Okay, great. Thanks, everyone, for continuing to join us here at the Guggenheim Conference. My name is Brad Canino. Very happy to be sharing the stage for the next Fireside with C4 Therapeutics. We've got Kendra Adams, CFO, Len Reyno, CMO. Thank you so much for joining us.
Thanks for having us.
For having us.
Maybe just kick off with an intro of the company and a discussion around the status of cemsidomide and the rest of the pipeline.
Sure. I'm happy to start. So we are a company focused on TPD. We have a clinical pipeline which includes our lead program, cemsidomide. That is an IKZF1/3 degrader, so same class as drugs referred to as IMiDs or CELMoDs. That asset is moving into later-stage clinical development. We've got a phase II study which we refer to as the MOMENTUM trial. That's in the fourth-line setting plus in combination with dexamethasone. And we will be starting that trial this quarter. Len will give you a little bit more color commentary in terms of where we are operationally, but things are going well. We also have a phase IB study that we will start in the second quarter with cemsidomide. That's dosed in combination with elranatamab. We have a supply agreement in place with Pfizer.
We also have an EGFR degrader that's in clinical development in China being conducted by our partner, Betta Pharmaceuticals. We have a discovery pipeline and platform that consists of our wholly owned programs. We have a focus on inflammation, neuroinflammation, neurodegenerative conditions and diseases. That's our wholly owned pipeline. We do have a number of discovery collaborations. In the past, we've had active research collaborations with Biogen. Biogen is now advancing two C4 degraders. That's for IRAK4 and BTK. They're in phase I development now. We have ongoing collaborations with Roche. There's two targets that we're working on with Roche. We also have a collaboration with Merck KGaA in Germany.
Okay. And maybe just to double-click on that, because as cemsidomide is now moving into later-stage development, what is the emphasis and messaging that you want to have around the pipeline priorities of focus beyond cemsidomide?
Yeah. So clearly, cemsidomide is a key focus for us. But beyond that, I will say we're very excited about the progress we've made in terms of our discovery efforts. We've really put a lot of work and thought into the platform, where we take it, and some of the new pathways and targets that we're exploring. We have not shared a lot just yet, mostly for competitive reasons, but expect to hear from us over time. And we'll share a little bit more on that. And then the discovery collaborations and our collaboration with Betta, those are important parts of our strategy. And so with Betta running the phase I study for EGFR, we'll take that data in-house and we'll make a determination whether or not we trigger any U.S. clinical development. We'll also evaluate that in context of the evolving landscape. And then our discovery collaborations, right?
We will continue to advance those and bring those to places where certainly we hope those molecules to succeed in the hands of our collaborators.
Okay. Well, we'll dig into some of the cemsidomide data. But maybe just a high-level question to start, because we know it's a very potent molecule. And potency means high MRD negativity rates. And we just had the FDA's new draft guidance on MRD as a surrogate endpoint for myeloma. How could that help expedite development? How much do you really look at as an important factor? And maybe what is still outstanding in your mind in terms of the specifics of leveraging that?
Yeah. So we read with interest, as everyone else did, the guidance. It still remains a guidance that came out regarding MRD negativity. Top-line summary, it helps. I'll tell you why I think it helps in a moment. But I mean, clearly, any time the agency embraces a new endpoint that can be incorporated into a regulatory approval pathway, then you've got to say it helps. How does it help specifically? I think that in and I'll talk about cemsidomide in a moment. But in terms of the broad space, how does it help specifically? Obviously, multiple myeloma, notwithstanding it remains a fatal disease, it also remains a disease now with the advent of effective therapies where some of the time-to-event timelines are very long.
Immediately, when you can introduce an endpoint that can be determined earlier in a clinical trial that may be used for approval purposes, it's got to help. It helps patients, but it also helps companies trying to develop drugs to de-risk the drug quickly and ultimately get a label. One of the big unknowns with it is how is the MRD negativity rate going to map to a time-to-event rate? If you go back to I think I'm bad with the years now, but I think it was April 2024 when there was the thought leader meeting, one of the points that the agency made was that a lot of your data for MRD negativity is from old trials where it was not prospectively measured and where the assays used may not have been the same.
That gives us pause in terms of what to expect when we start to do it in contemporary trials. At a minimum, you're all going to have to start measuring it the same way. So fast forward now, two years later, where are we at? Well, we know that Bristol declared in September, I think it was, that their phase III trial with iberdomide met an MRD negative rate. We don't know what it is. It hasn't been reported yet. From publicly available things, it looks like it's mapped the reporting will be mapped to a PFS event rate. So I think we really don't know how it's going to play out, but I think it will play out asset by asset. How does it help us, which is the more important question?
It helps us because it gives us a tool to further describe efficacy early on in our development program. As you know, we have two centerpieces of our clinical development program moving forward. The first one is a non-randomized phase II trial, which has been branded as MOMENTUM, in fourth-line plus patients. That trial, we hope to establish a robustly determined efficacy signal for the regimen that really mimics what we did in our first-in-human study. Now, in a fourth-line plus heavily pretreated population, you don't expect a huge amount of CRs. We know from our first-in-human study, we did get some CRs, including an MRD-negative CR.
So in terms of making the case that this non-randomized trial supports accelerated approval, even if we only have a small number of CRs and we can say that they are MRD negative, that will build the confidence that the efficacy signal is suitable for accelerated approval. It's perhaps even more useful, though, in our other part of our program in terms of our full approval strategy is rooted on our combination with BiTE. And as Kendra alluded to, that trial is on track to start in the second quarter. And how we built that trial from the ground up, where we're combining cemsidomide at one of three doses with elranatamab, is that we will, from the start, any patient who gets a CR will test for MRD negativity.
So we will end up expecting that regimen to be highly effective, getting a signal early on and not just CR rate and MRD negative for CR rate. Why does it matter? Because we would anticipate then planning a phase III trial where there would be a predefined endpoint in that randomized phase III trial of an MRD negative signal determined at point X, all predefined, and that would potentially could present that data for accelerated approval in that trial. So we're really excited about it. I think all the people in the field are excited about it. But the one cautionary note I would say is that it is a guidance. And I would anticipate that each discussion will have to stand on its own merits.
We, though having known and expected this was coming, built our programs from the ground up to say, how can we take advantage of this to augment our case that cemsidomide is an approvable drug on the path to approval or getting approved?
Okay. And now investors will start to see a lot of data Phase III data from Bristol's iberdomide and mezigdomide over the next two years. What should we keep in mind about what those data do and do not suggest about the potential for cemsidomide?
So let's start at a high level. I think those data will provide a read-through on the promise of highly potent degraders. And so while they're our corporate competition, we wish them well. And we hope that the trials that they've designed will actually provide further emphasis that these highly potent degraders can create real value for patients and investors. That's the first part. The second part is that those trial readouts, the randomized trials, aren't really in competition with us. They were designed at a time when Bristol mapped the treatment patterns and what we presume to be a franchise maintenance strategy to get the drugs approved. And I think what we anticipate is at least some of those trials will be positive. And that's good for the field.
But the question that will remain to be seen whether those trials are positive in a practice-changing way when, for example, in the second-line space, we see a really pronounced emphasis of moving immune-based strategies into second-line, hence our cemsidomide strategy. So I think they'll help. They also will tell us and give us some benchmark data that is contemporaneous. And I keep coming back to that concept, is that when you plan pivotal trials, you need to plan pivotal trials in the population you have now, not the population you had 10 years ago. And so the more data we have on the performance of novel agents and novel drugs in the sort of close to contemporary population helps us plan better trials.
Okay. And now, what were the learnings? And how do you see cemsidomide positioned after the phase I to be able to move into these late-stage studies? I think that it's probably the fourth line is more clear. But what supports moving as a combination with TCE and kind of a more granular disclosure term?
Yeah. I think to answer that question, you first have to pull back a little bit and think about the mechanism. So the mechanism IKZF1/3 degradation is now well understood. And it maps to IRAK4. And that provides a direct anti-myeloma cell kill effect. So that's box one. And we've shown that in the most heavily pretreated population tested, 75% of our patients in first-in-human were post either CAR-Ts or TCEs. We showed as high as a 53% response rate. So what we're saying with that mechanism is, irrespective of where you are in the natural history of myeloma, this MOA is relevant. But the other thing that we showed is that at every dose we tested, that in fact, we also get a robust immune enhancement signal.
That immune enhancement signal is emerging as something of great interest in the field because really there's data to support the idea that will help any immune-based strategy be more effective in either the depth of response or the durability of response. And what we saw at ASH is actually some early provocative data that supports that. As you know, at ASH, there were a couple of trials presented, small trials, evaluating BiTEs with IKZF1/3 degraders, either iberdomide or mezigdomide. You can't draw broad conclusions from those trials except for the following thesis. One, they were relatively safe. So there wasn't a lot of new toxicity. And two, that the actual overall response rate was very high and approaching 100%, numbers too small to actually drill down to MRD negativity, et cetera. So we think that our data itself gives us the permission slip.
And where the space is going has really created a lane for us that really allows us to differentiate and to reemphasize the importance of IKZF1/3 degradation as part of novel immune-based strategies. The other thing that I think where we're unique in terms of the drugs ahead of us, iberdomide and mezigdomide, is the nature of our efficacy signal. And I talked about the immune enhancement is at all the doses we tested. But it's really important to note, well, it's always good to focus on the highest response rate in the highest dose level. We had an overall response rate in all these heavily pretreated patients, notwithstanding what dose any of them got as they went through dose escalation. Our overall response rate is north of 30%.
And so we have a very active drug from a purely antimyeloma effect at every dose we studied, peaking at 53%, potent immune enhancement, and the opening of the aperture, if you will, of the appetite to test immune-enhancing strategies in earlier line of therapy. So I think we're in terrific shape now in terms of prosecuting the asset and doing so successfully, but ultimately in a meaningful way. And by that, I mean creating data that supports labels that matter that will sell. Because you can get a label that no one's interested anymore because that's not where the field is. That's not really winning.
Okay. And we'll get back to what you're doing with these BiTE combos in phase I and II in a second. But first, on the pivotal in fourth-line, which is single-arm, let's talk a bit about the expected timeline it's going to take to generate those data. And what do you see as the efficacy threshold needed to support a single-arm approval in myeloma?
So obviously, let's start with the timeline first and then go to the second part after that. So we have an execution timeline that's focused on enrolling the patients in 12 months. And as Kendra alluded to, we're on track to meet that timeline and are busy opening our first sites and anticipating being able to share that we've dosed our first patients imminently. So that's the timeline piece. Now, that's enrollment. Things then have to happen for the patients to have events. And there's three events that we need in order to post-enrollment. One is, what's the response rate? Two is, what is the durability of the response? Or more correctly, what is the PFS of drug-exposed patients and responding patients? And three is, what is the safety signal? I'm going to start with three.
To get accelerated approval, you really need to have a very clean safety signal and not lose patients to, in particular, side effects that cause them to stop drug. Because if you're losing patients to side effects to stop drug, the agency is going to say, well, we can't evaluate really what's happening. So we need to mimic what we already showed. And that's exciting. In our ongoing phase I trial, we had a very low chance of patients having either dose reductions or dose cessation from cemsidomide. The bottom line, what do you have to see from an efficacy point of view, is obviously a moving target. Accelerated approval is always an assessment of the contemporaneous expectations of patients when you present the data.
How we built the trial, though, is to say, look, we anticipate in these very late-line patients that even if a regimen is not approved, that off the shelf, people are going to get at least a minimum of a 20% response rate. With 100 patients, we'll be able to declare that we're different than that, targeting at least a 40% response rate, which is actually less than our highest response rate. So we think that the 100-patient sample size, rigorously controlled, out of the gate, everybody being treated and dosed the same way, but also in terms of independently verifying the response, et cetera, that that will be an efficacy signal to make the case. Obviously, if it's higher than that, great. But if you end up getting a 20% response rate, realistically, I don't think you'd get accelerated approval on that.
In terms of our disclosures, we have shared that we would do an early read of response rate, which would be investigator-assessed within about a year of closing the study. The actual full regulatory endpoints are going to require longer follow-up. They'll be into 2028.
Okay. Very helpful. Okay. And then maybe, Kendra, if you can talk about the recent financing and how that was structured to enable you to pursue this development over the next couple of years.
Yes, of course. Two important elements of the financing. One was we did receive financing in the fall of last year. That pushes our runway to the end of 2028, so about three years of runway. That allows us to execute the studies we've been talking about. And then there is another component of it, which is potential additional funding, over $200 million, potentially that we could receive for two classes of warrants. That would allow us to move very quickly then from the phase I B that we've been discussing, as well as the phase II, into phase III planning. And so the structure of the financing was really both securing funding to do these studies and beyond that, so generating the data that Len has talked about, but also additional funding that then allows us to not only start but also execute some of the phase III.
Okay. Perfect. Now, on to the BCMA-TCE combo. Key functions and factors of how you designed that study, doses, patients you're looking at, et cetera, to make sure it's the most informative study?
Yeah. So as you know, we're partnered with Pfizer for drug supply. And Pfizer, as all the BiTE companies, have an interest in moving BiTEs into at least second line. And so they have a preexisting interest in that. And so do we. So the first part is that we'll take patients who are as second line or to fourth line. So we're trying to not prosecute the patient that is the accelerated approval BiTE population, but rather at two to four lines of prior therapy. So that's who are we treating? The next feature of the design is we really want to go fast. And we want to maximize our learnings from the data we already have. So this is not a first-in-human study for cemsidomide. And we have a lot of data about cemsidomide.
As a result of that, what we've chosen to do is to start at a dose of 75 and limit our dose selection steps to three doses, either 75, 100, one above, or 50, one below. We then looked at the data we have. Understanding the kinetics of how patients move through a first-in-human study, we designed it that, well, we'll start with 75, that we ensure that we have a large enough cohort so we can conclude reliably whether it's safe or not quickly. That gives us an opportunity to get rid of some of the outlier patient in terms of noise.
Then once we clear that 75 dose, then that gives us an opportunity to either escalate to 100 or to actually de-escalate to 50 or expand to 75. Which one will we do? We potentially will do all three. But we will also look at the data we have from a point of view of emerging characteristics, including efficacy, and see what's going to be the highest value for us in terms of emphasizing where we add patients. Because we want to get into a situation where within 18 months of opening that study, we pretty much nailed down what a dose is that we could consider for a phase III experiment.
Okay. And besides just the dose itself, are you thinking about different dosing strategies to account for some of the overlapping toxicity of these mechanisms?
So the dosing strategy for Elra comes to us from Pfizer. And they haven't disclosed. We've disclosed as much as we can in terms of what that is. We want to make sure that we take advantage of the unique characteristics of cemsidomide. So how we're doing this is that the Elra, there's a step-up dosing. That's without cemsidomide. Why do you do that? It's because you can lose up to 10% of your patients in step-up dosing just when they have an intrinsic sensitivity to ELRA. And they're not going to be able to be an ELRA patient. Then we introduce cemsidomide once you've cleared step-up dosing. The ELRA dose is fixed because we're not fiddling with the dose. And that fixed ELRA dose comes from Pfizer. And then we give them a 14-day dosing regimen of cemsidomide exactly as it was done in the phase I.
To your point, we then carefully looked at what are the preexisting side effects of ELRA that might be associated with what could be a DLT and what are the side effects of cemsidomide. And distinct from our first in-human study before, where there were some restrictions on supportive care, et cetera, there's no restrictions of supportive care, meaning ELRA patients will get the full supportive care for ELRA. And if patients have low counts that need G-CSF, they'll get that without restriction. And the way we've defined the safety endpoints reflect a realistic assessment of what's the preexisting safety profile of ELRA. Clearly, the one overlapping toxicity that we need to monitor carefully and that that will be a data-determined event, but we've thought about carefully, is that for persistent neutropenia, there are ELRA hold orders.
We want to make sure that we don't push a dose of cemsidomide that makes elranatamab hold happen. So a lot of moving parts. But in fact, the good news is keep coming back to what we already know. And what was helpful from the ASH meeting was the elranatamab and iberdomide data actually gives us a proof that they worked out some of the wrinkles, if you will, in terms of defining DLTs and how to do the dosing that we can now take advantage of. And we've thought very carefully how to map out DLT definitions and ensure we can deliver ideally both drugs per the intent.
Okay. And then what updates do you expect to provide investors as this trial advances through these different dosing cohorts?
We recognize there's tremendous interest in the progress of that study. We also recognize that that interest is going to supersede us being able to hold all the data to present a big splash at a medical meeting. What we've committed to is that we will give reasonable top-line updates as we progress this year. Obviously, the first one, I think, to think about would be when we've completed the first cohort and followed them adequately for safety, then we would anticipate giving a report on that. It's probably via a press release mechanism, maybe with one of our quarterly earnings, but a top-line summary. Obviously, we will eventually present the full data in a medical meeting. There's a lot of interest from a lot of parties in how we make out with this.
We will share the data as much as we can on the top line as it's generated.
Is there a timing component to the first preview yet? Or is that TBD based on enrollment execution?
TBD. As you know, when you start a study, there's two things happening at once. You're opening sites. They don't all open on the same day. And so sometimes it takes a little longer to recruit your first cohort than subsequent ones, which occur when you have more sites open. So we haven't guided to the specific timing. But as soon as we can, we will certainly guide. And we will share when we've dosed our first patient, meaning dose them with cemsidomide, not the step-up dosing. And we'll share when we finish that first cohort.
Okay. Great. Well, it's been great to see all the recent progress. We are, unfortunately, out of time. But Len, Kendra, thank you so much for joining us. And thanks, everyone, for listening in.
Thank you for the.