All right. Good morning, everybody. Thank you so much for joining us for the next fireside here. My name's Derek Archila. I'm one of the senior biotech analysts here at Wells Fargo. Very excited to have the C4 Therapeutics team up here with us. From the team, we have Andy Hirsch, President and CEO, Scott Boyle, Chief Business Officer, as well as Kendra Adams, Chief Financial Officer. Team, welcome.
Great.
Thanks for joining us.
Thanks for having us.
Great. Well, Andy, maybe just to start off, give us a little bit of an introduction to C4 Therapeutics, what you guys are working on, and then we can get into the Q&A.
Sure, happy to do that. Actually, I will have Kendra do that.
Happy to. We are-
That is delegation.
Yes. Practicing delegation. I have done it a lot, and I feel like give somebody else a turn.
We are a targeted protein degrader company, and we have a portfolio of degraders that we're looking to bring to patients with unmet needs. I'll start with our lead program, which is cemsidomide. This is a cereblon modulating degrader of IKZF1/3. These are transcription factors that are critical in the treatment of multiple myeloma. We are advancing that program across multiple lines of treatment in the myeloma setting, both in the later line setting as well as the earlier line. That includes a phase II study, which is the MOMENTUM study I'm sure we'll talk about. That's enrolling now, as well as a phase I-B dose escalation or dose exploration study, cemsidomide in combination with elranatamab, which I'm sure we'll also get into that. Beyond the clinical portfolio, we also have an internal discovery portfolio that's focused on inflammation, neuroinflammation, neurodegenerative diseases.
We also have active discovery collaborations with Roche and Merck KGaA. One of those is focused on DACs, which I'm sure we'll talk about. We're progressing things across research and clinical development.
Excellent. Maybe to start off, working on your lead program, cemsidomide, I guess, how has your thinking evolved over the last 12 months? I guess what data today gives you the greatest confidence that it can be a pretty meaningful player in the multiple myeloma space?
Sure. The last 12 months have actually been quite exciting for myeloma patients in general and the field. Actually, the data and regulatory events that have happened over the last 12 months have really, I think, at a high level served to validate our approach. It's really emboldened us that we think we're headed in the right direction. I think there's really three things to think about there, right? The first is our data. We updated our data at EHA this year, and I think our data continues to support our perspective that we think we have a best-in-class asset in this space. The data didn't really change much from our initial presentation at IMS last year.
But we did see some deepening responses over time, and the profile continues to look like it really has the best of both worlds, really robust efficacy at multiple doses, as well as an excellent tolerability profile, which really positions it as a backbone therapy in myeloma, like the class has been, and we believe it will continue to be. In addition, there has been some positive clinical developments around the space, notably from the Bristol Myers Squibb CELMoD portfolio, that we think validates both the need and the efficacy for next-gen degraders of IKZF1, as well as, importantly, the recent approval of iberdomide with MRD negativity. That is really important, not just for cemsidomide, but also for the field, because as we are seeing newer and more effective therapies, patients are living longer. They are living longer progression-free.
That makes development harder because you have to do longer studies if you want a time to event endpoint. So having a really robust surrogate endpoint like MRD negativity that FDA has accepted based on the 2024 ODAC that really provides a surrogate for PFS benefit is really critical to enable future development, and we intend to use that. Then I think the third element of data over the last 12 months has been all the data coming out around T-cell engagers. That is something that we are very bullish on. We think T-cell engagers are going to be moving into the second-line setting, and there has been a host of readouts, both pivotal studies as well as earlier from all three of the originators of those drugs that really suggest that is a space where TCEs are going to play.
And obviously, as you know our development plan, we think it is important that we think cemsidomide can really enhance the activity, both depth and durability of remission. So when you look together, we really think it has validated our approach, and emboldened us to continue development because it is really supportive of where we are headed with cemsidomide.
Excellent. So maybe to start off in terms of your development plan, so maybe you can give us a sense of the recent updates from the monotherapy data set for cemsidomide, and I guess over this period of time that you guys have been developing it, what you really have learned between the relationship with dose efficacy, durability, and I guess the tolerability of this molecule.
Yeah. I will start with the relationship between dose and really actually exposure, right? That is what really matters. Actually, this was data that was presented at IMS, but when we look at the correlation of exposure and reductions in light chains, there is a very clear trend that obviously more exposure is better and drives deeper remissions, right? That is what got us as well as the clinical data to support the 100 microgram dose as our recommended phase II dose, right? It was clearly better. At the same time, we did see robust response rates at the lower doses from the phase I. At the 100 microgram, we had a 53% ORR, but at 75 microgram, we had a 40% ORR.
Then two patients at the 100 microgram achieved MRD negativity, which is something that is really important and not necessarily expected to see in the patient population that we have studied. Then those responses were durable. We had a median DOR of 7.9 months. The upper bound is not yet reached. The trial, obviously the patients are still on. I think the data that we presented at EHA was largely consistent. In terms of tolerability, really no change from the 2025 IMS data. We continue to see low levels of dose reductions. Grade 4 neutropenia tends to be fairly consistent across all doses at about a third of the patients. We have not seen any discontinuations due to safety, so we continue to see a very tolerable profile with robust efficacy.
The other important component, which we have presented some data but later this month at IMS, we have a poster on the phase I patient population, really articulating the immune activation component of the mechanism and looking at important biomarkers of T-cell fitness immune activation, which again, we think is an important mechanism as we think about future development for combining with immune-directed therapies.
Got you. I guess when you think about the overall tolerability profile at this point and being able to basically zone in that dose, do you feel like that is manageable for physicians and what they are used to, particularly the hematologists?
Yeah. I think there's been a lot made around neutropenia.
Yeah.
Neutropenia obviously creates infection risk for patients, but neutropenia in and of itself is a lab value, right? What we've focused on is what are the complications from neutropenia, and we know physicians manage neutropenia. We have a tool in our toolbox, G-CSF, that is very commonly used in this space. While it's important to look at and evaluate, and it does underscore some tolerability, physicians aren't worried about it. They know how to handle it. The other important thing we did learn around neutropenia is it really mostly occurs in the first two cycles, and part of it is not necessarily drug-related, but disease-related. We're talking about a hematologic disease, and you have proliferation of plasma cells that can crowd out neutrophils.
Some of that is just the nature of that we're treating patients who have progressed, and it's a hallmark of progressive disease. But really once you get through the two cycles, we don't really see that being an issue. Physicians, again, they're used to using it. They've used this mechanism for a long time. They know how to use it, so it's not something that they worry about.
Got it. Maybe you could talk about the registrational trial currently in the fourth line that you're studying cemsidomide in. I guess, how should we be thinking about the efficacy benchmarks there? Also, second part of that question is going to be the commercial opportunity. I think we've talked about this. This seems underappreciated among investors, so what gets you more confident there?
Yeah. First of all, we're studying effectively the same patients we studied in the phase I. We think it's a bit de-risked from that perspective. It's about 100 patients, the MOMENTUM study phase II, and the study's powered. Our assumption is that there's a background rate of about a 20% response rate that physicians may use whatever they choose in that late line setting. That's our anchor, and the study's powered to show a 20% boost in response rate. So approximately, 40% response rate over that background rate of 20%, obviously, with the lower bound not being below 20%. We think we need to see clinically meaningful durability, which is about six months of progression-free survival. Then we also need to see it continue to be well-tolerated, low levels of complications from safety or reductions or discontinuations due to safety.
All that has to come together. Additionally, I think one of the things about accelerated approval is it's only determined at the time you show up with the data to the agency and considered against the then current standard of care. So, that's how we're thinking about the study, and we think that we've set up the study in a way that gives us the best shot at it.
Got you. Before we go to the opportunity, can you just give us any updates on enrollment and where you guys stand there?
Yeah. The study's on track.
Okay.
Guided that enrollment completion by the end of the first quarter, that's on track to accomplish that.
Got you. Just on the opportunity, as I said, I think it's something that we feel is underappreciated by investors and ultimately-
Yep
certainly supports some value here given that there's really not a lot of options, but maybe you can sketch out for us really where you see the opportunity.
Yeah. I think if you look at the market today, we think there's actually a meaningful opportunity because the treatments, while effective, aren't cures. After people cycle through multiple treatment options, there aren't, and in fact, the data that the patients who showed up for our phase I study really reflect that patient population. We had a median of 7 prior lines of treatment, and we had a patient who had 17. Those patients do exist, but we do think that market opportunity is growing because one of the trends that we've seen through our market research and some of the data that I talked about earlier on the TCEs have supported this, is that those are going to move to earlier lines of treatment.
The result of that is those are more effective therapies, so patients are going to respond and they're going to live longer. But they're not cures, and unfortunately, they're going to progress. We expect that late-line patient population to grow over time as we see the migration of more effective therapies into earlier lines of treatment. Taken together, we estimate that to be about a billion-dollar opportunity. I think investors have said, "Okay, yeah, but let me add up the sales of all the other drugs. Look at the sales of other drugs in the space." I think when you look at individual drugs, yeah, you might say, "Hey, that's not a big opportunity." But if you add them all up, that's where you get to a large market opportunity.
Understood.
Yeah. Derek, maybe just to add one comment of, certainly in this later line patient population, a lot of these patients are in the community setting. To have an all-oral regimen that can be administrated in the community setting, especially as this patient population grows, we do think that that will contribute in terms of how the market will ultimately play out.
Yeah, that makes sense. I guess when you think about the population, the patient you enrolled in the phase I. Was there any kind of differing responses or efficacy based on prior lines of therapy, or was it all pretty uniform?
No, it was pretty consistent. I mean, we presented some of that data at EHA in the poster, right? When you looked at prior lines, you looked at BCMA versus not BCMA, the response rate was fairly consistent across patients.
Got it. This is the late line setting opportunity there. You are committed to moving earlier. You have talked about some combo trials. Maybe you can walk us through where that strategy is.
Yeah. Our registrational strategy in the second line or later is really around a TCE combo. Right now, we are conducting a phase I-B study, combining cemsidomide with elranatamab, which is the BCMA BiTE from Pfizer. That is currently-- We have started off that study at 75 micrograms of cemsi, and with the approved dose of elranatamab. That study is ongoing. I think that the idea here is that, we think that T-cell engagers have a really robust efficacy profile, really benefit patients. The efficacy is not quite on par with CAR-T, and actually both modalities sort of suffer from the same liability, which is T-cell exhaustion. Either patients do not respond because they come in that way, or over time that happens.
Leveraging the dual mechanism of cemsidomide, we think is important here in terms of both the activation of T-cells, as well as the direct anti-proliferative activity of down-regulating IRF4 through IKZF1 and 3. Our goal for this study is to establish a tolerable dose that we can combine for later development, with a TCE. The goal here is not really response rate. When you look at some of the combinations that are out there, you see very high response rates, right? You see the 80%-90%+ response rates. What we are really trying to do is increase the depth and durability of the response rates, and so that is something we are going to be watching for also is, can we drive MRD negative responses in these patients where they otherwise may not have them, which we know will result in hopefully longer PFS and longer clinical benefit.
Got you. Just in terms of the combinability from a safety perspective, I think there is some data out there looking at similar mechanisms and combinations. Maybe you can talk to that experience that we already know from the external data.
Yeah. I think that is an important data point that sort of de-risks it a little bit is that Pfizer ran a study combining iberdomide with elranatamab. I think it is the MagnetisMM-3 study. They presented data at ASH last year. It really does provide proof of concept. It was actually quite tolerable, which is helpful for us in terms of de-risking, because our safety profile is probably closer to what iberdomide's is than mezigdomide. They did see really a boost in ORR, but interestingly, they did not see a boost in the CR or better rate. We think that has to do with some truly the potency of iberdomide versus, let us say, cemsidomide or mezigdomide which are much more potent. We do know with this class that at almost every dose you get the immune activation.
But really at the higher doses is where you see that anti-proliferative effect. Our goal would be leveraging our tolerability and potency profile to really drive those deeper, more durable remissions in combination.
Got you. Just remind us, in terms of your trial, you are doing some sequencing of the therapy to ensure and mitigate any kind of neutropenia or any sort of tolerability issues. Just walk us through that strategy and why you have employed that.
Yeah. For those of you not familiar, the way the study works is when a patient enrolls in the study, like most of the TCEs, they have a step-up dosing protocol to really manage CRS and ICANS, right? We do not want to interfere with that, and so we do not introduce cemsidomide in the study, and the patient is not really DLT evaluable if they cannot reach the therapeutic dose of the BiTE. Then we add cemsidomide once they have reached the completed step-up dosing, and that starts the evaluation period. That was important because what we do not want to do is really interrupt how the BiTE is used. We want to make sure that it gets to the efficacious exposure before adding cemsidomide.
Got you. I guess, what should we be looking for for the next update? I think it is mostly going to be focused on safety. What would be a good result here and get you more confident going forward?
Yeah. What we have guided to is data from all the cohorts mid next year. What we are going to do, consistent with how we have done other safety escalation studies across the portfolio, is provide a little bit of an update. The protocol is designed to give us lots of flexibility. The first dose, as I mentioned, that we are studying is 75 micrograms. Based on the results of that study, right, we would update, "Hey, did we clear 75 micrograms? Did we not?" Right? How the result of that. We will not provide efficacy data, but we will provide the result of the safety evaluation. Then what the next steps are. Assuming 75 is safe, are we escalating to 100 micrograms? Are we expanding at 75 micrograms, which we are able to do, or are we exploring 50 micrograms, which we are able to do?
We think it is important to really understand a range of doses and what does the drug look like in that combination to really optimize the dose for future development. If you think about it as a safety study, we are going to look in the expansion cohorts at efficacy. That is not going to be until mid-2027, but you should expect a narrative about the path we are on with that study before the end of the year.
I guess what parameters will you be looking at to make that decision whether you want to go higher or go lower or just stay at 75 micrograms?
It's a pretty standard dose escalation study where we're enrolling six patients at each escalation cohort, and then evaluating them for dose limiting toxicities. Assuming the algorithm suggests that it's safe and that doesn't seem to be any untolerable DLTs that trigger the BLRM method to say, or I think it's a BOIN instead of BLRM, but similar, to determine whether it's safe. We're not exposing patients to risk by escalating. That will be guided. It is ultimately decided by an independent safety review committee. That's something that they'll meet to review the data, and we'll align with them and share of the path forward.
Got you. I guess when we get this data and then, kind of going forward to next year, we'll get the more comprehensive update with the efficacy. I guess, what should we be looking for there? As you said, Pfizer's got some data here. What are the benchmarks here that we should be looking for the TCE combo?
Yeah. Again, I'll caution that it'll be a limited number of patients, right? We have six patients in the safety cohort, and then we can expand up to 12 patients. It won't be a huge data set. But what we've seen from others, and especially from the iberdomide, as you see very high response rates, but that's not really the name of the game anymore. We really want to look at what does the MRD negative response rate look like. That's really what we're trying to go for here is, can we really drive deeper responses? What is the CR or better rate kind of look like, and how does that compare to what we've seen out there?
I think the interesting thing when you look at MRD negative rates across some of the trials that have been reported out, including the iberdomide study that just reported out and got approval, or at least in the label, you see about a 40% MRD negative response rate, really across mechanisms. That's an important benchmark for thinking about the study, but also for thinking about what do we have to show in a pivotal study and where can the improvement be. Again, we're going to look at the totality of the data, right? I think it's, again, I'll caution on the end, it's not a study designed to show a robust kind of high efficacy signal. It's going to have wide error bars. But it'll be informative as we think about the future development.
Do we know, are there key learnings that really help predict MRD negativity in patients? Again, are there certain other biomarkers or key features that have kind of given us that sense?
I think it's still new. I haven't really seen anything saying, "Hey, these biomarkers predict an MRD negative response rate." We certainly, like we do for a lot of our studies, have a pretty robust biomarker translational medicine strategy for this study. Maybe we can glean some things out of that, but I'm not aware of any real publication to date that says, "Hey, a few of these biomarkers are predictive of an MRD negative response rate.
Understood. Then yeah, I was just curious, going through the next 12 months, are there other external catalysts or updates from the competitors that you'd be looking at outside of your own to really better understand either opportunity or combos and things like that we should be paying attention to for cemsidomide?
Yeah, and I think IMS, there's some. It is always an interesting meeting, and I think there's going to be some important data there. Primarily, the EXCALIBER-RRMM study that was the basis for the accelerated approval for iberdomide, right? We've only seen MRD negative response rate and some safety, but we haven't seen PFS. We haven't seen the full presentation, and I think seeing that trial presented, and we expect it to be. I think they've got it to IMS. That will be really informative to learn more than what we can glean from the label. There's also, at ASH last year, there was an IST presented, I think with mezigdomide+ elranatamab, and I think there's an update. I think it's the MELT-MM that's also being presented there. Then I think we're going to see some data on AbbVie's TCE, which I think will also be interesting.
Got you.
Yeah. Maybe there's a couple of data points that we assume BMS will present for mezigdomide. So they do have some ongoing studies where they're looking at combination approaches, mezigdomide versus pomalidomide. We expect that data in 2027. We also would anticipate some additional data of mezigdomide in combination with elranatamab, the BCMA bi. Again, they've guided to 2027 venue we're not sure on.
Got you. Beyond kind of TCEs, there's still a plethora of other kind of combos you could explore. So maybe talk us through your kind of overall strategy there as you look to push earlier line.
Yeah. As I mentioned, we really think cemsidomide has the potential to be a backbone treatment. To do that, we want to establish broad combinability across different classes of therapies in the space. We've announced that we're going to start early next year, another phase I-B evaluating cemsidomide in combination with a CD38, which we've selected daratumumab as well as a proteasome inhibitor, which we'll use carfilzomib. That'll generate combo safety data. We don't expect to advance that combo into registrational development, but we do think it's important to broadly think about how does the drug combine well with other agents that are used fairly robustly in the treatment of the disease. As we think about other combinations, some of them or other, the roles for cemsidomide, we are very interested in thinking about how cemsidomide can work with a CAR-T.
We think that's probably best done with an IST strategy than a company-sponsored strategy given how complicated CAR-Ts are to use. We want to work with someone who's an expert in the space who really understands how they work and has a deep history versus trying to do a multicenter company-sponsored study. We're always watching as the landscape expands. We do think that broader TCE approaches, so trispecifics, et cetera, are also interesting. I think the sort of hypothesis that we can boost the activity I think the phase I-B study will go a long way to doing that. It should be independent of what surface antigen the antibody brings the T cell in contact with. We think that's a good proof point, but those are other things that we're watching, as well as other novel agents that may play a complementary role with this mechanisms of cemsidomide.
Got it. I guess you guys have a bit of a decision point next year with the readout of the fourth line in the registrational trial there. Again, is that something that you want to commercialize yourself? I know we've talked in the past about partnering cemsi, particularly for those larger opportunities. How are you weighing these kind of decisions and what's the general strategy?
Yeah, at a high level, and I'll have Scott talk about that a little bit, but a high level, we're focused on executing the plan that we have. Partnering requires someone else to do something in someone else's boardroom that I can't control. Our base case approach is that we can execute and commercialize the strategy that we've laid out. We think we feel confident we can do that. Obviously, we could do more. There's a lot more we could do with cemsidomide, given its potential as a backbone. Certainly, evaluating cemsidomide in the maintenance setting is something we probably couldn't do on our own, and that would be something a collaboration would be helpful for.
Got it.
Just amplifying, the growing regulatory and clinical success of the others in the class, along with, I think, our best-in-class profile and the multibillion-dollar opportunity, folks are continuing to track the space and the class. Beyond that, I can't comment.
Got it. Well, maybe the last couple of minutes here, we can talk about generally the platform and what is it capable of. You spent a lot of time with cemsi in multiple myeloma. You've looked at some other programs, which some of them you've been deprioritizing, but where do you really want to focus? What's the platform capable of? As a degrader platform, the whole idea was going after these undruggable targets. Is that going to be a renewed focus there?
Sure. Scott, you want to touch on that one?
Yeah. A couple of years ago, we made a decision to evaluate the targets that we had gone after ourselves in oncology as well as with our collaborators, and we'd learned some things. We've proposed a next generation of targets that are in other spaces, so inflammation, neuroinflammation, and neurodegenerative diseases. We believe these opened up as a result of some tactical learnings that we had. But they are in clinically validated pathways where the targets are amenable to targeted protein degradation, and so present first-in-class opportunities in clinically validated pathways where there remains unmet need. We haven't disclosed those targets, but one of the criteria that we used in selecting them was that we could get early clinical validation and then have an opportunity for indication expansion to expand that value creation. We've talked about what the pathways are.
There's some targets in the IL-23, IL-17, Type 1 interferon pathways, and then MAPK, PI3 kinase, and NF-kappa B. I think the other thing that we've done besides this target selection in these new areas is we continue to invest in our molecular glue capabilities to expand that platform at the Targeted Protein Degradation Summit this October. We have a presentation where we're going to talk a little bit more about that new and expanded approach to glue discovery.
I guess if you look back, when degraders really started to come to the forefront, it seemed like there was two different strategies of one, validated targets going there. Underlying biology is good, and it was more about kind of de-risking the modality. Others took both the modality risk and the target risk. Thinking back at the value creation of both of those strategies, which one do you lean in or favor, or which one would you think today is more relevant?
Yeah. So that is a good question. I think our shift that Scott articulated answers that question. I think now it is really going after some of the undruggable, the more novel targets that we can be first in class. I think it makes sense when you think about a brand new platform, to try to go after, take the biology risk out of the equation, and see if you can show an advantage to a degrader. I think the challenge with that is that you can think about that from a discovery perspective, but then when you think about how do you prove that in the clinic, that is going to require a large head-to-head study. Because we have been so successful in oncology in particular, we have lots of treatments out there.
That becomes a really challenging approach for a small company to really run a long head-to-head study against what we think are very effective therapies. We announced earlier this year that we were not going to advance our EGFR degrader outside of China, and that our partner is still developing it. Part of that decision was recognizing that the real opportunity was in the frontline setting. Osimertinib is a great drug, and while the L858R response for osimertinib is not as good as Ex19, that gap has shrunk. The clinical cost and time to be able to prove that it is better almost becomes not feasible for a company of our size.
Certainly you have competition across everything, but I think the clinical approach to validate a more novel target while you are taking biology risk is a little bit cheaper and quicker. At the same time, by working in validated pathways, that does mitigate some of the biology risk to a degree. It does not remove it, but it mitigates it.
Got you. So maybe lastly, and I know, Scott, you kind of mentioned a little bit about this, but the collaborations that you guys have ongoing, should we expect any updates from partners in the next 12 to 24 months? I guess, is it a priority to continue to do collaborations as you kind of unveil some of these targets within the pipeline?
Yes. We can't communicate all of our partners' timelines. I think we can say we're making progress, and there are discovery milestones in some of the collaborations that would be communicatable events for us. The decision around disclosing targets is on their side. Of course, we've delivered degraders to Biogen in IRAK4 and BTK, which is in their currently phase I.
I think Andrew and I, in our SLT, believe that discovery collaborations provide an opportunity to advance the science while also bringing some opportunities for non-equity dilutive capital. The Roche collaboration that we just did is a good example of that, where we get to push the boundaries of degraders by collaborating with Roche to attach them to degrader-antibody conjugates, or DACs, and so the degrader becomes the cargo. We get a push on a new science, but do that with a collaborator. There's financial and motivational benefits from a technical point of view.
Then maybe last, we just on runway, maybe Kendra, can you just talk to what we're funded through?
Yeah. Just a reminder, we have runway through the end of 2028. That allows us, obviously, to continue to execute against the cemsidomide clinical trials, get to the data readouts for both of the two ongoing studies that Andrew had discussed, and then beyond. It also obviously allows us to continue to advance some of our discovery programs as well, and the work on behalf of our collaborators. No doubt we'll need additional funding. Think about things like the phase III study for cemsidomide. Of course, some of that will be beyond the runway period, and will require some additional capital, but we'll be thoughtful in terms of how we do that. Clearly, the near-term focus is on executing the cemsidomide program and driving to some of those clinical readouts in the coming year.
Excellent. Well, I think we will leave it there. Thanks, guys.
Great. Thanks.
Welcome.
Good to see you, everyone.
Thank you.
Perfect. See you guys. Kendra, thank you so much.
Thank you.
Scott, great to see you.