C4 Therapeutics, Inc. (CCCC) Earnings Call Transcript & Summary

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. And gentleman, welcome.

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?

Yes. Sure. Happy to address that, David. So C4T was founded the end of 2015 by Marc Cohen and Jay Bradner and Nathanael Gray and Ken Anderson, kind of spun out of Dana-Farber and with the promise of 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 what the focus of the company has been. Our focus in terms of our proprietary pipeline is really in oncology. We were -- 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. And then largely, that's the vehicle we use to explore indications outside of oncology, with collaboration partners given our current focus. I would say, maybe in terms of our technology and differentiation, maybe combined, there's probably 4 key points to how we go about degradation. And 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 people who aren't familiar, I'll just take a step back. One of the important properties of degrader is that it catalyzes the relationship between E3 ligase and the target protein, right? Once it's targeted that protein for destruction, they 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 was 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 not only enables the efficient discovery of highly potent degrader candidates because there's a toolbox to optimize that catalytic efficiency. I would say the third component is -- 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 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 whatever, called 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. I appreciate this, Andrew. So maybe can you walk us through some of the key updates we should be expecting over the next 12 months?

Yes. So 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, want to just talk about what we've accomplished this year, I think, which is a lot, to date. First, as you probably have known, we prioritized our pipeline to focus really on advancing our 2 most advanced programs, so Cemsidomide, which is our IKZF1/3 degrader in both 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, we announced an important collaboration with Merck's KGaA to discover 2 targeted protein degraders against critical oncogenic proteins that we need to progress within our own internal discovery pipeline, but felt that a partnership was the best way to maximize value of those programs. We've also announced changes to our Board of Directors as part of our aspiration, become a fully integrated biotech company. We've appointed Ron Cooper as Chairman. And we look forward to leveraging his broad leadership experience across the full value chain in biotech. And finally, we delivered a development candidate to Biogen, one of our older collaboration partners, which we're very excited about. So 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 presentations. So first, we plan to present some initial monotherapy data from the 1946 Phase I dose escalation study, and that's enrolling patients post-BRAF inhibitor treatment in colorectal cancer melanoma and nonsmall cell lung cancer as well as other cancers that harbor V600X mutation. We did share data in April, some preclinical data at AACR, which demonstrated that 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, we shared data from the multimyeloma monotherapy arm and initial data from the first 2 kind of escalation cohorts in the myeloma plus dex arm last December.

That sounds great. So I think a good segue, just to jump into some of the programs. Let's talk about the Cemsidomide, your lead program in multimyeloma and 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.

Yes. So this is Len, the Chief Medical Officer. Just to sort of framework set, so the -- it's a first-in-human study that has 2 broad areas in it, multiple myeloma and lymphoma. We've not shared to date any of the experience in lymphoma but we share it later in the year. In terms of the multiple myeloma portion of the study, it has, again, 2 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 patients. That part of the trial is close to enrollment, and we disclosed that data set 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 the 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 4 to 6 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 3 additional cohorts or expanded cohorts since the December disclosure as -- and that will be 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 the multi-refractory lymphoma population. And we'll disclose that as well in the second half of the year.

That's excellent. So yes, I'd love to 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 show the 1 stringent CR, 1 PR patients, which looks pretty competitive versus Bristol-Myers' mezigdomide. How should we think about the sort of clinical meaningful benchmark in this line of therapy?

Yes. So obviously, mezigdomide is a drug that is characterized to signal in an advanced myeloma population, and 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 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 3 or 4 infections. I should note, though, that, that disclosure of about 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 1, patients can't get G-CSF. So it's a little bit different. Although in the expanded cohort, we've allowed it. So our data set will be smaller, but we still think that we'll have multiple dose levels with 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. And in that regard, I remind everybody about our trial is our trial is 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 have actually a refractory to the expected standard of care, but also the most recently approved mechanism. So in fact, because it's the U.S. center of excellence trial, we are actually seeing 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. And that's helpful. And so maybe let's talk more about your accelerated approval pathway. You noted recently that you're looking to start the Cemsidomide plus dex in multi-refractory multiple myeloma with accelerated approval pathway. So maybe share your thoughts around the registration of trial design and what the registrational regulatory pathway can look like.

Yes. So I'll take this one. So let me just -- we haven't actually guided to doing that. What we've said is we -- and we believe there is a potential. But 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, is they're not cure as patients do progress, and we think there is an unmet need in this patient population. And so that said, we haven't had any regulatory discussion on this approach. We have to consider that, take a data set to FDA and get alignment. I think the complication, right, is that 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 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 is to find it with a large partner, given the complexity of the myeloma space and multiple lines, multiple different combination regimens. So that's really going to be an important component of the next step of the program. We think the current data set, 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. Great. So let me just take a step back on the -- sorry, the overall relapsed/refractory multiple myeloma space as a whole. We've seen this space getting really crowded with T-cell engagers, CAR-T. So where do you see Cemsidomide fit into the current treatment paradigm?

Yes. 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 strategic belief is that we think IKZF1/3 degraders will continue to be part of a 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 immune therapy -- 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 going to be better developed in the hands of a partner.

Got it. And that's really helpful. And so then talking about the partnership then, Andrew. What would be sort of the ideal profile of a partner you're looking for?

Yes. So look, I think I'll answer fairly generically. But the goal is to find a partner that we think can maximize 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 that sort of mom-and-apple pie. And look, there are plenty of companies that meet this criteria. But that means company with a global footprint with deep pockets that 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 asset in their portfolio, right? Those goals can be accomplished with -- both with companies that have a robust myeloma portfolio or are also committed to the space and want a sort of anchor tenant, if you will, into the space. So I think there's -- there are plenty of companies where this asset is, I would call, on strategy. And obviously, we're not going to comment kind of beyond that.

Got it. That's really helpful. And so then just one last thing before we move on to next program. So for Cemsidomide, you're going after lymphoma right now. And so you should be -- we should be expecting data update later this year. So maybe just help us understand, right now, you're in dose escalation. What should we be expecting in terms of the update in the end of this year?