Great. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 7th Oncology Summit. For our next session, very excited to have a fireside chat with C4 Therapeutics, and it's my pleasure to introduce Andrew Hirsch, the CEO of C4, as well as Len Reyno, the Chief Medical Officer. Andrew and Len, it's a privilege to have you both here. Thank you very much for joining me.
Thank you for having us.
Yeah, thanks for having us.
Before I get started with the discussion and questions, for those of you logged in, feel free to submit questions via the portal. I have the dashboard up here, will be doing my best to get those asked by the end of our conversation. As you all may know, Extel voting kicks off today, the TD Cowen biotech team would appreciate your support if you feel that we've earned it. With that, we'll try to earn it and get into questions, starting with the cemsidomide phase II MOMENTUM study. You all are planning on sharing an update from the cemsidomide dex combo study at EHA, it'd be great if you could briefly start by recapping what you've shown to date and set expectations for what we should expect with the upcoming readout.
Sure. Thanks for the question. Just to remind everybody, the last robust update for this trial was at IMS last fall in Toronto with some brief update in a press release in the fall as well. That data set forms the basis for what will be presented at EHA, obviously with longer follow-up. Let's recap what we shared already. Within that data set, we showed that cemsidomide in a late-line population, a median of seven prior lines of therapy, including 75% of patients who had had post CAR-Ts or T-cell engager BiTEs or both, that in our recommended phase II dose of 100 micrograms, we had a 53% response rate.
What's relevant as well about that dose, however, was the robustness of the signal across dose levels, so that at the one dose level below, it was a 40% response rate, and around the whole population of patients recruited over four dose levels, the actual response rate was 36%. What the data set showed nicely for this potent, what we think is best-in-class degrader, was that over the range of doses it was tested that it was safe, and I'll come back to that in a moment. As well as you got to increasing exposures, you got to increasing signal of efficacy. As it related to safety, the safety signal we believe is class leading, and that class-leading safety pivots around, of course, neutropenia.
This class of drugs, no matter what drug you use, always has to be given with a treatment break because the drug itself also causes delayed maturation of neutrophils. With our 14-day on, 14-day off schedule, what we showed, in fact, is that we had class-leading neutropenia, especially as related to Grade 4 neutropenia, with only about 33% Grade 4 incidence across the dose levels and a very low rate of use of GCSF, 47% of patients ever receiving any G. What was interesting about the data set as well from the safety point of view, which is highly relevant, is that most of those safety events that related to immunosuppression were clustered in the first two cycles. That, in fact, once patients got through those first two cycles, the drug was extremely well-tolerated, and in fact, we had no patients come off the study for safety-related reasons.
Of course, we had patients come off for progression, but not safety, and that's a really key differentiator and important feature of the class. Finally, probably taking advantage of both our potency and our 14-day break, which is facilitated by our unique 48-hour half-life, we had very few dose reductions. Patients showed up for cycle two with only 6% of patients ever having a dose reduction. That was the basis of the presentation at IMS. Now, fast-forward, we're now almost nine months later. You've seen the abstract at EHA, which was that cutoff date, I'm going to call it X. The actual presentation at EHA will be at a new cutoff date, a little bit closer to the actual poster. At our last update, we showed you that there were eight patients still ongoing.
In fact, we had the least data on the patients who were enrolled at 100, because they were enrolled late in the program because it was a dose escalation study. What you can expect to see at EHA, in particular, is an updated experience from the 19 patients who were enrolled at 100, more evidence and more characteristics of long-term safety, and as well as the response characteristics over time. What you won't see is a new patient cohort, okay? It will be the same patients already described, but with more data. Therefore, what you also won't see is a change in the actual overall response rate, because that's already been defined in our press release that came after IMS.
You'll be able to get a more granular look at the nature of the responses and the nature of safety over time, all really important data. I'll end with one other reason the abstract is super important to us, and that is our original research was conducted only in U.S. sites. Our MOMENTUM study represents our expansion to include U.K. and Western European sites. This data-sharing event at Stockholm also provides an opportunity to speak more directly to investigators who may be less familiar with the cemsidomide story to date.
Very helpful overview. Appreciate that, Len. Just to be clear, set clear expectations for response rate and data there, but on durability, could we expect an evolution there in terms of what we've seen historically and what we'll see with this new patient, with more patients, 100?
All the parameters that we shared in the IMS, which included durability, will be updated with the new numbers for follow-up, et cetera.
Got it. You'll have more patients at the highest dose with longer follow-up?
Yeah.
All right. Understood.
I point out that the other thing that happened since that highest dose and that disclosure is we had formally declared that the 100 microgram dose is our P2D.
Yeah. Not just 100 microgram, it's all the patients in the study with longer-.
Yeah. It'll be a full, robust update of everybody treated. Yes.
Yeah. Obviously, the 100-dose patients could potentially have a meaningful impact on durability as we think about that. Okay. You did a great job of discussing the clinical profile and everything that's been reported to date. Maybe as you think about the CELMoD group of agents in development is not that big, certainly compared to some other classes. It's kind of you guys versus Bristol with MEZI and IBER. Can you help us understand the positioning or potential differentiation for cemsi versus MEZI and IBER?
Yeah. One of the ways, they're all potent degraders. Preclinically, the most potent molecule is cemsidomide, but it's a preclinical observation. If you look at our clinical observations, I think what you'll see, and if you compare apples to apples, because clearly they have more advanced development, and we can talk about that later, but if you talk about the same point in development, I think what you'll see the characteristics are is that at our highest and recommended phase II dose, we actually have essentially a response rate that matches MEZI, but we have a safety profile that looks more like iberdomide.
That's really a sort of a poor man's way of putting it together, but I think it's useful that we think we have, and we have reason to believe with clinical data that we have at least the potency of MEZI, but with a better safety profile that looks more like iberdomide. I'll put a pin in the at least the same as MEZI because I think one of the things that we're anxiously waiting to see, because obviously MEZI has treated more patients than us in different protocols, et cetera, is that the characteristics of the response curve in phase I is a little bit different. MEZI had a much bigger inflection between their second highest dose and their highest dose, suggesting you really had to give the highest dose to get the most efficacy.
What we know anecdotally from disclosures of Bristol trials moving forward since then, that often it's not clear they're able to give that highest dose when in combination. One of the things we await with interest is what dose is actually being used in some of the trials that some of which will be disclosed at the upcoming ASCO meeting in a few days. That's a way to think about it. That said, I think another way important to think about it is they have an entrenched pivotal trial program that's looking at a replacement strategy for len and pom in first and second line, and that's exciting and important for patients. Our development strategy is also a differentiated development strategy, which is thinking about there really is a value in late line as well as combining with BiTEs.
Very interesting. We'll get to ASCO and then eventually combinations here shortly. Can you just talk about the ongoing phase II MOMENTUM study, how enrollment is progressing, and what you've observed so far, and then also what you believe the market opportunity in this setting is?
Let me take the first part, and then I'll hand the second part off to the CEO with the dollars and cents. The first part, I have to be very careful. We are conducting the MOMENTUM study with regulatory intent, and that means that there's very little we can disclose, otherwise we will contaminate the study's opportunity for an accelerated consideration. What I can say is that enrollment is on track for meeting our publicly stated goal in the first quarter of 2027 that we will have achieved our enrollment goal. What I can also say is that we've had good acceptability of the trial. Obviously, to get that goal, to get to 100 patients, we need more sites. We've had excellent tractability in finding new sites in both the U.S. as well as the rest of the world.
There won't be a lot of granular updates on that trial as it unfolds because that would contaminate our ability to present it for consideration of accelerated approval in the late-line setting, which I'll hand over to Andrew to address.
Our estimate so far is that it's about a $1.5 billion market opportunity in kind of the fourth line plus setting. That's based on everything we know today. We do expect that segment to grow because, and we've seen this in other settings where, as you see the CAR- Ts and the BiTEs, which are more effective therapies, move to earlier lines of treatment, you now have patients in the second line and later setting living longer and surviving longer, but still progressing. If you look at the CARVYKTI data, I think it's something like two-thirds of patients progress sort of within five years. Those patients may have otherwise died, and now they're surviving, but relapsing. We expect that to grow, and we're working to sort of refine our estimates as we model that dynamic.
We think that opportunity will grow as we see this dynamic in the landscape, which is actually evolving quite rapidly.
That makes sense. It's a lot of BCMA treatment options at the end of the treatment paradigm, but we definitely need more for those that exhaust the BCMA options.
As Len said, 75% of the patients we saw in the phase I study were post that, so that really does speak to that. We didn't enrich for that. That's who showed up to clinic seeking a treatment option where there were none. We do think that speaks to the opportunity, just our data as it is.
Yeah. Even, I think the GPRC5D bispecifics have seen good uptake because of that. Obviously, you guys have a much more amenable safety and tolerability profile.
Yes. For sure.
All right. Turning to ASCO, which you alluded to, or you mentioned, Len.
The elephant in the room.
Exactly. Bristol's expected to present, I think, the phase III SUCCESSOR-2 data. It's the MEZI plus carfilzomib dex combo versus carfilzomib dex. What are you expecting from that update, and how could it inform your cemsidomide development plans?
Yeah. We know it's a positive study because they've shared that in press release, now the devil's in the details. We're not at all surprised it's a positive study, and put it differently, we're also very pleased that it's a positive study because what it shows that in a randomized global study, that you can introduce a potent degrader successfully and safely. That's great. Why we're not surprised about the efficacy signal, however, is that of course, this is a multi-drug treated population, and it would be shocking if adding a foundational mechanism like IKZF1/3 degradation to a doublet that doesn't have it wasn't positive.
That part is good, there is an important read-through to cemsidomide, and that is the effectiveness of being able to give, in a global study, this potent degrader that has a safety signal, if anything, is more complicated than our own. What are we looking for? We want to see the size of the delta. I'm particularly interested in looking for what the dose intensity actually was of the mezigdomide and what dose reduction patterns they had, and as well as supportive care and/or clinical complications vis-à-vis infections. None of it to influence what we do, more to inform how to think about collecting the data as we move our trials forward. We think it's an important positive read-through for the class that Bristol calls CELMoDs, we call potent degraders.
They're all in the same mechanistic pattern, and they're all in the pharmacologically optimized category of degrader.
Yeah. Our development, Len mentioned it, but our development plans assume that that was going to be a positive study. Nothing changes from our perspective based on the fact that it is positive.
Okay. That's a helpful addition. Maybe moving to SUCCESSOR-1, the data, I believe, are expected later this year or early next. It's a MEZI head-to-head versus pom, which may be a design that maybe is a little bit more robust based upon your comments with SUCCESSOR-2. What are your expectations from this trial, and how, again, might it influence the overall development of this class of drugs?
Yeah, look, I think this is going to be an important study because this is the first time that someone's really going head-to-head with the next generation degraders versus the first generation. That'll be an interesting readout. We think there's a clear benefit to the higher potency next gen degraders. Again, we think it's positive. Obviously, that's what we would expect, and so we'll have to see what that data looks like. I think the biggest concern we have with that study, is really around how that study's powered, because we haven't seen data that gives what that might look like.
Okay.
I think there is a risk, right, that does it win superior numerically, but not statistically? I think that's, for us, the big risk in that study.
I'd put it a different way. I think it will be a positive study qualitatively, like that it will win in terms of numerical, and Bristol obviously hopes it will be statistically a winner. The study was designed without a really robust understanding of what the effect size would be with that combo in that line. That's why this becomes an issue. That said, there's no scenario where the data's not useful to us, because we'll be in the business of designing a phase III in the not too distant future. The readout doesn't really compete with our CDP. It's going to be a very interesting study and an important study for us, and no matter what it shows, I think we're going to learn some important information that helps us de-risk our own pivotal program.
Right. Since we're on the topic of standard of care combinations, maybe we'll ask about the additional combination studies you guys just announced that will start in the first half of next year with the PI and CD38-based triplets. Obviously, virtually no patient is not seeing daratumumab nowadays, right? Smart to add that combination. PI is obviously part standard of care. Maybe just elaborate on why you chose those two combinations, among others.
Yeah. Maybe to go back one step quickly first, because I'm conscious of the time. Obviously, we think those are super important combinations because they're entrenched standard of care, and you need to know what dose to combine with. Our pivotal strategy is with a BiTE. The reason this is relevant to this conversation is that that trial is of a design where we start at 75 micrograms. We can then transport that design into this design to try to declare as quickly as possible what the combining dose is for cemsidomide. The overarching goal of the program is we believe that cemsidomide, because of its pharmacologic characteristics and its clinical differentiation, has a reason to believe to be the combination partner of choice. To get there, you have to have a reproducible and readily identifiable combination dose.
We're not going to do a lot of dose finding in any of these studies. We're really pivoting between trying to understand 75 micrograms and 100 micrograms. These studies are super important because they will build on that data set so that we get to a place very quickly that we can think about in the future. You don't have to do a lot of independent phase I-B studies with cemsidomide, but rather, if you're doing a new combination, you can start at a predictable dose and do a safety run-in in another study to sort of shave timeline off drug development. We'd like to get to a place where there's a lot more cemsi trials and that it's easy to give. The choice of those two is a starting point for the reasons you just said. Obviously, CD38, you have to have data.
Also it's important to note that I think the proteasome inhibitors are around to stay. We anticipate, in all likelihood, combining with carfilzomib because it's being used in later lines in some of the rescue regimens as well. We're not saying those are the only drugs we'll ever interrogate. Those are the ones we'll start with because we think they drive maximum value for patients, clinicians, and ultimate investors.
I think the other thing to note is this is about establishing, as Len said, the combinability profile. At this point, we don't plan to conduct pivotal studies with those regimens. That could change in the future, but right now that's not part of the CDP. The CDP is very clearly, as we've outlined, the MOMENTUM study in the late line and then the phase I-B with elranatamab sort of supporting a phase III registrational study in that combination.
Okay, that's clear. Then with the phase I, the combination study with elranatamab, can you just, for investors, reiterate the status of that study when we could get data and what a successful outcome with that readout would be?
The study is open and recruiting, and we've disclosed that the starting dose we've started with is 75 micrograms, one step below the sort of single agent dose or the dex dose. Open and recruiting. If the 75 micrograms is declared safe, we would then explore 100 micrograms, we would also expand 75 micrograms. We also, at any time, once 75 micrograms is declared safe, we can explore 50 micrograms, we wouldn't preferentially explore that. What do we expect to see? It's obviously a phase I safety study, the first thing we want to see is that you can combine cemsidomide 14 days on, 14 days off with elranatamab without compromising the ability to give the BiTE, it is obviously the standard of care. Although we're starting initial safety in patients who are fourth line, we're going to migrate an expansion to second-line patients. Safety, safety.
That said, we also expect it to be a highly active regimen, with a very high response rate, more importantly, that we should be seeing CRs early on, including MRD negative CRs. We've also built in a very elegant translational studies because we have some ideas of what the translational environment should look like vis-à-vis immune enhancement, that we can see. What we've committed to sharing is that in 2027, we should be able to share the study results. It is an ongoing study, and we know there's great interest in it. I think you can look to our press release cadence that we had for cemsidomide through end of 2025, where we would often in a press release say, with the quarterly earnings share, if we've cleared a dose level, what dose we're recruiting to, and whether we're expanding, et cetera.
Don't expect a really robust data set until 2027.
Okay, that's clear. Have a client question just on SUCCESSOR-1, Bristol's had adverse pom. If that shows a robust hazard ratio, I guess how do you expect to compete or what would your strategy be to compete on that front over the long term?
Well, I think we're not developing it in that setting, right? I think that's the difference is I would say that we have a bit of the Wayne Gretzky development strategy, where we're developing it, where the puck is going, not where the puck has been. Their strategy is very clear. They're trying to replace lenalidomide and pomalidomide in the current regimens in the relapse refractory setting. We're not trying to do that because we don't have a franchise to protect. We're trying to develop it in both the last line setting as well as in combination with the BCMA BiTE. We think there's a huge market and there's plenty of room for all of these drugs in the setting. Our label enabling strategy is quite differentiated. We think it's great for patients if that's where that drug ends up being.
For us, we're taking a different approach.
Yeah, that's great. Love that analogy. Just maybe the last question, since we are heading into the weekend of ASCO, are there any other data sets or CELMoD related data sets that you all are closely paying attention to that you think investors should be paying attention to as well?
Yeah, there's two other data sets that we're seeing. The first is an IST from the Mayo Clinic, which is actually looking at iberdomide in a quad regimen, so with daratumumab, bortezomib, and dex.
In front line.
in newly diagnosed patients. That's something that we'll be watching. That's a new setting that's not been previously described with iberdomide. Also looking at MRD negativity and deeper responses. We'll be looking at that data. The second data set is from not in the myeloma space, but the golcadomide data in NHL. They've got a study with newly diagnosed aggressive B-cell lymphoma. The pharmacology of that drug actually is much closer to cemsidomide in terms of deep tissue binding, similar regimen dosing, 14 days on, 14 days off. As you may know, we have pretty compelling data in PTCL. We're not developing it in NHL, but we do think it speaks to the broader opportunity with these next-gen degraders. We'll be looking at that data set as well.
Okay, wonderful. With that, time is up, so we'll go ahead and wrap. Andrew and Len, thank you very much for your time and the very interesting discussion. Thanks to everyone for logging in.
Thank you for the invite.
Thanks for having us, Tyler.
Take care, guys.
Yep, bye.