Perfect. All right, let's go ahead and get started. Next up, we have CEO of C4 Therapeutics, Andrew Hirsch. Thanks so much for joining us, Andrew.
Thanks for having us.
Yeah, of course. Let me just kick it over to you for an overview of the company, where things stand today, and then we'll go into some questions.
Yeah, great, so as many of you who know us or don't, C4 is a targeted protein degradation company. We're focused on leveraging that TPD science to create breakthrough medicines for patients in areas of high unmet need. We currently have two active clinical programs. Cemsidomide is an IKZF1/3 degrader. We recently presented data in IMS in Toronto, which is exciting, and I'm sure we'll get into that in a bit, so I won't give you the highlights there, but we're excited about moving that into the next phase of development, and we're on track to start that early next year. The other program is CFT8919. It's an EGFR L858R degrader. That's a phase one first-in-human study ongoing with our partner, Betta Pharmaceuticals in China, is running that study. It's been a really great year for the company. We've had strong execution. We've delivered across our programs, including our collaborations.
We delivered two development candidates to Biogen. One's been in the clinic. Another one we expect to go in shortly. We're working well with Roche. We're making great progress on the two additional targets there, as well as working with Merck KGaA on degraders in the KRAS family, and we recently financed the company, which provides us runway through the end of 2028, which enables us to execute the next set of clinical trials for cemsidomide, which I'm sure we'll talk in detail about.
Awesome. A lot going on. Yeah, let's start right off on cemsidomide. Maybe just recap the data that you did put out recently and kind of remind us of the trial design, too.
Yeah, yep. So the last data cut we presented at IMS was a September data cut. And that was a phase one dose escalation study. So pretty typical. Escalation is driven by BLRM versus 3+3 design, which I'm sure we'll get into, and that may cause some of the, not confusion, but some questions on data and DLTs, which I know we'll touch on. But we were really pleased to see that across all 72 patients in the escalation portion, this is with cemsidomide plus dexamethasone, we had an overall 36% ORR, and at the two highest doses, 75 mcg and 100 mcg, we had a 40% and 53% ORR, respectively. So we think really a strong profile, competitive with others in the class. In addition, at the 100 mcg dose level, we did see two CRs. One was an MRD negative CR.
The other, we don't know because the patient didn't consent to a biopsy, so we were unable to determine that. And at the data cut, our median duration of treatment was 9.3 months. Again, that's an immature data set. There's a lot of patients still on study, and so that will continue to evolve as time goes on. And the safety profile, we're really pleased with that, very differentiated. We didn't see any discontinuations related to safety, and only 6% of patients had dose reductions due to safety reasons. So we were really pleased with the profile of the drug, and that's why we're excited about advancing it to the next phase of development.
Awesome. I think one of the key points here is you enrolled a lot of prior BCMA CAR T- cell engager refractory patients. Can you just remind us how many patients were refractory, and what were the prior treatments that they had received?
Yeah, so most of the patients, in fact, 100% of the patients were triple-class exposed. So meaning they'd seen an IKZF1/3 degrader, one of the BMS products. They'd seen a proteasome inhibitor, and they'd seen an anti-CD38. In addition, 75% of the patients across the whole study cohort had either seen a CAR T or a T- cell engager therapy, which speaks to a more contemporaneous patient population than the others. Importantly, at the 100 mcg dose level, 16 of the 19 patients we enrolled had either prior CAR T or T- cell engager therapy. And the ORR that, frankly, we saw in those patients was no different than the ORR for the broad patient population. So very consistent response rate.
All right, great. And then at the 100 mcg cohort, there were three DLTs, I believe.
That's correct.
It's probably worthwhile just touching on the design.
Yeah.
Yeah.
Yeah. So I think, again, as I said, the misconception here is what constitutes MTD. When you use the BLRM method, Bayesian Logistic Regression Method, it actually looks at all of the data to determine whether you've hit or exceeded MTD, very different from a 3+3 design where you're only looking at the patients in that individual cohort. And so that's why the three of nine did not constitute exceeding the MTD or MDD at that point. So that's why I think people may look at that and say, "We don't understand why you didn't say that it is MTD or exceeded MTD.
Yeah, makes perfect sense. Awesome. It's probably worth calling out the adjudication of these AEs. Do you think these were all drug-related?
We don't, so there are two things to consider. A lot of these patients came on with progressive disease and a hematologic malignancy, and so by definition, these patients are immunosuppressed to begin with, and so there is some level of underlying immunosuppression at baseline. In fact, one of the patients had evidence of viral pneumonia at baseline. The other thing to note is that this dose, the 100 mcg as well as the 75 mcg dose, we enrolled it during cold and flu season, and so that also has an impact on the safety and the patient outcome, so it was determined that two of those were not drug-related to those viral bacteria cases.
Got it. Probably worthwhile to do a quick cross-comparison to mezigdomide and the other imids, especially given such a high response rate that you saw.
Yeah. I think the one thing that is really important is we were very happy about the response rate. If you think about comparing cemsidomide to mezigdomide with all the caveats of cross-trial comparisons, they had, at their highest dose and their phase one dose escalation, showed, I think, about a 55% response rate. We had a 53% response rate. So very, very competitive. I think from a tolerability perspective, that's where the real difference comes in with mezigdomide. They had very high levels of discontinuations and dose reductions due to safety, high levels of G-CSF use. I think the important thing is when you compare the baseline characteristics, it's a very different patient population. 100% of our patients were triple-class refractory compared to only 56% of theirs.
As I said earlier, 75% of our patients had seen BCMA-directed therapy, either CAR T or BiTEs, whereas only 12% for the mezigdomide patient population. Then we also saw, as I said, a 9.3-month median duration of response. I think they saw about a six-month, with the caveat that ours is still ongoing. But ultimately, we think it's a much more compelling profile, very, very competitive efficacy. What's really important is from a safety perspective, we did not see the same rates of neutropenic complications and infections that were seen in the mezigdomide phase one.
Yeah, great result. All right, maybe we can talk about kind of the go-forward cadence of updates. So as this study is still ongoing, number one, when do we get the next update? Is there any evidence the efficacy could keep deepening over time? And then also, you're pretty close to a phase 2 dose selection, I believe. Maybe you could just walk through that.
That's right. Yeah. So at this point, we don't have any plans to disclose anything updated from the phase one in terms of a medical meeting. We don't think there's any new questions to answer. We're really focused on advancing the next phase of studies. Maybe when the study is done, we'll put it together and submit a manuscript. But at this point, we don't have any plans for new disclosures at a medical meeting around the phase one. I think from a dose perspective, later this month, we'll have a meeting with FDA where we'll align on dose. And so that's probably the next update, potentially, as we start the next phase of studies. But that's really where we are. The team is working incredibly hard to get these studies ready to start enrolling patients and dosing early next year.
I think you had, especially for the 4L+ trial, before we talk about the combination earlier on, but for the 4L+ trial, I think you had a Type C meeting already?
We had a Type C meeting earlier in the summer. But that was really more of a high-level discussion around development plans and consultation around what we're thinking and getting FDA feedback. So we had that meeting, and the plan that we've shared is kind of what came out of that discussion and the feedback and the input we got from them.
Yeah. And I guess just given a lot of the news and headlines this year, what's your level of confidence that a single-arm study will be approvable here?
I think if we're continuing to show a robust, durable response rate in this patient population, I think there's a good chance, with the caveat that accelerated, they never will tell you a priori, yes, this will be accelerated approval, because accelerated approval is always given in the context of what's the then current standard of care when you submit the study. That's important. There's no guarantee. Certainly, it's not riskless. There is clear precedent. There's others, both in other indications as well as in the myeloma space, that have gone down this path of accelerated approval with a single-arm study with a confirmatory randomized study in an earlier combo regimen. To the degree that there's precedent there, we feel pretty comfortable. Of course, we don't know who's going to be at the FDA in 2028 when we show up with the data.
And so that's always a risk as well.
Yeah, I think that's well said. All right, so for the 4L+ study, what's your expected mix of prior T-cell engager CAR T patients? Any other characteristics that are worth calling out?
Yeah. So it's going to be a global study, right? And so there'll be some different characteristics based on geography. For patients that enroll in the U.S., we expect that everyone will be triple-class refractory. So they will have seen an IMiD. They will have seen a proteasome inhibitor. They will have seen a CD38. And we think in the U.S., a lot of them will likely have seen either a BCMA BiTE or a CAR T. But there may be some patients, because they're not eligible or they can't access those, where cemsidomide plus DEX will be their fourth-line treatment. As we think about Europe and other geographies, we think they'll probably have a fewer number of patients that have had prior CAR T or BiTEs, just because of accessibility. And we'll be watching the enrollment to make sure we have the right balance.
We're not pre-specifying, but we're going to make sure we have enough patients that are kind of post-BCMA CAR T in the study to be able to understand and look at that subpopulation.
Yeah. And keeping that patient population in mind, with that context, what's a good ORR outcome on this study?
Right now, the way we're thinking about it is when you look at the late line setting, we're looking at a background rate of about 20% response rate, and the study's power to show kind of a 20% improvement on top of that. 40-ish% is what we're looking for.
All right. That makes sense. Let's actually talk commercial quickly.
Sure.
What's your expected pricing in the setting? I was just pulling up some analogs recently. Xpovio is about $400,000 a year WAC. I just pulled up Elrexfio on the T-cell engager side. It's actually pretty close to that range. How do you think about the IMID pricing?
Yeah, so it's a little premature. We obviously have things that we've assumed in our models, but we're not ready to share that. But I think our goal is to price it competitively based on what we think the value is that the profile will bring to patients. But not prepared to share what that would be yet, but we think it'll be competitive in the space.
Yeah, and I guess this is partially a commercial question, partially a data question. What's your expectation on duration of treatment or duration of response here?
Yeah, I mean, I think when you think about a last line setting, typically, if you can achieve six months duration of response, that's a good outcome in that setting. As I mentioned, the data we've had so far, and again, it's moving because there's a lot of patients still on treatment, was 9.3 months. So I think if we can show kind of an improvement over six months, I think that's a real win. But we'll see as that data matures.
Awesome. All right, so let's shift gears here. Let's go to the bispecific combo opportunity in earlier lines. Just mechanistically, beyond your own preclinical data, if you could just summarize the evidence that cemsidomide actually will synergize.
Yeah, so I'd say there's two pieces of evidence. The most mature data is there's a study of Talvey plus POM. Talvey is the GPRC5D BiTE from J&J.
I think it's J&J, right?
Yeah. So they presented data that showed about an 86% ORR with 46% of patients achieving a CR or better, which compares to Talvey alone at 73% ORR with a 9%-13% CR rate. So that's the most mature data. There are, I think, three or four abstracts at ASH coming up this weekend that show combinations of IKZF1/3 degraders and BiTEs. And from the abstracts, it looks like there are improvements over the BiTE alone. We'll wait to see what that data looks like in terms of the detail when we see the posters of the presentations. But also, that's also supportive and kind of de-risks the approach. And then mechanistically, it makes lots of logical sense given the immune activation mechanism in addition to the anti-myeloma direct effect.
Yeah. And the way that the Elrexfio label reads, essentially, you can step down in dose over time or dose frequency, I should say, over time. How are you expecting to actually do this in a clinical trial? Would you just do it based on their label, or would there be some other dosing regimen to consider?
Yeah. So right now, the way the study is designed is we're not going to introduce cemsidomide because most of the BiTEs have a dose loading. So we're not going to introduce cemsidomide until patients are at the loaded dose. And they'll have cemsidomide on cemsidomide schedule, 14 on, 14 off each cycle. And then dexamethasone will be dosed once weekly through cycle four. And then we'll be using the Elrexfio dose that they're using in combination.
Okay. That makes sense. What are your expectations on the safety tolerability side of things, specifically on grade 3/4 neutropenia?
Yeah. I mean, I think that's the question we're going to answer in the study, and I think that's why we're eagerly looking forward to the data coming up this weekend to really get a read on what some of the others in the class look like in those combo settings. I think the grade 3/ 4 neutropenia is an important thing to look at because that is something that's an overlapping toxicity, but I think the most important thing that we want to be able to understand is we don't want to do anything to interrupt the BiTE dosing. That's the most important thing because there is no dose reduction strategy with the BiTE. It's dose interruption, and that's what we want to avoid, and so that's actually what we're going to be looking for.
If you look at some of the grade 3/4 neutropenia rates from the abstracts, it looks to be in the 60%-80%. But again, we'll look more closely at that this weekend.
And what do you think that the patient population, like prior treatments, are going to be for this study?
For our study?
Yeah.
It's going to be a second-line study.
Second line?
Yeah, or later. So that's the goal.
Okay. Makes sense. I guess zooming out, thinking about pipeline strategic financial considerations, you mentioned the EGFR side with your partner, Betta. They've been enrolling in China for a while. There's a lot of patients there.
I mean, it's only been a year. So that's about what a phase one looks like. So we're excited about that program. And I think we'll be in a position by the end of Q1 of 2026 to be able to make a decision on that program and does the data support advancing or not.
Yeah. I guess if you do make that decision, do you have a, and it might be a little bit early here. We'll have to see some data, right? But do you have a sense for kind of the capital requirements, what you would do for another study there? Is that still TBD?
It's still TBD. I think that's something obviously, that's not currently funded in our current runway. But we have some thoughts about what the development plan might look like. But we've been really focused on moving cemsidomide to the next phase of development while that study has been running with Betta. We've been involved in supporting them. But that's something that we'll start to think about once we kind of get cemsidomide the next steps up and running.
Perfect. You mentioned cash runway. Maybe you could remind us what that is and maybe more importantly, what milestones, especially from all the partnerships you listed, are or are not included there?
Yep, so our runway does not include any milestones from partners. We expect that there could be up to $40 million in milestone payments over 2026 and 2027 from the collaboration partners, but we've not broken that down by individual partner or program. Our cash runway, based on our recent financing, is through the end of 2028. What that will get us are data readouts from the phase two study that's the MOMENTUM study, is what we're calling it, and there's two data readouts from that. So we think sort of toward the end of 2027, we will have an ORR read, but that will be based on investigator assessment. The data for central assessment that we'll use for the agency will come later because we'll want to have some durability with that, and so that'll be a little bit later in 2028.
And then the phase 1b combination with Elrexfio study, that's a phase one, and we'll be able to update as we move through each segment of that study. We're going to be starting at 75 mcg. And then if that's deemed safe, we'll be able to expand at that dose, but also we could expand at 50 and then escalate to 100. So that could happen in parallel, but we'll be able to update as we move through each segment of that study. We think that we'll have the sort of completed data set from that study.