Conference Transcript - CCCC 2026-06-04

Operator

Hey everyone, thanks for attending the Jefferies New Year Conference, day two, also last day, short but sweet. I am happy to welcome the C4 Therapeutics Management Team. We have Andrew Hirsch, the President and Chief Executive Officer, as well as Scott Boyle, the Chief Business Officer. I'll turn it over to them for opening remarks.

Andrew J. Hirsch, CEO

Great, thanks, thanks for having us here. We're really excited to share what we're working on at C4. Obviously the, you know, our new program, is front and center, especially in the wake of some of the exciting data in the space coming out of Aska. So, happy vision.

Operator

Excellent, well, maybe let's take a step back. You will have a good amount of data next year, right? So if we think about the next 12 to 14 months, what are the major catalysts you think investors should be paying attention to?

Andrew J. Hirsch, CEO

Yeah, so I think about our own programs, right? We're very excited about the data that we shared at IMS last fall around semisidamide, which we think demonstrates a potential best-in-class profile in the IKZF-13 to greater space. We saw really compelling signs of efficacy at our overall 36% response rate across 72 patients across all doses, and at our highest doses, which are 75 micrograms and 100 micrograms, we saw a 40% and 53% response rate respectively across those two cohorts, which we think is very competitive with what we see as the other portfolio of IKZF1 pre-degraders, but importantly and important for the landscape, the safety profile was incredibly differentiated. We saw very low rates of neutropenic complications, low rates of discontinuations and dose reductions, which is important as you think about the myeloma space where it's a combination treatment regimen. There are no real monotherapy treatments that are existing there, triplets, quads, et cetera. And so having a tolerable profile where you're able to give what we think is the optimal dose, our recommended phase two dose is 100 micrograms, but even at 75 we saw really compelling activity in combination with other agents is critically important. And so, you know, I think that really tees up where we're headed. And what we've done from that is started two additional studies. The first is a phase two study called the Momentum Study. That's a single-arm study of simcinamide plus dexamethasone in the fourth-line-plus patient population. That study is conducted with registrational intent, and our goal is to submit that for a late-line study should the data be supportive. In addition, we've started a phase 1B combination study with L-Renatumab, and that's the BCMA bite from Pfizer. And that is going to be a dose-finding study, a safety study, which will support a potential pivotal study in that combination, serving as a confirmatory study for the single arm, as well as expanding the label into a second-line or later patient population. So those are the key things for us that we're working on. we've guided to initial data in the second half of 2027 from the momentum study. That'll be the investigator assessed endpoint. The regulatory endpoint is an independent monitoring committee endpoint along with some durability. That won't be until mid-2028. And then with the phase 1B, we'll have the complete data, kind of mid-27, but we will be providing updates as we move through dose escalation cohorts as we have done in the past with our first in human phase one study.

Operator

Okay, awesome, super helpful. We've started to see cell mods and cell mod-like therapies heat up, especially in the past couple of months with Bristol studies, right? We'll definitely talk about successor too, which was huge, but I guess you're taking on a different strategy than what Bristol is. Can you kind of explain, you went over kind of the programs you're starting, but the intent of your combination regimens, where you see CEMSE fitting into the respective settings relative to Bristol's, and I guess your confidence that there could be differentiation with either your regimen or your drug on safety and efficacy.

Andrew J. Hirsch, CEO

Yeah, so I'll start as we think about the landscape and how it's evolving has really informed our development strategy. So I think Bristol has been very clear about what their development strategy is in terms of replacing their current image franchise with the next gen, they call them cell mods, that's their sort of branded names, but whether you call them image cell mods, they're all, all of them are IKZF13 the graders, including ours, they're all the same. What we see happening in the landscape is really two main shifts and maybe a third emerging. The first is we see a lot of these new immune directed agents, BCMI bites, CAR-Ts, and even some tri-specifics. But those immune-directed agents are moving into earlier lines of treatment. So focus on the second-line setting, and we saw that recently with the J&J Majestic 9 dataset that was presented at ASCO in the second-line setting. What the consequence of that is, is that patients now in the earlier lines are seeing more effective therapies, they're living longer, but they still progress. that's going to increase the size of the late fourth line plus patient population and that's where our first pillar of our strategy is the momentum study developing it in that setting we think that's going to grow bigger than it is today our estimates today are about a billion and a half dollar market opportunity but we think that will grow as more effective therapies move earlier so that's the first piece the second is we do think those more effective therapies are going to be earlier, but we think that combining them with an IKZF1-3 degrader is really important because of the dual mechanism of IKZF1-3 degradation. Those mechanisms are as follows. The first is it actually is foundational to the biology of the disease. It stops the proliferation of plasma cells, which is the cause of the disease. But the second is that it activates the immune system. And what we've seen with these immune-directed agents is they lose efficacy because of T-cell exhaustion. And so combining those together, we think can create a more effective combination therapy, bringing the response rates and the depth of response rates on par with what we're seeing with the current state of CAR-T therapies, but in a more easily administered regimen. So our strategy is really going after those two trends so that we have labels in combination with where we think the market's going. The third trend that's just recently emerging is this idea of fixed duration of these highly toxic but really effective agents. We see once a patient gets into a deep MRD-negative CR, the question is, do you need to be on a bite or some other bite-dara combination forever, or can that be removed and put into a maintenance treatment? And a profile like simsidamide is perfect for that because it both gives you the best of both worlds. It's very effective, but has high levels of tolerability, which makes it well-suited for that maintenance treatment. We haven't started work there, but we've been engaged in discussions with KOLs about how do we think about development in either post-CAR-T or kind of post-bite IKZF-13 to greater maintenance setting.

Operator

Okay, that makes a lot of sense. And then just moving on to the successor to data that was presented at ASCO, what were your major takeaways? Was there anything that was surprising from the data? I guess the major things that, and as a reminder for everyone, you know, Bristol's successor to the progression-free survival was 18-month versus 8.3 months. That said, the control arm was doublet. They are running a head-to-head versus POMELIS, PV, you know, POMELIS combo regimen, and that data is going to be next year. I think that will be, you know, strategically exciting for Bristol, but given how big of class IMIDs are, if a cell mold-like treatment of that class can show, you know, superiority in a head-to-head, you know, that would be, like, I think that would change kind of the landscape as to how you consider where this fits in therapy, right? So love to hear your thoughts. Yeah, so as

Andrew J. Hirsch, CEO

you said, we're not surprised that that trial had a significant impact on PFS. I mean, they sort of said that without sharing the data, and even before that, you know, it's a triplet versus a double it and the triplet had three effective therapies versus two you know it would have been a real problem if that that didn't win so so that part wasn't a surprise um actually nothing it was a surprise but consistent with what we saw in the phase one right we did see high levels of dose reductions and discontinuations due to safety etc and and so you know i think the median uh relative dose intensity in that study um for mezi was 83 percent right i think the average is probably lower than that, given that that's the median number. So that was consistent again with what we know about the profile of the drug and what we saw from both their phase one dose escalation and their phase 100 patient expansion in terms of how well patients are tolerated. They didn't really present all the data on safety. We don't know, for instance, what the GCSF use was, etc. So there's a little bit more, and maybe we'll see that in the forthcoming Lancet publication. So that wasn't a surprise. And then when we think about successor one, to your point, I think that is the real important study. And when you triangulate, which is always risky, but cross-trial comparisons, I think looking at both the comparator arm in the Majestic 9 study as well as a small 52-patient study called the SELECT study, that showed about an 11-month PFS for a PKD regimen. Yeah. And the combination, the comparator arm also showed about an eight month in the majestic nine study. So I think there's a good shot if they replicate the 18, that whether it's 11 or nine, that study is going to win also. And that makes sense just given, you know, the improvements that both we and BMS have made from the first generation IKZF1 three degraders that are on the market.

Operator

okay awesome super helpful um and maybe just on because you're not running any head-to-head studies right when you ask bristol they said you know this study they're confident about but they don't necessarily need to file on it it's more to like what do you think you would benefit like are you planning on running a head-to-head or do you think you would kind of benefit from physicians looking at this you know benefit from you know bristol study and be like hey this is kind of proof of concept on the efficacy.

Andrew J. Hirsch, CEO

Yeah, we don't intend to run ahead to head against any of the existing approved IKZF1 three-graders, lenalidomide and pomalidomide because that's not really our strategy. Our strategy is not to try to replace those in the marketplace. Our strategy, as I articulated, is to get a label in the late-line setting with some cinamide plus dex as a doublet where we've already shown quite compelling efficacy and tolerability in probably the most heavily pretreated patient population that this mechanism has been studied. And so we think that data is quite compelling and really de-risks the phase two momentum study. And then in combination, you know, with L-renatumab, that's really our strategy. It's not to go head-to-head, and we don't really plan to do that. They do need to do that because I think they're going to need it for reimbursement, right, and they're going to need it because they're trying to replace, you know, lanalidomide and pomalidomide, you know, with

Operator

abertamide and mesignamide. Right. Awesome. Super helpful. And then, Andrew, you alluded to this. You guys are focusing on the dose reductions and the dose intensity, right? And you've said SEMZ is a potentially, you know, more tolerated drug. Can you go over the data points that support this? And then do you think the current, you know, regimen leaves efficacy on the table if you could, you know, dose higher and maintain higher dose intensity?

Andrew J. Hirsch, CEO

Yeah, so I think if I look at the data that we have, I think from the phase one, right, we had very few, I think 6%, you know, dose reductions, you know, due to tolerability. But we didn't really, and we said very low levels of GCSF use. I think what's important is everyone focuses on the neutropenia rate. That's just really a lab value, right? What matters is are there complications in terms of infections, dose reductions, or discontinuations. And that's really where the drug differentiates, right? We saw, you know, very low levels of, you know, kind of infections compared to the Zygdimide and even Abertamide. And they had something like 25% when you're, as apples to apples as you can be in cross-trial comparisons, they had 25% dose reductions in that phase one study, right? And we only had six. So that to me is really what speaks to the tolerability and safety benefit is you don't have that. And we had much lower rates of GCSF use. I think it was a 36%, if I'm remembering the number correctly. Their numbers were kind of north of 60.

Operator

Okay, interesting, interesting. Because I think people are focused on the overall rates as well as the grade 3-4s, in which I think both regimens look generally in line. But you said focus on the dose discontinuations, GCF use.

Andrew J. Hirsch, CEO

Again, it's a lab value, right? And now, certainly, if you're in grade 4 neutropenia, that increases your risk of infections. And I think what was encouraging for us is everyone reports the grade 3, 4 rate. But when you look at the grade 4 rate across our study, across our doses, very consistent. Only about a third of patients have grade 4 at any of our dose cohorts. What moves around a little bit is the grade three number. And that's because these aren't random. People like to look at dose escalation and think, are these randomized for each dose? And they're not randomized. And I'll give you an example. In our 75 microgram cohort, 95% of patients were prior transplant. That was a huge outlier compared to some of the other dose cohorts. And so you can't really look at them as independent randomized studies. But we did see consistency in terms of the phase, the grade four across all studies, all those dose cohorts.

Operator

Maybe just talking about your prior phase 1b, at the 100-microgram dose, this is with a heavily refractory population rate, you're seeing a 53% overall response rate in a difficult-to-treat population. Granted, this was very small. And do you think that will translate to a larger population? population? And how are you thinking about kind of the durability in a larger trial?

Andrew J. Hirsch, CEO

Yeah. So I would say the top line is we would expect it to translate. And if you look at the IBRN-MESI experience and you look at their phase one, but their expansion, those numbers held pretty consistently. And that's been the case with this class of medicines. There's two caveats that I'll give is the phase one dose escalation study was conducted only in the U.S. and the momentum study is going to be a global study so it'll be both kind of U.S. and European sites and so we may expect slightly different treatment plans. We think in Europe there's less likely to be as many patients who have seen CAR-T or T-cell engager treatment than we have in the U.S. but we think it's largely going to be the same patient population. Okay,

Operator

Okay. That's super helpful. And then you guys are going for accelerated approval next year in the fourth-line population, right? Can you kind of...

Andrew J. Hirsch, CEO

20-28.

Operator

20-28. Can you go over your discussions with the FDA on what the bar you need to show in order to

Andrew J. Hirsch, CEO

So just as a practice, we don't get into sort of the back and forth with our FDA discussions. What I can say is we have had your typical type C meetings that one would have around development strategy, certainly around recommended phase 2 dose, and our development strategy takes that input into consideration as we have planned and executed that strategy.

Operator

Okay. Makes sense. And then your second line strategy, you have this supply agreement with Pfizer. Have you disclosed what the trial design is in terms of the doses for both? Is it just kind of the commercialized dose or go-forward dose, or is there kind of a balance of the two

Andrew J. Hirsch, CEO

components that you're considering? Yeah. So our goal in that study is not to change the our Natamap dose.

Operator

Okay, makes sense.

Andrew J. Hirsch, CEO

We've disclosed the design, and so the way that trial works is when you enroll a patient, the patient goes through the step-up dosing regimen that is currently right in the label. And if a patient doesn't get to that step-up dosing, they don't get simcinomide. And so only when a patient gets to the full dose dose, we then introduce simsidamide. Because we don't want, there are toxicities associated with L-ronatumab, including in the step-up dosing period, and so those shouldn't be attributed to the combination. And so that's part of that design. And then, you know, we're enrolling about six patients per cohort, we're starting at 75 micrograms, which is one dose lower than our recommended phase two dose, which is pretty standard for a new combination and then the trial is designed to be incredibly flexible so if we declare 75 safe in those six patients you know what we can do is we can expand at 75 we can choose to escalate to 100 or we could open an expansion at 50 but if we want to explore that okay and then depending on on what we see you know we may want to add patients at 75 we may want to open a safety cohort at 50 so it's incredibly flexible to really explore the combination across the range of those three doses 50 75 and 100 and that'll be determined based on the data that comes out of that at first 75 microgram

Operator

combination yeah that makes a lot of sense and then is there a I guess upper end of safety that you are willing to tolerate when you're thinking about the

Andrew J. Hirsch, CEO

doses you want to move forward with? That's hard to say. Obviously, the goal is to not interrupt the bite dosing because there's no dose reduction strategy for bites, right? You stop and hold therapy, which we don't want to do. So, you know, a little bit is going to be the proof is in the pudding and we'll see what we see. And then once we do that, that'll help us inform sort of next

Operator

steps, but it's all going to be data-driven. Okay, makes a lot of sense. And then in terms of, I think we kind of talked about this, but Bristol has both Mezzi and Iber, right? You have a potentially more tolerable drug that they want to use up front and then less tolerable, more efficacious. What is, how do you think of SEMZ, you know, positioning? Because you're talking, I mean, it almost sounds like you think you can get to the efficacy of MESI and then the safety of IBER, right? Which is, by the way.

Andrew J. Hirsch, CEO

You said it, I didn't.

Operator

But which is a high bar. I guess, like, how are you thinking about positioning? Like you said, refractory setting, moving up lines of therapy, but then you are also combining with Pfizer. And it seems like, you know, you're looking at how the safety profile evolves. Is there kind of an appetite to evaluate other second-line regimens over time?

Andrew J. Hirsch, CEO

Yeah, absolutely, and I think that's a great question. You know, I think our goal is, you know, this is, my ultimioloma is a combination regimen disease, and so we think that it would be important to establish simcinamide as the combination agent of choice, you know, where IKZF1-3 degradation can, you know, increase the benefit to patients. And so that's really what our strategy is shaped around. And in fact, on our latest Q1 financial results call, we announced that we're going to start a second phase 1B to combine with an anti-CD38 antibody and a proteasome inhibitor. Now, that doesn't mean that it's going to be a label-enabling phase 3 strategy, but we do think the important thing to do is really establish broad combinability with the key major agents, MOAs, in the class. and that's really the objective here and what we would love to be able to do is establish a single dose that is the combinable dose for whatever regimen you're trying to do and so that's really the goal given what you talked about as the profile we think we have you know when we say best in class we mean we have optimal efficacy and safety whereas as you pointed out I think the other two agents in the class that are being developed sort of make a trade-off between efficacy and safety and we think given the properties of our drug and the pharmacology

Operator

we don't have to do that. Okay that that makes a lot of sense and then I guess moving on to the market can you just go over how big that market opportunity is for momentum as well as in second line we'll give Scott some air time. Sure yeah so like as Andrew said we

Scott N. Boyle, Board Member

We believe that the immune agents are going to move earlier, creating a larger fourth-line opportunity. The Momentum study is intending to tackle that fourth-line patient population. We've made some assumptions, and we think it's $1 to $1.5 billion of revenue peak opportunity in that patient cohort. And then as we move into the second line with the others, we believe together those two can get us to about, you know, $4 billion opportunity for simsidamide in combination there. Obviously, if other combinations come on board, we expect that opportunity can grow for

Operator

simsidamide. Okay, awesome. Maybe just to go over the Roche agreement that you guys had recently. So in terms of the, sorry, the DAC agreement, can you go over what, you've said that you haven't disclose with the targets but you guys are being very smart about target selection you don't want to you want to add look for targets that can actually be differentiated right but there is also a framework that that you're using when looking at prior degrader so can you kind of walk us you know into you know your approach in the framework and if there's anything you know

Scott N. Boyle, Board Member

and then some of the target profiles you're looking at yeah so DACs are degrader antibody conjugates where it's an ADC but replacing the cytotoxic cargo with a degrader. The concept there is that degraders have catalytic activity and then can be designed in the way that we've done in our orally designed ones to be highly selective for the greater target of interest. And so this new DAC modality has the potential of a highly selective one-two punch in cancer targets. We've had a long-going collaboration with Roche in designing oral degraders, and when they got interested in this DAC concept, of course, we were happy to find a way to extend our relationship. And as you said, we've announced a collaboration with Roche where we've gone after two targets together. The way that we think about target selection is the The degrader opens up a lot broader anti-cancer activity than a cytotoxic agent could be. And Roche was aligned with the way that we were thinking about this. They're also, with a DAC, you could go after degrader targets that might not be able to be tolerated in a systemic delivery of a degrader. And so the antibody does the targeting to the correct cell type. And then you could imagine perhaps a more, you know, less tolerable deraider target. That being said, we haven't disclosed the DAC targets with Roche yet. But philosophically, we were aligned and happy to have them leverage our learnings in that space.

Operator

Okay, awesome. And as you think about, I mean, would you want to take your DACs into an area where you've already seen, I mean, there's oral CERDs, right? And then I think the data there is starting to say there is going to be a population where you get the most benefit, and then there's going to be a population where you're not really seeing, you know, much of a benefit with the Dick Rader approach. How are you thinking about both indication selection and, you know, target selection?

Scott N. Boyle, Board Member

Yeah, I mean, so certainly on the DAC piece, I think that it's going to be a combination of the concept around the target of the antibody as well as the greater. If taking a step back on C4's next generation discovery pipeline, and perhaps maybe that's where we could go, we're aimed at indications in inflammation and neurodegeneration and neuroinflammation. We took the lessons that we learned over the 10 years of targeting oncology agents as well as non-oncology targets with our collaborator Biogen. And we've made decisions to go after clinically validated pathways, but where the greater modality is the right way to unlock a particular target where there's a first-in-class opportunity there. And so some of those learnings we've embedded into our target selection in the next generation. I think the other thing that drove the target selection there was an insight that we and others have developed in degraders over the time. Initially, the point of view was that these large heterobivalent degraders wouldn't cross the blood-brain barrier and penetrate into the brain. And so I think initially the point of view was that those sorts of indications would be excluded. We demonstrated with our data and some of the other players in the greater space is that you can actually design heterobivalent degraders to grow into the brain. We saw that with two of our oncology programs and, of course, some of our collaboration programs. And so that opened up a larger indication class that we hadn't considered before. And so that's it. You know, putting those two pieces together, it unlocks some of those opportunities. I think the other point around target selection that is tuned to the degrader modality as opposed to inhibitor is you can design degraders to bottom out at a certain level of degradation. So, for example, you could say we only want to degrade 60% of the target. You can design degraders to do that based on the kinetics and the preclinical activities that we do. And so it allows the concept of normalizing levels as opposed to having to get to deep levels of degradation, which you would expect you might need in oncology. And so, again, I think some of those three principles dictated the target selection in our next generation portfolio.

Operator

Awesome. That's super helpful. And then are there any timelines you can give us on that collaboration?

Scott N. Boyle, Board Member

So we've not disclosed any timelines with our Roche collaboration.

Operator

Okay. Remind us again how many of these are pre-IND versus early, you know, phase one.

Scott N. Boyle, Board Member

Yeah, so all of our collaborations to date are still in the discovery stage. Biogen, which we had a collaboration with, has taken two molecules degraders into their clinical portfolio, and so those have advanced it to that point.

Operator

Okay, awesome. Super helpful. And then I guess we have time for one last question. So in closing, I'm just going to ask a generic, you know, C4 story. What do you think is the most underappreciated aspect of C4 right now?

Andrew J. Hirsch, CEO

Well, I'll say the whole thing, but certainly the pre-clinical pipeline is underappreciated, but partially because we haven't shared data yet, mostly for competitive reasons. So when we get to the right stage, we're excited to share that, so that's understandable. But I do think the subsidiamide story, despite the recent run-up in the share price, is still underappreciated. I mean, this is a wholly owned, post-proof-of-concept asset that shows best-in-class potential you know in a large and growing market with a very differentiated development plan focused on where the market's evolving versus where it's been and so you know I think that is something that hasn't really been been appreciated I do think it's starting to as some of the BMS data supports what we've been saying for the last several years and hopefully our data will follow that but I do think that's probably the biggest you know underappreciated part of the story. Awesome well

Operator

Well, thank you so much for the time, C4 team. And then thank you so much for everyone for being here.

Andrew J. Hirsch, CEO

Great. Thank you. Thank you.