relationship between neutropenia and its complications and their highest efficacy. They also have a very different shape in the therapeutic benefit curve, meaning they have relatively few responders at doses below the top dose, and then a very steep increase in the curve. They got a lot of press appropriately that at their 1 mg dose, the drug seemed to have a really, you know, impressive response rate. We know subsequently in combinations, the drug actually in combinations is not being given at that dose, and in fact, often is not given at the same schedule. The other differentiating tool we have, which is incredibly important for creating value for patients, is the utility of a 14-day on, 14-day off cycle. Why is that important? It makes it very easy to combine with preexisting therapies in myeloma. We know that patients love the 14 days off, and that 14 days off is associated with recovery of the neutrophil signal. Taken together, it led us to two places. What's the dose we bring forward for the phase II? There we've brought forward a dose of 100 micrograms, the dose that has the highest response rate. We recognize that in a larger scale study, there may be some patients that need dose reductions. They would dose reduce to 75, where we have a response rate of 40%. We have a very active sort of dosing strategy there. We recognize when we combine with a BiTE, you may need a different dose. However, we don't think it's very different because our neutropenic rate is actually class-leading. There we're starting at a dose of 75 micrograms. If that dose is safe, we'll have permission from a design point of view to explore 100 or 50. We're actually looking in that trial is that we're looking for a dose that we run in for a phase III study. We're not spending a lot of time in that phase Ib doing large expansion cohorts. We'll do some expansions, et cetera, but what really we're looking to use that data for is to give us the data we need quickly to rationally design a phase III study. Got you. We're going to get into the phase Ib study, but before we get there, you guys recently announced, as you mentioned in the presentation, that you've started to dose patients in the phase II MOMENTUM study. Congratulations on that. Thank you. How has enrollment progressed so far, and what have you seen so far in the early execution? We're really still early in the execution phase, you know, what we're doing is expanding from our phase I recruiting sites to a phase II recruitment footprint. The first part of that execution is, yes, getting the first patients on study, but it's heavily weighted towards activating new centers. We're well on our way to doing that. That includes us activating centers in the rest of world because our first phase I study was only U.S., and we'll be using some European countries for this. It's, you know, from an execution point of view, we're satisfied where we are on the curve. We've committed to try to do a 12-month enrollment period. The shape of enrollment curves are such, they start out slow, and they accelerate. We anticipate finishing enrollment in the first quarter of 2027. From a regulatory standpoint, what elements of the trial design matter most for the Accelerated Approval path? What matters most for Accelerated Approval discussion is the quality of the data. First and foremost, we're conducting that study with great rigor in terms of ensuring the data integrity, including blinding us as sponsor to ongoing emerging data, and including to make sure that efficacy endpoints are evaluated by an independent committee. From a point of view of the agency is the conduct of the study to ensure that we've not contaminated the data by prematurely looking at it or altering enrollment to reflect, you know, biases. In terms of what we're looking for to present is we really map back to our first-in-human study. In our first-in-human study, we think we have reason to believe that we should be able to get a response rate that at least 40%. What the agency always looks for in Accelerated Approval discussions is that response rate is a durable. I think it needs to be at least six months durability. Is it associated with predictable safety? Meaning, are patients coming off? You know, patients can come off for progression. Unfortunately, the drug doesn't help everybody. You don't want to be losing patients to safety events because that makes it difficult to interpret the relative merit of the drug in terms of safety. We'll be eventually putting together a package of data that will be anchored on response rate but also heavily dependent upon duration and safety. The other obviously important part of Accelerated Approval, right, it's always judged in the context of the then available therapies at the time we submit. That's the other context that we have to also, the data that Len just described will be viewed by the agency in that context, which obviously we won't know until we get there. Yeah. Wonderful. You also touched on the new FDA draft guidance for MRD negativity. I was wondering how that factored into your thinking for cemsidomide, both in MOMENTUM and as you think about the. Yeah. The recently released, the draft guidance is actually consistent with the minutes, if you will, from the meeting that was held in the spring of 2024, I believe. Basically what the agency said, and it says in the guidance, that we'll consider MRD-negative CRs as a component of an approval package, including for Accelerated Approval. We designed our studies knowing that that likely would be the guidance. As it relates to the phase II, it's not really a front and center feature, in the sense that we don't predict that we'll have a huge number of MRD-negative CRs. We are going to measure if we have a patient with a CR, we'll confirm whether or not they're MRD negative, because in terms of creating the weight of evidence that the drug works, even if you have a low proportion of MRD negative CRs, that argument in favor of a deep drug effect. Where it's much more exciting and useful for us is in the phase III design. There, what we anticipate when we design the phase III trial, which will grow from the phase Ib, is that we will have a predefined MRD negative CR analysis point. We'll figure out when that will be, but just in terms of principles, after X number of patients have been enrolled and followed long enough to achieve it, can you do an analysis of the CR and the MRD-negative CR rate between two arms? The agency said they'd look at that in the context of its ability to predict true benefit. We have a case study coming ahead of us with Bristol, because Bristol has announced that their iberdomide trial in the second line is going to be evaluated on MRD-negative CR. That's actually great news for us in two ways. Okay. One, is we know it's a trial that's in favor of iberdomide, which is in favor of next generation or more potent degraders. There's a read-through for us because of on the degrader sort of pathway, we're more potent than iberdomide. That's good. The second part of it that's good is we'll see how the agency actually evaluates their data, what this delta is between the two arms, what the event rate is that they're using to map it to. It'll give us some tools, if you will, to design the final phase III. As we get through the phase Ib, we wanna make sure we design the phase III trial that is the most cost-effective trial to get the drug across the goal line as quickly as possible. We see all this incoming data as actually really helpful to us as a small company in designing, you know, a high-quality trial that's cost-effective and fast. Gotcha. All right. Quickly, as we move into the Phase 1b combo study with the BiTE, you know, what would you guys view as success in that study? You know, what data so far, you touched on a bit in the presentation from other CELMoDs and TCEs, combos give you confidence in this approach? Yeah, let's start with the, with the second part. You know, what we really were pleased when we went to ASH this year and we saw the, in particular, the elra data, with iberdomide, is notwithstanding there were some hiccups in that trial design as they figured out the elra schedule and the best way to combine these drugs. Once they got that behind them, it was safe. What's the safety thing you're looking for? You really make sure that you're, in fact, able to give the drug without giving our drug without compromising the BiTE. The BiTE is the standard of care that you're trying to add to, and you don't wanna change that. We look at that data as really proof of principle that we can do this safely. The other piece of the data that we look at there is we have tools now to design how to manage safety, in particular in the first two cycles. We see that data as very helpful. What do we wanna see therefore from our own study? We obviously wanna get a dose, at least one dose, that is safe over multiple cycles. We'd anticipate, because we're going into earlier line patients, the response rate's gonna be close to everybody. It's almost gonna be 100%. We wanna see a high CR rate, and we wanna see MRD-negative CRs. Now, it's really important to level set. You can't do a phase 1 study empowered enough to really answer that question. We'll be using that data in the context of emerging data with the iberdomide PDUFA review and what we need to see to figure out what dose to bring forward in phase III and the sample size that we need to achieve. We won't be looking from that data to be able to say, you know, "Here's a 30-patient cohort and the response rate is this." We will describe responses. We will describe the quality of responses. It's much more important for us and for investors to get on from that data and design the phase III and enroll the phase III because remember, that's our full approval strategy. Right. Okay. You also guided to initiating other combination studies with other agents. Yeah. You know, what framework are you using to prioritize the different combinations that you're gonna test? Yeah. If you go back to Andrew's presentation, and one of the points he made is that this is really potentially a foundational asset in myeloma care because the targeting of these transcription factors is always relevant. That being true, we firmly believe that, and so do sort of clinicians, it's important for us to get data with other drug partners so we have a dose that you can combine. We will initially focus on key drugs, such, for example, carfilzomib or CD38, to get a dose that you can combine with. Separately, the field is dynamic, and one of the things we need to monitor is what are other drugs that are emerging in the myeloma care space we may wanna think about sooner than later about getting data sets with cemsidomide. It's a little trickier because those drugs are technically not already approved. There's opportunities and mechanisms through thought leader networks and the FDA facilitates this, that we'll also be open to novel combinations. The first goal will be to get some combination safety data with some other drugs that are clearly front and center of care right now and will be for the foreseeable future. I think the other thing to think about is too is how could this be used, you know, in conjunction, you know, with a CAR T. Yeah. Not necessarily given together, are there ways to sequence them to sort of improve the durability of those outcomes. All right. In the closing seconds here, we didn't get to cover the pipeline, but maybe you can touch on it here. In closing, what aspect of the C4 story is the most underappreciated by investors? Both of you, of course. Well, I think the whole thing. Look, I do think cemsidomide is probably very underappreciated. Right? It is a wholly owned asset that is foundational to the myeloma care that demonstrates a best-in-class potential in a large and growing market. I think, you know, that to me is probably most underappreciated. I don't think people fully understand the pathway, the relevance of the pathway, what I talked about earlier. That's the biggest one. Obviously, the discovery, not that I would expect because we haven't shared enough, but, you know, we're very excited about that and excited to hopefully share progress and what we're working on with that. I would just add that the other thing that I think people are not appreciating but are starting to is notwithstanding all the improvements in myeloma care, there are two things that remain true. Patients are still showing up late line seeking disease modifying care that's well-tolerated, and we tick that box. That's a growing opportunity. The second thing that the key opportunity that our CDP reflects is notwithstanding the excitement in immune-directed strategies, there's room for improvement and the unique mechanism of action of these drugs, including the immune enhancement feature, is making them really attractive, but that attractiveness is really attenuated in your ability to give it safely. Our best-in-class safety profile, we predict, will help us, you know, go to the head of the line there. I think there's a high level underappreciation, but in the weeds there's a need for appreciation of those two things as well. Wonderful. All right, we are up on time. Yeah. Thank you, Andrew. Thank you, Len. Thank you. Pleasure. All right. Thanks.