We'll get started. I'm Eric Joseph, Senior Biotech Analyst with JP Morgan. Our next presenting company is C4 Therapeutics, and presenting on behalf of the company is 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. With that, Andrew.
Great. Thanks, Eric, thanks for JP Morgan 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 what we have upcoming in store for 2023. Before I begin, I'll be making forward-looking statements, this is our disclaimer on that matter, subject to risks and uncertainties that are outlined in the risk factors in our SEC statement. 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. 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 oral, orally bioavailable and highly catalytically efficient degraders. 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.
Our whole platform is really focused around that catalytic efficiency. The second is a rigorous target selection process. Targeted protein degradation has very broad applicability. You can degrade many targets, but it's really important to figure out those targets where there's a true degrader rationale.
Why do we need a degrader against this target versus maybe some other approach? Every program, and you'll see that as I go through our portfolio, we have what's called a degrader rationale, why we need a degrader. Then second, our platform is unique in that we're the only company that has both MonoDACs or molecular glues and BiDAC degraders that are actually in clinical studies right now. That platform has resulted right now in we have four programs that we're gonna 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 new pipeline programs. We initiated work on seven new targets in this past year. 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. 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 wanna 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 like we think is gonna be a transformative year for 2023. In addition to our lead program, CFT7455 in the clinic, last year we started two additional clinical studies with CFT8634, which is our BRD9 degrader and CFT1946, our BRAF degrader.
That really positions us for 2023, where we expect to have data readouts in the second half of the year for two programs, the CFT7455 and CFT8634, as well as continuing to advance our BRAF degrader, and put our EGFR degrader into the clinic. Really exciting upcoming milestones in 2023. This slide, if you're online, this is slide six. 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 degrader hits on 30 of those.
Of those 30, we have 11 ongoing programs where there are chemical series of degradable molecules. We continue as we move forward to always address at each stage step along the way, does the degrader rationale hold? Does the market opportunity hold? Is there still, you know, capability to develop those? That progress has resulted in the four 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 if you think that's critical for, you know, patient benefit. 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 exquisite selectivity, and you'll see that as I walk through a number of our programs in a moment. We also wanna ensure we have cross-species PK for all these programs where, and we have the ability to support an achievable human dose. Where, where needed, we need CNS penetration.
That platform's 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.
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. Let me start with our lead program, CFT7455, that targets two transcription factors, IKZF1 and IKZF 3, for multiple myeloma and non-Hodgkin's lymphoma. Many of you may be familiar with these targets. These are the targets of the IMiD class of medicines, you know, lenalidomide and pomalidomide.
And what's interesting is when those drugs were developed, no one knew that they were degraders. As a result, they're not optimal degraders. They have off-target toxicities since they do hit some off targets. Resistance mechanisms can develop since they're not optimal degraders. 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. 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, phase II clinical study. This was dosed at 50 micrograms with a 28-day schedule with a one-week drug holiday. It's important to note all medicines of this class are dosed with a one-week drug holiday given the on-target toxicity well known of neutropenia. 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. We went in thinking it was gonna be about 24 hours, and it turned out that it was about 48 hours.
The consequence of that, you can see in the lower panel on the left, is that we actually had, you know, surprisingly unacceptable sort of grade four 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 and IKZF 3 and meaningful reductions in the difference in serum free light chains, which are IMWG measures of efficacy. We saw that exposure is lower than any approved or currently developing molecules.
That gave us some encouragement that we were onto something, we did design a really potent degrader, and we just needed to modify the schedule. Based on this data set and the data set, that's existing out there with the Bristol Myers Squibb Celgene compounds, our clinical pharmacology team did some really nice modeling you can see on the right, we adapted the schedule to dose the drug with a two-week holiday over a 28-day cycle. For most of last year, we've been enrolling in our clinical trials in 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, and we still are as a single agent.
That's important because, one, it suggests we've crossed a safety threshold, which we did a while ago to open that arm. Secondly, it's consistent with our enrollment strategy to optimize enrollment. We will continue to escalate in all three arms, B1, B2, and C over the course of the year. From where we sit today, we can say that we expect to share phase I dose escalation data in multiple myeloma in the second half of this year. I 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 mezigdomide, to be the backbone of the current treatment landscape. As many of you know, there's been some really exciting advances in multiple myeloma, with very new novel agents, bispecific CAR-Ts, and we think there's a role for CFT7455 in combination with those agents. That's part of why we have the monotherapy and the single-agent arm because we probably don't wanna include dexamethasone in those combinations.
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 SMARCB1-deleted tumors.
BRD9 is probably a biology that people are maybe less familiar with. Without going into lots of detail, basically, synovial sarcoma cells as well as tumors with SMARCB1 deletions have a unique dependency on BRD9, so it's a synthetic lethal target. What makes it a great degrader target is depicted here on the right panel, is that inhibitors just don't work. You can inhibit the bromodomain, but that doesn't lead to inactivity. The oncogenicity of BRD9 is really driven by other subdomains, you need to really take down the entire protein in order to drive activity.
There's a huge unmet need in this space. As you can see here, current treatments just aren't really that satisfactory. PFS of seven months in the front-line setting and about five months in the relapsed to refractory setting. We think there's a huge opportunity to really provide a improvement in patient care. We designed CFT8634 to be orally bioavailable, potent, and selective. Pre-clinically, 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.
That's what led us to start, which we started in May of last year, the phase I, phase II study, looking at both SMARCB1-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 CFT7455. I'm actually really excited to share with you 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. On the left, you can see the PK curves at the 2 mg, 4 mg, and 8 mg 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 at the 2 mg dose and at the 8 mg dose. You can see on the left, BRD9 is the protein's indicated by the brown staining. You can see in these tumor samples it's quite abundant. At day 15, both at the two and 8 mg dose, you can see almost complete ablation of that BRD9 protein. This is really exciting. It suggests proof of mechanism for us.
You know, what it means is, we actually now 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 benefit to patients that really have no need, have a huge unmet need. 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. CFT7455 is a MonoDAC or a molecular glue.
You know, this proves that we can do both, and we can de-develop BiDAC's that have drug-like properties despite violating the rules of five, that have existed in med chem for a long time. I'm 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. Again, look forward to providing an update on some clinical data in the second half of this year.
Synovial sarcoma and SMARCB1-deleted tumors are fairly small indications, but because this is emerging biology, there's been some recent publications that got us got our attention for additional indications for BRD9. You can see some of those here on this slide.
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? 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 the very end of last year. 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, you know, that's not acceptable. They also have toxicities associated with wild-type activity. 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. 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. 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. 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. You know, this is gonna 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 a improvement in patient care.
The last program I'll touch on is our EGFR L858R degrader, CFT8919, for non-small cell lung cancer. You might say, well, non-small cell lung cancer is fairly well treated with EGFR mutations. Why do we need a degrader here? This was designed to really two benefits here.
The first is that when you look sort of under the hood, osimertinib is an amazing drug. For the L858R patients, the PFS is only 14.4 months. That's consistent. You see that difference between, you know, L858R and exon nineteen across even first line inhibitors. Our drug was designed to bind to an allosteric site that is specific to the L858R mutation. That allows us to really have efficacy no matter what resistance mutations arise, whether they be T790M or C797S. In addition, it allows potential in combination with an inhibitor since we won't compete for the orthosteric binding site.
You can see that here on the left, you can see in the KINOMEscan graph, it may be hard to see, but that demonstrates its exclusive selectivity. You can see the one red dot there, for the L858R mutation. You can see we're active on the right panel in the setting of resistance mechanisms. Osimertinib, where osimertinib, based on the red line there, is sort of dead inactive. The plan for that program is to have an IND in 2023. Hopefully I've demonstrated that we're a leader here in the field.
You can see that we have a world-class platform, our rigorous target selection process, our broad degrader approach results in our robust clinical pipeline. Just to end here on our, you know, forward sort of guidance. Again, as I mentioned, we think 2023 is gonna 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. For CFT1946, the BRAF degrader will progress that through the escalation during the course of the year.
We plan for CFT8919 submit a IND in the first half of this year. From a balance sheet perspective, we're funded through the end of 2024 to accomplish these and these milestones you see here. 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. 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 up and join me.
Great. Well, I can start out with Q&A. I, maybe just given the preliminary PK/PD data that you're presenting with the BRD9 degrader program, you have treated through three dose escalation cohorts. I guess, is there some initial commentary on tolerability that you might sort of expand on as well? I also just wonder when it comes to looking at, I guess, 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 BAF complex, with BRD9 degradation.
Adam, you wanna take that?
Sure. I think it's fair to say in the first three dose levels, we've been very satisfied with what we've seen from the safety profile. You know, some of the data is still rolling in, but, you know, Andrew emphasized that we saw no DLTs in those three dose levels, which is of course true. And we were very comfortable escalating from 8 mg, 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 downregulation 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.
Right. Okay. I guess just in general, how to think about the therapeutic index or perhaps the, you know, the on target, sequelae that might be associated with BRD9 degradation as you look to further dose escalate.
Yeah, it's hard to say what to expect in terms of emerging toxicities. Notably BRD9's, you know, until very recently, not been targeted clinically, certainly not with a degrader. Really our understanding of tox is based on the literature that existed before we began studying it and the GLP toxicology. You know, our GLP toxicology 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. In terms of our efficacious dose range, there was a, quite a positive therapeutic index.
You know, 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 will read out, and we're excited to share when it does.
Okay. Just anything in terms of 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 SMARCA4 loss might have in different tumor histologies?
The most honest answer I can give you to the second part of the question is not to my knowledge.
Okay.
The biology is extraordinarily similar between the two, even though the genetic lesion's a little bit different. Effectively, in both of those tumor types, a protein called SMARCA4 is absent from the non-canonical BAF complex, which results in the dependency on BRD9.
Okay.
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. I've said in some settings that I lost sleep for a couple of years before we started this program.
Effectively, oh my God, is it gonna 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; enrollment hasn't really been a problem.
Okay. Okay. Maybe a question or two on the IKZF1, IKZF3 degraders, CFT7455. I guess now you're enrolling 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 give 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?
Yeah. I think it's a, 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 wanna 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." Some say, you know, "Give me dexamethasone.
I want dexamethasone now." In terms of how we enroll, you know, it's operational more than it is driven by an overriding strategy of getting the right patient in at the right time. In terms of how to think about the data we present, our goal is to, you know, get to a dose with the single agent. I think it remains to be seen whether or not we'll be there or have enough data for a publishable unit for the plus dexamethasone. If there's a story there that we consider publishable and mature at the same time, we would consider presenting it.
Yeah. I mean, we just opened that cohort, like, in the last couple weeks.
Okay.
there'll possibly be more patients in the single arm than.
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 to sort of down dose from that?
Yeah.
Yeah.
Yes. Go ahead.
Well, I was gonna say, so we haven't commented on where we are, and we're not gonna comment at this point. I think that the important thing to reiterate is that the goal of going to 25 was to establish a safe dose at the new schedule to escalate from. We've done that obviously. If we hadn't, you know, we probably wouldn't be here talking about this program today, right? You look at the data from ACR, right?
The thing we know we need to be above 50 to have efficacy because 50 at three weeks on, one week off, you know, didn't lead to any kind of objective responses. So, we know we need to go higher. But in terms of where we are, you know, we're not sharing that data today. We are excited to be able to share, you know, that collection of dose escalation data in the second half of the year.
Okay. Okay. You, you know the competitive landscape, obviously, it's an evolving space with probably two additional IMiDs or CELMoDs kinda coming to the fore fairly near term. I guess how should we be thinking about the, I guess, what opportunities have you had to sort of compare the activity of CFT7455 versus iberdomide, mezigdomide, I guess, non-clinically?
I think non-clinically, the data that I point to is really impressive and launched the program, let's call it two and a half years ago, wherein in vivo models or molecules, approximately 100-fold more active than mezigdomide. That's impressive. That's why we were and are so excited about the program. I think if we can find the right way to give it, we can have maximal efficacy. I think in terms of mezigdomide and iber, how we think about them is I think both do have bona fide paths to development.
That's why BMS are pursuing them really with iber and intent to replace len in the earlier settings, and with mezigdomide and intent to replace pom in the later settings. The data that's most recently emerged that I think is important for us is the mezigdomide dataset from ASH.
What we saw there in an expansion set, really approaching 100 patients, is the overall response rate in a similar patient population to ours of about 40%, which is consistent with what they showed from escalation. Critically important, they also showed a significant amount of neutropenia. To the tune of about 75% grade three, four neutropenia and a febrile neutropenia rate of about, I think it was 14.5%.
This is better than a lot of the therapies that are out there, and I think okay from a is it safe for patients, yes, it can be perspective when you compare with, for example, the BiDAC, which really are wonderful drugs.
When you compare them with Len and Pom, you know, the Len and Pom febrile neutropenia rate is about 3.5% to 4%. It really is different. I think when we look at that data, we wonder if three weeks on one week off is the ideal schedule from CFT7455. Their molecule has a lot of similarities to ours in terms of PK/PD, and we remain convinced that the path we're taking is the right one moving towards two weeks on, two weeks off.
I think the other thing to just keep in mind when you compare their data set and ours is their data set is all with dexamethasone. You know, to date, you know, the data we shared at ACR is single agent.
Maybe just coming back to the BRD9 program. Really just kind of framing what the performance of standard of care in these settings, right? You have highlighted in your presentation what PFS looks like. I guess the first data that we might see really might sort of be fairly early and maybe at best we might get a sense of objective response rate. I guess what would be kind of a compelling objective response in this setting? I guess how relatable is that endpoint to longer term survival outcomes?
Absolutely. First line therapy patients tend to respond to its old school chemotherapy, Adriamycin, Ifosfamide, plus Mesna. It's fairly brutal chemotherapy. Patients tend to respond with a median PFS of about seven months. That is not great. The second line setting is really doc dependent because none of them work particularly well. We're talking about agents like pazopanib or gemcitabine or high dose Ifosfamide. Really, the median PFS is probably less than five months, which is what we put in the deck. We're confident that the molecule can do better than that, given what we've seen pre-clinically.
I think the path to, let's say, approval registration in the second line setting the bar is quite low. There are historical precedents of a couple of sarcoma drugs being approved with overall response rates in the 10% range. I think that, you know, better than that would be quite exciting. How much better? This is escalation data.
Yeah.
I think we need to see enough data to convince ourselves the molecule's impressively active enough to move to expansion, and then we can really talk about benchmarks after we've enrolled 20, 30 patients at the expansion dose.
Okay. All right. All right. No other further questions, I think. Pause here for any questions from the floor. Sure.
Just out of curiosity, you talked about the oral bioavailability of these molecules. Thank you. Are they orally bioavailable on their own or does it require some sort of creative formulation?
No, I mean, it's I mean, they all need to be formulated obviously, but.
Yeah.
They're all orally bioavailable sort of on their own, when they come from the discovery shop.
Any others? Okay, well, I think we'll leave it there for time. Thanks very much to the C4 team for joining us today.
Great.
Thank you.
Thanks, Eric.