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

Okay. We'll get started. I'm Eric Joseph, Senior Biotech Analyst with JPMorgan. Our next presenting company is C4 Therapeutics and presenting on behalf of the company CEO, Andrew Hirsch. We'll be doing Q&A after the presentation in the room and for those viewing on the digital conference book, feel free to submit questions via the portal. So with that, Andrew.

Great. Thanks, Eric, and thanks for JPMorgan for having us here today. It's very exciting to actually be here in person and not presenting from my living room, which we did last year. I'm really excited to provide an update on the progress we've made at C4 Therapeutics over the past year, and we have upcoming in store for 2023. But before I begin, I'll be making forward-looking statements, and this is our disclaimer on that matter, subject to risks and uncertainties that are outlined in the risk factors in our SEC statement. So C4 is a leader in the field of targeted protein degradation. Our mission is to really deliver on the promise of targeted protein degradation science to create new generation of medicines that really can transform patients' lives. And there are really four elements to how we do that. The first is we have a world-class degrader platform. We've demonstrated the ability to design orally bioavailable and highly catalytically efficient degraders. And those types of degraders are what maximize the benefits of degraders over other modalities. That's really central to how we think about designing degraders, and our whole platform is really focused around that catalytic efficiency. The second is a rigorous target selection process. Targeted protein degradation has very, very broad applicability. You can degrade many, many targets. But it's really important to figure out those targets where there's a true degrader rationale. Why do we need it to greater against this target versus maybe some other approach? And so every program, and you'll see that as I go through our portfolio, we have what's called the degrader rationale why we needed to greater. And then second, our platform is unique and we're the only company that has both MonoDACs or molecular glues and BiDAC , they are actually in clinical studies right now. And that platform has resulted right now. And we have four programs that we're going to have in the clinic. There are three in clinical trials right now, and we'll put a fourth one in this year. In order to achieve that mission, our strategy really rests on three pillars. The first is to continue to progress our oncology portfolio. As I mentioned, we have three currently in the clinic, and we'll have one in 2023. In addition, we continue to invest in discovery and creating a new platform, new platform -- or new pipeline programs. We initiated work on seven new targets in this past year. And we've really evolved our target selection strategy. Some of our early targets you can see are more clinically validated targets where there's still a degrader rationale. And we've now shifted out on the risk curve to focus on targets that are more classically undruggable, difficult to treat targets where there may be less biologic rationale given the fact that they're unable to be targeted with traditional methods. And then the third is to continue to expand the use of the platform with existing and new collaboration partners. The platform, as I mentioned, has broad applicability. We're focused on leveraging it in cancer, but we want to work with additional partners to see where that targeted protein degradation can go for other therapeutic areas. As I mentioned, we had a number of important achievements in 2022 that really position the company for what looks what we think is going to be a transformative year for 2023. So in addition to our lead program, 7455 in the clinic last year, we started two additional clinical studies with CFT8634, which is our BRD9 integrator and CFT1946, our BRAF degrader. And that really positions us for 2023, where we expect to have data readouts in the second half of the year for two programs, the 7455 and 8634, as well as continuing to advance our BRAF to greater and put our EGFR degrader into the clinic. So really exciting upcoming milestones in 2023. This slide, and if you're online so Slide 6, this really is a snapshot of the success we've had with our Torpedo platform that can deliver, as I mentioned, both MonoDAC and BiDAC degraders. Through our history, we've gone after about 50 targets, and we've had cereblon mediated to greater hits on 30 of those. And of those 30, we have 11 ongoing programs where there are chemical series of degradable molecules. And we continue as we move forward to always address at each state step along the way. Does the degrader rationale hold? Does the market opportunity hold? And is there still capability to develop those? That progress has resulted in the footprinour programs that I'll talk about. All of those programs, though, have the qualities you see here on this slide, we need to make sure there's differentiated in vivo efficacy at achievable human doses. All of our programs have oral bioavailability. We think that's critical for patient benefit. And we have clear unique selectivity to the desired target. That's engineered through medicinal chemistry, but also the degrader mechanism provides a number of filters that give us that exclusive selectivity, and you'll see that as I walked through a number of our programs in a moment. We also want to ensure we have cross-species PK for all these programs where -- and we have the ability to support an achievable human dose. And then where needed, we need CNS penetration. That platform has resulted in this pipeline here that you see on this slide. You can see, again, the four programs that I'll talk about. We have a number of programs in earlier discovery, which we won't be talking about today, but we continue to have an active effort to bring the next wave of programs into the clinic. And hopefully, at some point in the future, we'll be able to share what we're working on and we're really excited about some of the targets the team has started to work on. So let me start with our lead program, CFT7455 that targets two transcription factors, IKZF1 and 3, for multiple myeloma and non-Hodgkin's lymphoma. So many of you may be familiar with these targets. These are the targets of the mid class of medicines, lenalidomide and pomalidomide. And what's interesting is when those drugs were developed, no one knew that they were degraders. And as a result, they're not optimal degraders. They have off-target toxicity since they do hit some off targets. And resistance mechanisms can develop since they're not optimal degraders. So we thought that there was an opportunity with a degrader platform such as ours to come up with the most efficient optimal degrader and really position CFT7455 as the backbone therapy for multiple myeloma. Our goal here, as I said, was to make the most catalytically active degrader, reduce the off-target liabilities and overcome the resistance that we currently see with the approved set of medicines. And that we thought would lead to a real path to differentiation in what we think is quite a large market for medicines against these targets. At AACR last year, we presented data from Arm A of our Phase I/II clinical study. This was dosed at 50 micrograms with a 28-day schedule with a 1-week drug holiday. It's important to note all medicines of this class are dosed with a 1-week drug holiday, given the on-target toxicity well known of neutropenia. And the most important thing we learned from that experience was that the half-life of the drug was about twice as long as what we'd expected. So we went in thinking it was going to be about 24 hours, and we turned out that it was about 48 hours. And the consequence of that, you can see in the lower panel on the left is that we actually had surprising unacceptable sort of grade 4 levels of neutropenia due to the fact that we weren't giving that break in treatment, given the half-life. However, what we did see, which was very exciting for us, was really a deep durable degradation of both IKZF1/3 and meaningful reductions in the difference in serum-free light chains which are IMWG measures of efficacy. And we saw that exposure is lower than any approved or currently developing molecules. And so that gave us some encouragement that we are on to something we did design are really potent degrader, and we just needed to modify the schedule. And so based on this data set, and the data set that's existing out there with the BMS Celgene compounds, our Clean farm team did some really nice modeling. You can see on the right, and we adapted the schedule to dose the drug with a 2-week holiday over a 28-day cycle. And so for most of last year, we've been enrolling in our clinical trials an Arm B1 and C at that new schedule, and we continue to move forward with escalation in those. Recently, we just actually announced today that we've opened Arm B2, and that's the arm that looks at CFT7455 in combination with dexamethasone. Prior to that, we were evaluating this we still are as a single agent. And that's important because, one, it suggests we've crossed the safety threshold, which we did a while ago to open that arm. But secondly, it's consistent with our enrollment strategy to optimize enrollment. And so we will continue to escalate in all three arms, B1, B2 and C over the course of the year. And from where we sit today, we can say that we expect to share Phase I dose escalation data in multimyeloma in the second half of this year and look forward to sharing that with you. If we're successful in achieving the profile that we expect with this program, we think there's really two development paths forward. On the left is a more traditional path, which is really replacing lenalidomide and pomalidomide and potentially their successors iberdomide and ezetimibe and to be the backbone of the current treatment landscape. But as many of you know, there's been some really exciting advances in multiple myeloma with very new novel agents bispecifics, CAR-Ts, and we think there's a role for 745 in combination with those agents. That's part of why we have the monotherapy in the single-agent arm because we think it's -- we probably don't want to include dexamethasone in those combinations. And so there's really two different paths that if the profile supports we'll move forward with. Turning to our next program, CFT8634, that targets BRD9, and we're currently evaluating this program for synovial sarcoma and SMART B1 deleted tumors. So BRD9 is probably a biology that people are maybe less familiar with and without going into lots of detail, basically synovial sarcoma cells as well as tumors with smart B1 deletions have a unique dependency on BRD9. -- so it's a synthetic lethal target. And what makes it a great to greater target is depicted here on the right panel is that inhibitors just don't work. You can inhibit the bromo domain but that doesn't lead to inactivity. The oncogenicity of BRD9 is really driven by other sub domains, and so you need to really take down the entire protein in order to drive activity. And there's a huge unmet need in this space. As you can see here, current treatments just aren't really that satisfactory. PFS of 7 months in the frontline setting and about 5 months in the relapsed or refractory setting. And so we think there's a huge opportunity to really provide an improvement in patient care. So we designed CFT8634, to be orally bioavailable, potent and selective. Preclinically, that's what we saw in synovial sarcoma models. In the left panel, you can see deep degradation of the target and then on the right panel, sustained degradation of tumor in a PDX model. And so that's what led us to start, which we started in May of last year, the Phase I/II study, looking at both SmartB1-deleted tumors and synovial sarcoma. We're currently in the Phase I dose escalation portion of that study. We've gone through actually three escalation cohorts. And based on that, we expect to be able to share dose escalation data in the second half of this year, along with 7455. But I'm actually really excited to share with you some of an initial look at data from the first three cohorts today, and this is new data that we've not yet presented. Some PK and PD data, which we're really encouraged about. And so on the left, you can see the PK curves at the 2 milligram, 4-milligram and 8-milligram doses that really show really nice absorption, dose proportional scalability and about a 13-hour half-life, which supports the daily dosing that we're using. On the right, we're looking at pharmacodynamics as measured by immunohistochemistry. This is from two patients, a patient with a 2-milligram dose and at the 8-milligram dose. You can see on the left, the BRD9 is in -- the protein is indicated by the brown staining. You can see in these tumor samples, it's quite abundant. And then at day 15, both at the two and the 8-milligram dose, you can see almost complete ablation of that BRD9 protein. So this is really exciting. It suggests a proof of mechanism for us. And so what it means is we actually now -- we've proven we can degrade BRD9 in humans. And if that leads to the efficacy we saw in the preclinical slides I just showed you then that really should result in a benefit to patients that really have no need -- have a huge unmet need. And so we're excited to be able to move that forward. The other thing that it does is this is our first BiDAC in the clinic. CFT745 is a MonoDAC or a molecular glue. And so this proves that we can do both, and we can develop BiDACs that have drug-like properties despite violating the rules of five that have existed in MedChem for a long time. And so really excited to move this forward. We continue to escalate. I should also note that from a safety perspective, this has been well tolerated. And at these dose levels, we've not seen any DLTs. So again, I look forward to providing an update on some clinical data in the second half of this year. Now synovial sarcoma and SMARCB1 tumors are fairly small indications, but because this is emerging biology, there's been some recent publications that got us our attention for additional indications for BRD9. And you can see some of those here on this slide. And so right now, our team is currently evaluating whether or not it makes sense to move forward in those indications. Can we validate some of the work and does it make sense to develop in those indications? And so as we move toward a recommended Phase II dose with -- in the synovial sarcoma and SMARCB1-deleted tumors and that data reads out, we can think about potentially expanding beyond those two indications. Our third program, CFT1946, this is a degrader targeting BRAF V600 mutations for melanoma, colorectal cancer and non-small cell lung cancer. This program, we just started the clinical trial at the end of -- the very end of last year. So as many of you know, we have a number of approved BRAF inhibitors, but they all really have the same liability. You get resistant mutations fairly early, which results in a PFS of really less than 15 months. And in this day and age, that's not acceptable. They also have toxicities associated with wild-type activity. So the rationale for why a degrader in this space is depicted here on the right. The reason why we have this resistance is that inhibitors cause paradoxical activation. The monomer incorporates into the dimer and then you have wild-type RAF signaling and that results in the resistance mutations. And so the only way to really stop that is through a degrader where we can take down the whole protein. With the protein gone, it can't incorporate into the dimer and you don't get that paradoxical activation. We developed CFT1946 to be orally bioavailable, potent and selective against the V600 mutant while sparing wild-type activity. And you'll see some preclinical data here that suggests that against approved BRAF inhibitors, we show both deeper and more durable remissions as well as in settings on the right panel of BRAF resistance. And so that's the data that -- as well as additional data that we presented more broadly at ACR last year [that got us] excited about starting that study. This is the trial design right now. We're currently in Arm A. We've just started the study, as I said, in December, escalating in the tumor types you see here in patients post-BRAF inhibition. This is going to continue escalation through most of this year. So we don't expect there to be a data readout on this program in 2023. Again, and if we can achieve that, we think there's a huge opportunity here across all the tumor types you see on this slide where there are BRAF-mutant tumors, and there are resistance mutations, and we think this can lead to an improvement in the patient care. The last program I'll touch on is our EGFR L858R degrader CFT8919 for non-small cell lung cancer. And so you might say, well, non-small cell lung cancer is fairly well treated with EGFR mutations, why do we need a degrader here. And this was designed, there's really two benefits here. The first is that when you look sort of under the hood, osimertinib is an amazing drug. But for the L858R patients, the PFS is only 14.4 months. And that's consistent. You see that difference between L858R and exon 19 across even first-line inhibitors. And so our drug was designed to bind to an allosteric site that is specific to the L858R mutation, and that allows us to really have efficacy, no matter what resistance mutations arise, whether they be T790M or C797S. In addition, it allows potential combination with an inhibitor since we won't compete for the orthosteric binding site. And you can see that here on the left, you can see in the kinome scan graph, and maybe hard to see, but that's because that demonstrates its exclusive selectivity. You can see the one red dot there for the L858R mutation. And then you can see we're active on the right panel in the setting of resistance mechanism to osimertinib, where osimertinib based on the red line there is sort of dead and active. And the plan for that program is to have an IND in 2023. So hopefully, I've demonstrated that we're a leader here in the field. So you can see that we have a world-class platform, our rigorous target selection process and our broad degrader approach results in our robust clinical pipeline. Just to end here on our forward look sort of guidance. Again, as I mentioned, we think 2023 is going to be a transformative year for C4 Therapeutics. We have two data readouts from our lead program, CFT7455, our IKZF1/3 degrader; and CFT8634, our BRD9 degrader. Those will be in the second half of the year. And then for 1946, the BRAF degrader will progress that through the escalation during the course of the year. And then we plan for 88919, submit IND in the first half of this year. And then from a balance sheet perspective, we're funded through the end of 2024 to accomplish these milestones you see here. So let me quickly close by thanking all of my colleagues at C4. Without them, this would not be possible. I also would love to thank the patients, investigators and caregivers who participate in our clinical trials, which we wouldn't be able to do what we do without them. So with that, I think we're turning to the Q&A session, and I'll ask Adam Crystal, our Chief Medical Officer; and Lauren White, our Chief Financial Officer, to come and join me.

Great. Well, I can start out with Q&A. Maybe just given the preliminary PK/PD data that you're presenting with the BRD9 degrader program. Given you are -- so you have treated through the three-dose escalation cohorts. I guess is there some initial commentary on tolerability that you might sort of expand on as well? And -- and I also just wonder when it comes to looking at, I guess, additional so there are other PD markers that you're investigating, looking at in order to get a sense of how you're modulating the, I guess, the bath complex with BRD9 degradation.

Adam, do you to take that?

Sure. So I think it's fair to say in the first 3 dose levels, we've been very satisfied with what we've seen from the safety profile. Some of the data is still rolling in, but Andrew, I emphasize that we saw no DLTs in those 3 dose levels, which is, of course, true. -- and we were very comfortable escalating from 8 milligrams, which we're currently enrolling to a higher dose. In terms of other biomarkers, I think it's fair to say we are collecting other biomarkers, which I consider to be exploratory. I don't think there's anything in the literature that we've discovered that's a slam dunk for saying, "Oh my goodness, we're sure that we have functional consequences of down regulation of BRD9. We're also collecting BRD9 in PBMCs in addition to the IHC that we showed you. I think that provides some advantages of really hopefully showing longitudinal data. First of all, you can get more than one sample per patient as well as a better opportunity to show dose dependency, which is sometimes hard with IHC, which tends to be not particularly quantitative, also hard to get samples with IHC.

Okay. I guess just in general, how to think about the therapeutic index or perhaps the on-target sequel that might be associated with BRD9 degradation as you look to further dose escalate?

Yes. It's hard to say what to expect in terms of emerging toxicities, notably, BRD9 until very recently, not been targeted clinically, certainly, now with the degrader. So really, our understanding of tox is based on the literature that existed before we began studying it in the GLP toxicity. Our GLP tox was such that I'd say, two important things emerged. One, we were confident that we would be starting at a dose with some activity, and I think we demonstrated that by the IHC. And that in terms of our efficacious dose range, there was quite a positive therapeutic index. So based on the data that we presented today and all the preclinical data as well as the literature, I anticipate that we'll be able to demonstrate efficacy in the absence of dose-limiting toxicity. At this point, I think it's fair to say the clinical data we'll read out, and we're excited to share when it does.

Okay. Okay. And just anything in terms of the types of tumors -- the tumor types that you're seeing enroll in the study? And I guess is there any difference in the strength of synthetic lethality that SMARCB1 loss might have in different tumor histologies.

So the most honest answer I can give you to the second part of the question is not to my knowledge. The biology is extraordinarily similar between the two, even though the genetic lesion is a little bit different. Effectively in both of those tumor types, a protein called SMARCB1 is absent from the canonical BAF complex, which results in the dependency and BRD9. That absence is caused by a different reason, one by a deletion, one by a fusion protein, but still the underlying lesion is similar. I think it's fair to say, and now you know we started in May, and we've completed three cohorts. That's faster than we thought we were going to be able to accomplish. And I've said in some settings that I lost sleep for a couple of years before we started this program effectively on my guide, is it going to be possible to enroll quickly in these rare cancers. I think the data has borne out that, yes. We are able to do that. Our investigators are very engaged and enthusiastic and enrollment hasn't really been a problem.

Okay. Okay. So maybe a question or two on the IKZF1/3 degraders -- sorry, CFT7455. I guess now you're enrolling both B -- both B cohorts and the C cohort. Is there sort of -- I guess, within the multiple myeloma cohorts, is there sort of a prioritization that you're seeing taking place, whether you might seek to accrue patients to either cohort, one being without dexamethasone, the other with dexamethasone. I guess, when you update the study later in the second half of this year? I guess how should we be thinking about the balance of patients across the two Cohorts?

Yes. I think it's a super fair question. Our intent is to enroll both of those arms in parallel quickly. I think it's always been our intention to study both dex-sparing and with dexamethasone, and we were strategic in terms of when to open it because we didn't want to open it at a point that we felt we would slow our path to the goal, which is an RP2D for both. In terms of how we're prioritizing it, I think it actually is investigator dependent. Some, for example, say, I'm extraordinarily excited about single agent. I'd like to give my patients that single agent and some say give me dexamethasone, I want dexamethasone now. So in terms of how we enroll, it's operational more than it is driven by an overriding strategy of getting the right patient at the right time. In terms of how to think about the data we present, our goal is to get to a dose with the single agent. And I think it remains to be seen whether or not we'll be there or have enough data for -- to have a publishable unit for the plus dexamethasone. But if there's a story there that we consider publishable and mature at the same time, we would consider presenting it.

Yes. I mean we just opened that cohort in the last couple of weeks. So there'll obviously be more patients in the single arm than the [indiscernible] .

I guess how should we be thinking about the dose levels that you're now evaluating in each of these cohorts just given sort of where you were last year and needing down dose from that -- yes.