Welcome to the UBS call. Mr. David Dai, you may begin. Fantastic. Thank you, operator, and welcome everyone to the UBS Targeted Protein Degradation Day. I'm David Dai, one of the biotech analysts here at UBS. It's our great pleasure to welcome C4 Therapeutics. We have Andrew Hirsch, President and CEO, and Len Reyno, Chief Medical Officer. Andrew and Len, welcome. Great. Thank you. Thanks for having us, David. Great. So C4 Therapeutics is one of the leading players in the targeted protein degradation space. Maybe to start things off, could you give us an overview of C4, your targeted protein degradation technology, and what are some key differentiations versus other protein degradation companies in this space? Yeah, sure. Happy to address that, David. So, C4T was founded toward the end of 2015, by Marc Cohen, Jay Bradner, Nathaniel Gray, and Ken Anderson, kind of spun out of Dana-Farber, and with the promise of, you know, leveraging this new modality, targeted protein degradation, to really make a new generation of medicines that can help transform patients' lives. And that's really kind of, you know, what the focus of the company, you know, has been. You know, our focus in terms of our proprietary pipeline is really in oncology. We had a foundational collaboration with Roche that's still in effect to this day, and we have a number of other collaborations in various aspects of protein degradation. Then, you know, largely, that's the vehicle we use to explore indications outside of oncology with collaboration partners, given our current focus. I would say, you know, maybe in terms of our technology and, you know, differentiation maybe combined, there's probably four key points to how we go about degradation. I would say the first and probably most important is our focus on catalytic efficiency. This is really, really important and fundamental to how degraders are different from other small molecule modalities, and I'll just... For those of you people who aren't familiar, I'll just take a step back. One of the important properties of a degrader is that it, right, it catalyzes the relationship between an E3 ligase and a target protein, right? Once it's targeted that protein for destruction, it can actually go back and connect another target protein with an E3 ligase. So we call that the catalytic cycle. That can happen anywhere from 300 to 3,000 times per minute, but we think the best degraders are those that operate in the sort of 3,000 times-plus per minute. That's where you get the most efficacy and differentiated biology compared to inhibitors. And so our entire approach is really designed to accomplish developing the most catalytically active degraders, and it's fundamental to how we think about optimizing them. I think others in the field may focus on different parts of that cycle, for example, optimizing ternary complex formation, and that's the complex of degrader, E3 ligase, and target protein, for those who aren't familiar with the lingo in the space. Well, that's a really important part of the process. We don't find that optimizing ternary complex is what results in the most potent and optimal degraders, and so that's the focus. And so in order to accomplish this, this is really the second important piece of our technology. We've developed a proprietary set of tools and methods that are really based on fundamental enzymology principles that enable us to really predict in vivo performance of a degrader once we know in vitro potency and PK properties. So this, this not only enables the efficient discovery of highly potent degrader candidates but gives us a toolbox to optimize that catalytic efficiency. I would say the third component is, you know, again, all related, is because very, very subtle changes in that exit vector of the Cereblon binding portion of a degrader can have a pretty big impact on the catalytic efficiency of a degrader. We've made a pretty big investment in what we call our Cereblon Toolkit. That's a proprietary library of, at this point, probably over 10,000 molecules that our medicinal chemistry team can work with to really create these optimal degraders. And then I would say, lastly, because of that extensive proprietary library, that enables us to develop and use both types of degraders, or what I would call heterobifunctional degraders, or we call them BiDACs, or molecular glues, we call them MonoDACs. And so that's the fourth component, is we have the flexibility to tailor our degrader approach to what the physical, chemical properties of the target of interest is. That's an excellent overview. Thank you so much. Appreciate this, Andrew. So maybe can you walk us through some of the key updates we should be expecting over the next 12 months? Yeah. So, you know, we've got an exciting second half of the year coming up. We haven't actually given any 2025 guidance yet, so I'll really focus on the balance. But before I do, I want to just talk about what we've accomplished this year, you know, I think, which is a lot, to date. You know, first, as you kind of probably have known, we prioritize our pipeline to focus really on advancing our two most advanced programs, so cemsidomide, which is our IKZF1/3 degrader in multiple myeloma and NHL, as well as CFT1946, our BRAF V600X degrader. And we've really been in execution mode for most of the year. In March, you know, we announced an important collaboration with Merck KGaA to discover two targeted protein degraders against critical oncogenic proteins that we had progressed within our own internal discovery pipeline but felt that a partnership was the best way to maximize value of those programs. You know, we've also announced changes to our board of directors as part of our aspiration to become a fully integrated biotech company. We've appointed Ron Cooper as chairman, and we look forward to leveraging, you know, his broad leadership experience across the full value chain in biotech. And finally, we delivered a development candidate to Biogen, you know, one of our older collaboration partners, which we're very excited about. For the second half of the year, we're really focused on executing against the priorities that we laid out at the beginning of the year. ... and that primarily is around some data presentation. So, first, we plan to present some initial monotherapy data from the 1946, 1946 phase I dose escalation study, and that's enrolling patients post BRAF inhibitor treatment in colorectal cancer, melanoma, and non-small cell lung cancer, as well as other cancers that harbor a V600X mutation. We did share data in April, some preclinical data at AACR, which demonstrated that, you know, 1946, both as a single agent and in combination has superior activity to BRAF inhibitor standard of care combinations across multiple tumor types. And so we're excited to share that initial phase I clinical monotherapy data in the second half. And then we're also on track to present data from the multiple myeloma and plus dexamethasone cohort and from the NHL monotherapy arm with cemsidomide in the second half of the year. As a reminder, last December, you know, we shared data from the multiple myeloma monotherapy arm and initial data from the first two kind of escalation cohorts in the myeloma plus dex arm last December. That sounds great. So I think it's a good start. We'll just jump into some of the programs. You know, let's talk about the cemsidomide or lead program in the multiple myeloma and the NHL. So maybe for the investors who are new to the story, just give a quick overview or summary of what has been shown for cemsidomide in multiple myeloma, and just give a quick update on the program. Sure. I can-[crosstalk] I call on you. Yeah. So this is Len, the Chief Medical Officer. Just to sort of framework set, it's a first-in-human study that has two broad areas in it, multiple myeloma and lymphoma. We've not shared to date any of the experience in lymphoma, but we'll share it later in the year. In terms of the multiple myeloma portion of the study, it has, again, two components of it, which is the first part was monotherapy, and so exploring doses of cemsidomide across a range of doses as a monotherapy in multi-refractory, multiple myeloma, myeloma patients. That part of the trial is closed to enrollment, and we disclosed that dataset December last year, at the same time that we pivoted to the second part of the myeloma program, which is to characterize the safety and efficacy of cemsidomide when combined with dexamethasone. You'll recall that in the December 2023 disclosure, we disclosed the first few patients treated at 37.5 micrograms plus dex, and we've continued to enroll that portion of the study. What that looks like in the first half of this year is we've already disclosed that we declared 62.5 safe plus dex, as well as a next dose level has been recruiting. The other thing that happened in the study in 2024 is once these dose levels have been declared safe in the first four to six patients, we've then opened it to enrollment to add additional subjects to get those dose levels of 10 to 12 patients. So taken together, the myeloma portion of the disclosure will focus on the plus dex cohorts across at least three additional cohorts or expanded cohorts since the December disclosure, as well, and that will be a full characterization of safety as well as IMWG criteria vis-à-vis myeloma response. The lymphoma part of the program continues in parallel. There, the drug is dosed only as monotherapy, and we've continued to dose escalate in a multi-refractory lymphoma population, and we'll disclose that as well in the second half of the year. That's excellent. So, yeah, I'd love to get, kind of dig into each of these programs. So focusing on the multiple myeloma, so of course, we've seen some interesting data in combination with dexamethasone, where you showed 1 stringent CR, 1 PR of 4 patients, which looks pretty competitive versus Bristol Myers' mezigdomide. How should we think about the sort of clinically meaningful benchmark in this line of therapy? Yeah. So obviously, mezigdomide is a drug that is characterized a signal in an advanced myeloma population, and you know, we can reference back to the experience described in the New England Journal of Medicine article in September of last year, which has an overall response rate benchmark of about 40%, in that population, as well as the safety characteristics, which include an expected incidence of neutropenia, but also a persistence of neutropenic complications. So in their particular disclosure, they had 15% of the patients with febrile neutropenia and 15% of the patients with Grade three or four infections. I should note, though, that that disclosure of 100 patients was a global trial, and that that patient population was recruited where there was no restrictions on use of G-CSF. In our own trial, in cycle one, patients can't get G-CSF, so it's a little bit different, although in the expanded cohort, we've allowed it. So our dataset will be smaller, but we still think that we'll have multiple dose levels with 10, 10 patients or so to bring out the numbers of patients across those multiple dose levels to be on the order of close to 30. The issue, with respect to efficacy characteristics, we'll fully describe our anti-myeloma effects using working group criteria, but those patients will not all be recruited at a single dose. So it'd be difficult to say what the actual response rate is at a single dose. But to be clear, we accept that we need to be competitive to that overall signal, recognizing there's differences in the total population. In that regard, remind everybody about our trial, a U.S.-only trial at Centers of Excellence, and that's helpful in that it means that our patients that are currently enrolling on our trial are actually refractory to the expected standard of care, but also the most recently approved mechanism. So in fact, because it's a US Centers of Excellence trial, we are actually seeing, you know, a significant number of patients that are post-BCMA, post-CAR T, et cetera. So we think it's a great population to wrap your arms around of the promise of the drug in a myeloma setting. But it's not a definitive declaration of the best dose to move forward, et cetera. Got it. That's helpful, then. So, maybe talk more about your accelerated approval pathway. You noted recently that, you're looking to, you know, to start the cemsidomide plus Dex, you know, in refractory multiple myeloma with accelerated approval pathway. So maybe share your thoughts around the registrational trial design and then what the registrational regulatory pathway can look like. Yeah, so I'll take this one. So let me just. We haven't actually guided to doing that. You know, what we've said is we believe there's a potential in this kind of post-BCMA therapy, CAR Ts or bispecifics, we're seeing these patients. We know patients do, despite the really impressive response rates and durability, it's they're not cures. Patients do progress, and we think there is an unmet need in this patient population. And so, you know, that said, we haven't had any regulatory discussion on this approach. We'd have to consider that, you know, take a data set to FDA and get alignment. I think the complication, right, is that, you know, you need to have a confirmatory study fully enrolled at the time of accelerated approval for FDA. And so that's something we haven't yet just decided to do. As we've talked about many times, our goal, we think this is the best way to maximize value for patients and investors for this program, you know, is to find it with a large partner, given the complexity of the myeloma space and in multiple lines, multiple different combination regimens. So, you know, that's really gonna be an important component of the next step of the program. We think the current data set that this current trial will generate will be sufficient to enable that. So I think at this point, it's premature to really discuss kind of trial design and regulatory pathway. Got it. Okay, so let me just take a step back on the sort of like the overall relapsed refractory multiple myeloma space as a whole. You know, we've seen this space getting really crowded with T-cell engagers, CAR T. Now, so where do you see cemsidomide fit into the current treatment paradigm? Yeah, so... And that's what I was referencing in terms of the population we're treating. So we're seeing patients now who've had those standards of care or those emerging standards of care, more correctly, and have progressed. And the thesis that we have of the case, and that we will show data to support this, is that those patients still have an opportunity to use IKZF1/3 degradation to improve outcomes. And the first read on that evidence is actually manifested in the disclosure in the second half of the year vis-à-vis our anti-myeloma activity. In general, though, that fits with a broader, you know, strategic belief that, you know, we think IKZF1/3 degraders will continue to be part of the backbone of myeloma therapy moving forward. And the question becomes how to optimize that backbone in the context of these emerging strategies. And so when we think about the drug and its need for a combination partner, we're particularly intrigued as well by the data we shared last December with the monotherapy effects on immunotherapy or on immune activation and an increasing effector T cell population. That's a really important feature of the drug because it occurs at doses lower than the doses required for the pure anti-myeloma cytotoxic effect. And those doses, we think, could be used in combination with BiTEs and/or post-CAR T to increase the durability of response. So that aspect of the path for the IKZF1/3 degraders is actually just emerging. But the second part of that puzzle, of course, is that the issue of incorporating a drug like cemsidomide into other lines of therapy with the more traditional partners, including CD38 and proteasome inhibitors, et cetera, there's no reason the drug can't be given there. But what I've described actually, obviously, is a big investment, and that's part of the reason why we think this drug is ultimately gonna be better developed in the hands of a partner. Got it. And that's really helpful. So then, talking about the partnership then, Andrew, you know, what would be sort of the ideal profile of a partner you're looking for? Yeah. So look, I think I'll answer fairly generically, but you know, the goal is to find a partner that we think can maximize the value of this asset, right, across multiple lines of therapy and multiple combination regimens in both myeloma and non-Hodgkin's lymphoma, while at the same time providing kind of meaningful economics to C4T. So, you know, that's sort of mom and apple pie. And look, there are plenty of companies that meet this criteria, but that means you need a company with a global footprint, with deep pockets, and has a commitment to the myeloma space. And I think there's many companies that sort of meet that criteria, but I think beyond that, we haven't sort of said they have to have this, this, and this asset in their portfolio. Right? That those goals can be accomplished with both companies that have a robust myeloma portfolio or, you know, are also committed to the space and wanna sort of anchor tenet, if you will, into the space. So, you know, I think there are plenty of companies where this asset is, I would call on strategy. And, you know, obviously, we're not gonna comment kind of beyond that. ... Got it. That, that's really helpful. And then, so then just, one last thing, before we move on to the next program. So for cemsidomide, you're going after lymphoma right now, and so you should be- we should be expecting some data update later this year. So let me just help us understand, you know, right now you're in dose escalation, what should we be expecting in terms of the update in the end of this year? Yeah. So as a reminder, this is a separate arm of the same first-in-human study, with its own safety dose escalation, dose finding. So the first part is just to set expectations that in this particular indication, cemsidomide is given as a single agent, not with this, not with dexamethasone, and that we're recruiting patients with refractory NHL, but not from specific subtypes to in preference. So it means that it will be a heterogeneous group of refractory NHL patients. We'll disclose the safety experience over any individual dose level, which typically will be four to six patients per dose level. And of course, we'll fully report any objective anti-lymphoma side effects or anti-lymphoma efficacy signal. But there is unlikely to be a number of lymphoma patients with the exact type of lymphoma that you'll be able to conclude anything about the true utility in a given subtype, but there will may be clues to who you might study in the next study with the drug. Maybe just to kind of hone in on the numbers then for investors who are new to space. I know that non-Hodgkin lymphoma is extremely heterogeneous, but maybe just help us understand what would be considered clinically meaningful in, you know- Uh... in harder to treat DLBCL, for example. Well, if you think about Revlimid and lenalidomide, the overall response rate, for example, is 26% for mantle cell lymphoma. I think in general, you know, you need to get as a benchmark a signal that supports an efficacy of at least 30% of high-quality responders. But it's very difficult to sort of specifically say what's, you know, a go, no-go response rate, because it's the totality of the data, the nature of the lymphoma, the safety signal, and duration of therapy. But you obviously, I think, can keep in mind that most successful drugs are gonna have at least a baseline response rate close to 30%. Got it. That, that's helpful. So let's move on to the next program, which is the CFT1946, the BRAF V600X degrader. You know, Andrew, you said earlier that you presented some data at AACR, which seems to be very interesting, and, and we agreed, actually. We saw some interesting CNS effect, especially at reducing CNS burdens in melanoma, in the CNS models. Maybe just, could you further elaborate on the sort of CNS benefit we're seeing with this program? How do you think that would translate into the clinic? Yeah, look, So I think obviously it's an important component 'cause a lot of the patients that have, you know, BRAF-driven tumors, you know, do develop brain mets. And so, you know, this is an interesting kind of art of medicinal chemistry that our team is able to accomplish. And I think, you know what? The way to think about it is, while the molecule kind of violates, you know, many of the rules of five and wouldn't be classically brain penetrant, in kind of the one-to-one brain plasma ratio, you know, this was CFT1946, was rationally designed to be very catalytically efficient, with excellent oral bioavailability properties. And so one of the properties that we've engineered in is, it's something called chameleonicity, and effectively, with the molecule folds in on itself to appear smaller and enhance blood-brain penetration. And so it then opens up, you know, when it needs to, to perform an activity. And then because, as I mentioned earlier, the high potency and catalytic nature of the degrader, you know, the concentration requirements to see physiological activity, you know, they don't really follow traditional guidelines that we would follow for inhibitors. So, you know, the doses that we can use, you know, are in the same range as those, you know, that we see as efficacy in our preclinical model. You know, we're very comfortable that despite kind of the physical, chemical characteristics overall of the degrader, that we are seeing sufficient CNS penetration to address you know, brain mets in these patients. Got it. And then let me just tell them more about, you know, how your CFT1946 compares to other, you know, next-generation BRAF inhibitors, like PLX8394 or any other BRAF inhibitors out there. How do you think that this program differentiates from other BRAF inhibitors out there? Yeah. So again, we've not done really any head-to-head studies, so I think it's premature to sort of call anything conclusively. But I, you know, I think the fact that it's a degrader in and of itself is differentiating. And you know, when we brought this program into the clinic, we were quite concerned initially about how competitive the BRAF next gen space was in terms of, you know, enrollment. And actually, that's, we've been surprised that we've seen a lot of real excitement among investigators around the degrader approach. So I think ultimately when you think about the mechanism of what a degrader is doing versus an inhibitor, you know, there's an inhibitor is trying to block the, the activity, and we, we think despite, you know, the paradox breakers or, you know, dimer disruptors, they're still an inhibitor, and they're still potentially subject to some of those liabilities. We think a degrader approach is a more elegant solution, where effectively, we're removing the protein from the system. You know, that means that it is no longer there to dimerize or do anything, to you know drive additional signaling through that MAPK pathway. So we think that's really how it's going to differentiate ultimately. You know, the clinical data will have to play out. You know, I think other ones, like you mentioned, you know, Plexo, I think, you know, that's interesting. It's slightly different approach. You know, we know it has to be administered with another drug to improve the PK profile. You know, and while, you know, CFT1946 is selective for type one BRAF V600X mutants, which is the vast majority of patients, you know, believe that Plexo goes across, you know, all three. But it's also only being developed, as far as we can tell, in BRAF fusions and splice variants, and not in the broader V600X mutant class. I think it'll be hard eventually to differentiate, just 'cause I think we're going to be enrolling different types of patients in our clinical studies. Got it. Then that's really helpful. And so then, for this program, I know right now you're in dose escalation, too. So any thoughts in terms of when we should be expecting an update from this program? Yeah. So as, as I mentioned at the beginning, you know, we, we've guided to data in the second half of the year. And so that's going to be really the phase 1 monotherapy dose escalation experience. Got it. And if you were to prioritize any tumors in this space, any thoughts in terms of, you know, how to think about which tumors to prioritize at this time, or is it too early to say at this time? You know, I think it's too early to say. We're going to, you know, make data-driven decisions. And while, you know, the study is going to have, you know, multiple patients. You know, multiple different tumor types at multiple doses, I think we're going to look for the signal that comes out of that study. I think when you look at the landscape, you know, I think certainly the greatest unmet need is probably in colorectal cancer. You know, those patients, you know, treated with cetuximab and a BRAF inhibitor, have only about a 20% response rate, with a very short 4.2 months median progression-free survival. So huge opportunity for improvement. I think that's a lot more complex. The mechanism of resistance there is more intrinsic resistance, which is why you need an EGFR, anti-EGFR agent like cetuximab. You know, we think we'll likely need that, that too, just because down-regulating MAPK leads to upregulation of EGFR. But, but that's an interesting space. We also think, you know, melanoma, you know, while the response rates are higher, median PFS is 11.4 months, and we think there's potential to improve on that and increase durability, you know, based on the degrader rationale. So, you know, we think those are probably two of the three. Non-small cell lung cancer just happens to be smaller. We still think there's an opportunity there, but I think from a sort of size and unmet need, I would maybe, you know, think the, the melanoma and CRC are probably more of a priority than lung. But certainly, again, we'll be data-driven as we collect the data from the current study. That's excellent, Andrew. So we have two minutes left. Maybe just very quickly on the CFT8919 program. So it's quite interesting program, is it has a allosteric binding site, which could potentially avoid resistance mutations and, combinable with other, or with other orthosteric inhibitors, for example. Maybe just very quickly, can you elucidate the mechanism behind this? How should we think about the market opportunity for this program? Yeah, I mean, you kind of hit on it, right? I think, you know, the EGFR mutant lung cancer patients with a L858R driver mutation account for about 35% of all EGFR-driven lung cancer. It's even higher in the Asian population. And after frontline treatment with osimertinib, about 10%-15% of those patients develop a secondary mutation, EGFR, which renders that inhibitor kind of impotent, and you see progression. And so we think that patient population is probably the fastest path, and the reason why we're able to do that, as you mentioned, is we bind to an allosteric site, which is created uniquely by that L858R mutation. So you know, it's a degrader. It does, you know, UPS-based degradation. But we have exquisite selectivity for that mutation, and so that, as you mentioned, you know, that means it's potentially combinable, right? We don't really care what resistance mutation occurs in the orthosteric site. And then we also don't expect to see any wild-type activity, given that it's, you know, unique to that. That binding site's not present in the wild-type EGFR. So we're excited about this. As you're probably aware, you know, we've partnered with Betta Pharmaceuticals in China to run sort of the phase I dose escalation study. We think that's the fastest path to get data, and then we retain ex-China rights, and, you know, we effectively can decide how to develop it, you know, based on the data that we see from the phase 1 study. Great. Maybe one last question just around the cash and cash runway, could you maybe just help us understand the cash position right now? Yeah, sure. So, we ended Q1 with approximately $299 million in cash, and that is expected to provide our runway into 2027. Excellent. All right, with that, I think we're at the half-hour mark, and Ash is going to be hosting Bioh aven 12:30. It has been a great pleasure discussing C4 Therapeutics with you, Andrew and Len. Thank you so much for taking your time. Great. Thanks, David. Thank you for having us. Have a nice rest of the day, everyone.