C4 Therapeutics, Inc. (CCCC) September 10, 2026 Conference Transcript

All right. Good morning, everybody. Thank you so much for joining us for the next Fireside here. My name is Derek Archilla. I'm one of the senior biotech analysts here at Wells. Very excited to have 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. 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, what you guys are working on, and then we can kind of get into the Q&A. Sure. I'll have Kendra do that.

Happy to. So we are.

That's delegation.

Practicing delegation.

I've done it a lot.

I feel like, you know, 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 simsidamide. 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 two study, which is a momentum study I'm sure we'll talk about. That's enrolling now, as well as a phase one B dose escalation or dose exploration study, simsidamide in combination with L-renatumab. 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 DAX, which I'm sure we'll talk about. And so we're, you know, progressing things across research and clinical development.

Excellent. So maybe to start off, you know, working on your lead program, SimSidamide, I guess how has your thinking evolved over the last 12 months, and I guess what data today gives you the greatest confidence that it can be a pretty meaningful player in the multiple myeloma space?

So the last 12 months have actually been quite exciting for myeloma patients in general and the field. And actually the data and regulatory events that have happened over the last 12 months have really, I think, had a high level serve to sort of validate our approach it's really emboldened us that we think we're headed in the right direction and I think there's really three things to think about there right so the first is our data you know 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-of-class asset in this space you know 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 like you know kind of 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'll continue to be. In addition, there's been some positive clinical developments around the space, notably from the BMS cell mod 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 obertamide with MRD negativity. That is a really important, not just for some sitamide, but also for the field, because as we're seeing newer and more effective therapies, patients are living longer, they're living longer progression-free. That makes development harder, because you have to do longer studies if you want a time to have an endpoint. So having a really robust surrogate endpoint like MRD negativity that FDA has accepted, you know, 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. And then I think the third element of data over the next last 12 months has been all the data coming out around T cell engagers. That's something that we're very bullish on. we think t-cell engagers are going to be moving into the second line setting and you know there's been a host of readouts you know both pivotal studies as well as earlier you know from both you know all three of the originators of those drugs that really suggest that's a space where where tces are going to play and and obviously if you know our development plan you know we think it's important that we think simsidamide can really enhance the activity in both depth and durability of remission. So when you look together, we really think it's validated our approach and in bold in us to continue development because it's really supportive of where we're headed with simsidamide. 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 simsidamide. And I guess Over this kind of 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, so I'll start with the relationship between dose and and really actually exposure Right that that's what really matters and actually we didn't this was data was presented IMS But when we look at kind of the correlation of exposure and reductions in light chains It was a very clear trend that obviously more exposure is better and drives the deeper deeper remission And so that's what kind of got us, as well as the clinical data, to support the 100-microgram dose as our recommended phase 2 dose. It was clearly better. But at the same time, we did see robust response rates at the lower doses from the phase 1. At 100, we had a 53% ORR, but at 75, we had a 40% ORR. And then two patients at the 100-microgram achieved MRD negativity, which is something that's really important and not necessarily expected to see in the patient population that we've studied. And then those responses were durable. We had a median DOR of 7.9 months. The upper bounds not yet reached that the trial, obviously the patient's repair, the patient's still ongoing. So 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, You know, grade four neutropenia tends to be fairly consistent across all doses at about a third of the patients. And we haven't seen any discontinuations due to safety. So we continue to see a very tolerable profile with robust efficacy. You know, the other important component, which we've presented some data, but later this month at IMS, we have a poster on the phase one 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. And I guess when you think about the overall kind of tolerability profile at this point and kind of being able to basically zone in that dose, do you feel like that's manageable for kind of physicians and what they're used to, particularly the hematologists? yeah I mean I think there's been a lot made around neutropenia and you know neutropenia obviously creates infection risk for patients but neutropenia in of itself is a lab value right what we focused on is what are the complications from neutropenia and and we know physicians manage neutropenia we have a tool in our toolbox GCSF that is very commonly used in this space and so you know what well it's important to look at and evaluate and it does underscore some tolerability it's you know it's physicians aren't worried about it they know how to handle it and so you know the other important thing we did learn around neutropenia is it's really mostly occurs in the first two cycles and part of it is not necessarily drug related but disease related you're talking about a hematologic disease and you have proliferation of plasma cells that can crowd out neutrophils and so 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 in physicians. Again, they're used to using it. They've used this path, this mechanism for a long time, and 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, you know, in the fourth line that you're studying simsidamide in. So, you know, I guess, How should we be thinking about the efficacy benchmarks there? And also, you know, second part of that question is going to be, like, the commercial opportunity. You know, I think we've talked about this. This seems underappreciated among investors. So what gets you more confident there?

Yeah, so first of all, we're studying effectively the same patients we studied in the phase one. So we think it's a bit de-risked from that perspective. It's about 100 patients, the momentum study phase two. and and the studies powered our assumption is that there's a background rate for about a 20% response rate that you know physicians may use whatever they choose in that late line setting and so that's our anchor and the studies powered to you know show a 20% boost in response rate so approximately you know 40% response rate over that background rate of 20% obviously with the lower bound not being below below 20 we think we need to see clinically meaningful durability which is about six months of per months of progression free survival and then we also need to see you know it be continued to be well tolerated you know low levels of complications from safety or reductions or discontinuations due to safety so all that has to come together and then additionally I think you know one of the things about extended approval is you don't know you know 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 you know that's how we're thinking about the study and we think that we've set up a the study in a way that gives us the best shot at it oh and before we go to the opportunity can you just give us any updates on kind of enrollment and where you guys are stand there yes so the studies on track I've guided that enrollment completion by the end of the first quarter and then that's on track to accomplish that. Gotcha.

And then, yeah, just on the opportunity, as I said, I think, you know, it's something that we feel is underappreciated by investors and ultimately, you know, certainly supports, you know, some value here given that there's really not a lot of options, but maybe you can kind of sketch out for us, you know, really where you see the opportunity.

Yeah. So I think if you look at the market today, right, we think there's actually a meaningful opportunity because the treatments, while effective, aren't cures, right? And so after, you know, people cycle through multiple treatment options, there aren't. And, in fact, the data that, you know, the patients who showed up for our phase one study, you know, really reflect that patient population. We had a median of seven prior lines of treatment, and we had a patient who had 17. And so 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. Unfortunately, they're going to progress, and so 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. So taken together, you know, we estimate that to be about a billion dollar opportunity. And I think investors have said, okay, yeah, but let me add up the sales of all the other drugs that are, you know, 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, you know, that's where you get to a large market opportunity.

And 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. And so 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, so the patient you enrolled in the phase one, so 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, then we presented some of that data at EHA in the poster, right, that when you looked at prior lines, you looked at BCMA versus not BCMA, the response rate was fairly consistent across patients. Got it.

So I guess, you know, this is kind of the late line setting opportunity there. You know, you're committed to kind of moving earlier. So you've talked about some combo, you know, you know, trials. So maybe you can walk us through where that strategy is.

Yeah. So our registrational strategy in kind of the second line or later is really around a TCE combo. Right now, we're conducting a phase 1b study combining simsidamide with L-renatumab which is the BCMA bite from Pfizer and that's currently we've started off that study at 75 micrograms of SEMSI and you know with the approved dose of L-renatumab and that study is ongoing but I think that the idea here is that you know we think that T cell engagers are 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 don't respond because they come in that way, or over time that happens. And so leveraging the dual mechanism of simsidamide 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 like AZF1 and 3 and so our goal for this study is to establish a tolerable dose that we can combine for later development you know with with with a TCE and 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 you know the 80 to 90 plus percent response rates what we're really trying to do is increase the depth and durability of the response rates and so that's something we're gonna be watching for also is you know can we drive MRD negative responses in these patients where they otherwise you know may not have them which which we know will result in hopefully longer PFS and clinical benefit.

Gotcha and just in terms of the combined ability from a safety perspective so I think there's some data out there you know looking at you know kind of similar mechanisms in combination so maybe you can kind of talk to that you know experience that we already know from from the external data.

Yeah, and so I think that's an important data point that sort of de-risks a little bit is that Pfizer ran a study combining Ibertamide with Renatomabbing. It's the Magnetism 30 study. They presented data at ASH last year, and it really does provide proof of concept. It was actually quite tolerable, which is, you know, helpful for us in terms of de-risking because our safety profile is probably closer to what Ibertamides is than mesignamide. And they did see a really a boost in ORR but interestingly they did not see a boost in the CR or better rate and we think that has to do with some of the potency of a vertamide versus let's say some sedamide or mesignamide which are much more potent so you know 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 effects and so you know our goal would be leveraging our tolerability and potency profile to really try to drive those those deeper more durable remissions in combination.

Gotcha and just remind us in terms of your trial I mean you're doing some sequencing of the therapy to kind of ensure and mitigate any kind of you know neutropenia or any sort of tolerability just walk us through like that strategy and why you've employed that.

Yeah so so for those of you not familiar the way the study works is when a patient rolls in the study like most of the TCEs they have a step-up dosing protocol to really manage CRS and ICANS, right? And so that we don't want to interfere with that. And so we do not introduce simsidamide in the study, and the patient is not really DLT-evaluable if they can't reach the therapeutic dose of the bite. And so then we add the bite, or we add simsidamide once they've reached the completed step-up dosing, and that starts sort of the evaluation period. And that was important because what we don't want to do is really interrupt how the bite is used. We want to to make sure that it gets to the efficacious exposure before adding some cinamide. Gotcha.

So I guess what should we be looking for for the next update? I think it's mostly going to be focused on safety. So what would be a good result here and get you more confident going forward?

Yeah, so what we've guided to is data from all the cohorts that in mid-next year, but what we are going to do, consistent with how we've done other safety escalation studies across the portfolio, is provide a little bit of an update. so the protocol is designed to give us lots of flexibility the first dose as I mentioned that we're studying is 75 micrograms and then based on the results of that study right we would update hey to be clear 75 you did we did we not right how how the result of that we won't provide efficacy data but will provide the result of the safety evaluation and then what the next steps are you know assuming 75 is safe are we escalating to 100 are we expanding at 75 which we're able to do or are we exploring 50 which we're able to do we think it's important to really understand a range of doses and and what does the drug look like in that combination to really optimize the dose for future development so you know you think about it as a safety study we are going to look in the expansion cohorts at efficacy that that's not going to be until till till mid in 2027 but you should expect sort of a narrative about the path we're 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 you're rolling six patients at each escalation cohort and then evaluating them for you know dose limiting toxicities and assuming the you know the algorithm suggests that it's safe and that it doesn't seem to be any intolerable you know DLTs that trigger the BLRM method to say, 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, so that's something that they'll meet to review the data and we'll align with them and share the path forward.

Gotcha. So I guess when we get this data and then, you know, kind of going forward to next year, we'll get the more comprehensive update, you know, with the efficacy. I guess what should we be looking for there? And then, as you said, you know, Pfizer's got some data here. You know, what sort of benchmarks are or what are the benchmarks here that we should be looking for for the TCE, you know, combo?

Yeah. So, again, you know, I'll caution that it'll be a limited number of patients, right? So, you know, we have six patients in the safety cohort and then we can expand up to 12 patients. So, you know, it won't be a huge data set, but what we've seen from others, you know, and especially from the IRL is you see very high response rates, but that's not really the name of the game anymore. So we really want to look at, you know, can we really, you know, what is the MRD negative response rate look like? That's really what we're trying to go for here is, you know, can we really drive deeper responses? You know, what is the CR or better rate, you know, 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, you know, the IBR 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. And so 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? And again, we're going to look at the totality of the data, right? And I think it's, again, a 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.

Do we know or are there key learnings that really help predict, you know, MRD negativity, like in patients and are there certain other biomarkers or key features that, you know, have kind of given us that sense?

So, you know, 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. And so maybe we can clean some things out of that. But I'm not aware of any real publication to date that says, hey, these biomarkers are predictive of an MRD-negative response rate.

And, yeah, I was just curious, like, you know, going through the next 12 months, you know, there are other, you know, external, you know, catalysts or updates from, you know, the competitors that you'd be looking at outside of your own to really better understand either opportunity or combos and things like that that we should be paying attention to for SEMSY.

Yeah, I mean, I think IMS is always an interesting meeting, and I think there's going to be some important data there, primarily, you know, the Excalibur study that was the basis for the accelerated approval for Ibertamide, 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 so 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 mesignamide plus alronatumab. And I think there's an update that's the MELT-MM that's also being presented there. And then I think we're going to see some data on AbbVie's TCE, which I think will also be interesting.

Yeah, and maybe there's a couple of data points that we assume BMS will present for mesignamide. So they do have some ongoing studies where they're looking at combination approaches. is mozigtamide versus pomalidomide. We expect that data in 2027. We also would anticipate some additional data of mozigtamide in combination with alrinatumab, the BCMA bite. Again, they've guided to 2027 venue we're not sure on.

And so beyond kind of TCEs, you know, there's still a plethora of other kind of combos, you know, you could explore. So maybe talk us through your kind of overall strategy there as you look to push earlier line.

Yeah, so as I mentioned, we really think somzinamide that has the potential to be a backbone treatment. And so to do that, we want to establish broad combinability across different classes of therapies in the space. And so we've announced that we're gonna start early next year, another phase 1B, evaluating simsidamide in combination with a CD38, which we've selected, daratumumab, as well as a proteasome inhibitor, which we'll use colfismib. And so 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 how does the drug combine well with other agents that are they're used fairly robustly in the treatment of the disease as we think about other combinations some of them or other the roles for simsidamide we were very interested in thinking about how simsidamide can work with 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, you know, to use. And so 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, you know, multi-center company-sponsored study. And then, you know, we're always watching as the landscape expands. You know, we do think that broader, you know, TCE approaches so try specifics etc are also interesting I think the sort of hypothesis that we can boost the activity I think the the phase 1b study will go a long way to doing that right it should be independent of what surface antigen the antibody brings the T cell in contact with and so 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 some cinemide. Got it.

So I guess, I mean, you guys have a bit of a decision point next year, you know, with the readout of the fourth line of the registrational trial there, you know, whether is, and again, is that something that you want to commercialize yourself? And I know we've talked in the past about, you know, partnering SEMSY, particularly for those larger opportunities. So like, how are you weighing these kind of decisions and what's kind of the general strategy?

Yeah, I mean 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 and you know partnering requires someone else to do something in someone else's boardroom that I can't control so so our our base case approach is that you know 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 right there's a lot more we could do with subsidized given its potential as a backbone and certainly you know evaluating simsidamide in the maintenance setting is something we probably couldn't do on our own and that would be something that collaboration would be be helpful for.

And 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 multi-billion dollar opportunity, folks are continuing to track the space and and the class and beyond that I can't comment well maybe the last couple minutes here we can talk about you know generally the platform and what is it capable of I mean you spent a lot of time with SEMS II in multiple myeloma you've looked at some other programs which you know some of them you've been deprioritizing but you know where do you really want to focus what's the the platform capable of and you know as a degrader platform you the whole idea was going after these undruggable targets, is that going to be you know kind of a renewed focus there? Sure. Scott, do you want to touch on that one?

So you know a couple 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 and 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 technical learnings that we had but there 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 so 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, you know, when, you know, degraders really started to come to the forefront, and it seemed like there was like two different strategies of, you know, one, validated targets going there, underlying biology is good it was more about kind of de-risking the modality others kind of took both the modality risk and the target risk I mean you know thinking back at you know kind of the value creation of both of those strategies which one do you kind of lean in or favor or which one would you you know think today is more relevant yes so that's a good question I think you kind of our our shift that Scott articulated answers that question I think now it's really going after some of the undruggable right the more novel targets

that we can be first in class I think it makes sense when you think about a brand new platform right you know 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 know 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's going to require a large head-to-head study and and because we've been so successful in in oncology in particular we have lots of treatments out there but that's a really challenging approach for a small company right to really run a long head-to-head study against what we think are very effective therapies and so you know we've announced earlier this year that we were not going to advance our EGFR to greater outside of China and that our partner is still developing and part of that decision was recognizing that the real opportunity was in the frontline setting Osimertinib is a great drug and there have been and while the L858R you know response in for Osimertinib is not as good as Del19 that gap has shrunk and so the clinical cost and time and to be able to prove that it's better almost becomes not feasible for a company of our size and so certainly you have competition across everything, but I think the clinical approach to validate a more novel target while you're taking biology risk is a little bit cheaper and quicker. And at the same time, by working in validated pathways, that does mitigate some of the biology risk to a degree. It doesn't remove it, but it mitigates it. Gotcha.

So maybe last thing, I know Scott, you kind of mentioned a little bit about this, but like the collaborations that you guys have ongoing. So So should we expect, you know, any updates from partners, you know, in the next 12 to 24 months? And I guess what's the, is it a priority to continue to do collaborations as you kind of unveil some of these targets, you know, within the pipeline?

Yes, so of course we can't communicate all of our partners' timelines. You know, I think we can say we're making progress and there are discovery milestones in some of the collaborations that would be, you know, communicable events for us. You know, the decision around disclosing targets is on their side. Of course, we've delivered degraders to Biogen in IRAC-4 and BTK, which is in their currently phase ones. You know, I think Andrew and I and our SLT believe that discovery collaborations provide an opportunity to advance the science while also bringing some opportunities for non-equity dilutive capital. and 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 the greater 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 and so there's you know financial and you know motivational benefits from a technical point of view.

And then we last we just on runway maybe Kendrick can you just talk to what we're funded through.

Yeah. So just a reminder, we have runway through the end of 2028. That allows us obviously to continue to execute against the syncytomide 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 three study for simsidamide of course that's beyond the run 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 and clearly the near-term focus is on executing the simsidamide program and driving to some of those clinical readouts in the coming year so excellent well I think we'll leave it there thanks guys great welcome to see you guys thank you perfect good to see you guys