All right, so welcome to this next fireside chat with C4 Therapeutics. My name is Michael Schmidt, and I would like to welcome the management team here, starting with Andrew Hirsch, CEO. Andrew, for investors who are just getting to know C4, what is the core idea behind cemsidomide, and how does it differ from other cereblon-based drugs in myeloma?
Yeah. Thanks for having us. So first, for those of you who are unfamiliar, cemsidomide, it is a cereblon-modulating protein degrader of two transcription factors, IKZF1 and three, which are critical in multiple myeloma. In fact, they are foundational biology. Our vision for cemsidomide is to become a backbone therapy for myeloma across the evolving landscape, and it is really based on the fundamental MOA, which is really, there are two mechanisms. The first mechanism is around plasma cell proliferation. It blocks that. The second and equally critical mechanism is immune cell expansion and activation, and that is critical in the evolving landscape. How cemsidomide differs from others in the class is really around its pharmacology.
It has a longer half-life, it is less protein-bound, and that enables us to dose in a different schedule, much lower doses, which manifests itself in a differentiated safety and efficacy profile, which we think gives it a potential for a best in class across all of the next-generation cereblon-modulating degraders.
Okay, great. I will get back to the landscape and how it fits in, but first, just wanted to touch on the data that you have presented so far and talk about that and how much confidence it perhaps gives you in the clinical profile so far.
Yeah. Leonard, you want to tackle that?
Yeah, sure. I've been doing this a long time, and I've had the privilege of working with a lot of drugs that are now successful. cemsidomide has, in my view, the most robust de-risk proof of concept safety signal, certainly of the class, but of many drugs to come along, and let me give you the evidence for that. Andrew alluded to this in his first comments. cemsidomide was built from the ground up to be a better molecule, and the clinical data supports that thesis. How does it support the thesis? We can start with the top-line summary, that in a first-in-human study where we treated 72 patients with cemsidomide plus dex, we have an overall response rate of 53% at the highest dose level, which is our RP2D, 100 mcg, 40% at the next dose level.
Impressively, we have a 36% response rate regardless of what dose they saw in the study. Importantly, that response rate signal is differentiated in the class in terms of early development, because fully 75% of our patients in that first-in-human study had either had CAR-Ts or BiTEs or both. This is an incredibly important clinical signal in the most contemporaneously refractory population to date. That signal would be not so impressive if it wasn't also associated with the most impressive safety signal in the class. Importantly, this class of drugs, the reason for the break in dosing is they all must be given a break in dosing because of the neutropenia, and more importantly, neutropenic-associated side effects. But with the 14 days on, 14 days off dosing, we also have, in fact, notwithstanding the clinical potency, we actually have the most favorable safety profile.
In particular, we have the lowest rate of Grade 4 neutropenia. We have the lowest rate of G-CSF use. This is really crucial in conversations we had today. If you look at early drug development, you're trying to predict future success in larger-scale studies. We have very, very few dose reductions or dose delays. In fact, you can deliver cemsidomide on schedule with the lowest need for G-CSF and the most modest neutropenic signal. Taken together, that's the sort of thesis for what we're building on. How we're building on that is obviously in our next generation of trials, which we can talk about, which exploit both the direct anti-myeloma effects, but also importantly address the issue that Andrew brought up in terms of the secondary mechanism of action of immune enhancement.
I think one way of describing the molecule has been sort of the efficacy of mezigdomide with the safety of iberdomide, sort of having that best of both worlds combined in one molecule. Can you talk a bit about how you approach dose selection between the 100 mcg and the 75 mcg dose?
Sure. Let's talk about it in two ways, because there's two questions. There's how to use it with dex as a late-line refractory drug, and then potentially how to combine it with other drugs in the class, which is also equally important. Let's do the late line first. One of the things that we've done with our dataset is we really have an incredibly powerful dataset, both in the points of dose effect and outcome, but we also have a pop PK model. That model doesn't get much attention, but it actually was disclosed and published as a poster at the American Conference on Pharmacometrics meetings last October. What does the model show? The model shows for cemsidomide, unequivocally, that you are going to get higher rates of anti-myeloma control with higher exposures. That's not rocket science.
But it pushes you to give the highest dose possible to get there. But what's in that model, which is the differentiating piece, is over the range of doses we tested, there's only a very modest increase of cemsidomide's risk of neutropenia as you got to higher exposures. It goes up a little bit, but it does not dramatically go up. It's statistically a very weak correlation. So why does it matter? It gets back to the original thesis. You've got potency with safety. So, when we made the case for our recommended phase II dose, because we also don't have dose reductions and we don't have patients coming off for safety events, we discussed and got alignment on a dose of 100 mcg as the dose for late-line refractory.
Now, that dose may end up being the combination dose, but as you know, you have to, in a combination thesis, usually you start out by saying, "I'm going to go at least one dose lower." We've done that, and we've actually shared the top-line outcome of that with their combination with elranatamab, a BiTE. What's that top-line number, the thing that we shared? It was a press release at IMS. We cleared 75 mcg for safety, and now we've escalated back up to 100.
Okay.
But the unique piece of the 75, which is already differentiating, is 75 mcg, remember I told you, that's a 40% response rate. So, we've already been able to give a dose that has a 40% response rate in late-line refractory, including BiTE refractory, cleared it for safety, escalated, and are now expanding at 75. So we'll have a more detailed discussion about the combo dose for things that aren't dex, but we're off to a really, really good start, which is already differentiated from some of the other communications that have come out for combinations with BiTEs for the class of drugs.
Right.
Yeah, I think just to build on that, I think what Leonard was referring to is if you look at the mezigdomide experience in combination with elranatamab, they've had to dose reduce down to 0.6 and 0.3. We've cleared 75, and we're escalating. That, to me, is a very stark differentiating fact just off the bat.
Right. So we'll come back to that combo opportunity. But maybe first, just the fast-to-market opportunities, obviously, as a monotherapy over the dex combo, I guess, in late line in the MOMENTUM study. So maybe just talk about how enrollment has been going, and perhaps how the patient characteristics compare to the phase I experience in the MOMENTUM study.
Sure. So we've guided that that study will be finished enrollment in the first quarter of 2027, and we certainly have no reason to change that guidance. Been excited about the execution of that study because, in fact, it represents for us really expanding our operational footprint. So we did our original first-in-human study, U.S. only, but 13 centers of excellence. We've expanded the MOMENTUM clinical trials operating group to be up to 60 sites, including sites in the U.S. as well as the U.K. and Western Europe. So out of the gate, we're now broadening the population of prescribers. We were careful when we designed the trial to make sure that the trial was of interest to as many prescribers and trialists as possible. So in that regard, we didn't change the eligibility criteria fundamentally. So it includes the same eligibility population.
They're essentially fourth line plus or third line plus. We anticipate many of those patients in this trial are going to end up having been BiTE exposed and CAR-T exposed. We didn't want to have it completely only those patients, because there's a need, and this speaks to the ultimate commercial opportunity. The idea that every patient with refractory myeloma is lining up to get a BiTE or a CAR-T is only true at the podiums of major medical meetings. We know from the research we've done and in talking to community docs and knowing the penetration of drugs into the community, multiple myeloma at its core is a disease of older persons, and we think there is a real need for simple-to-give all-oral regimen as well.
We've continued to include those patients, and we think the value of the late-line MOMENTUM signal is going to be biggest for both patients and ultimately commercial value by including both of those groups.
Right. Most approved multiple myeloma drugs have achieved their initial approval in a similar context.
Yeah.
I guess, what is the efficacy bar now, do you think, that would support accelerated approval in this setting?
The efficacy bar, it will be high enough. I am not being facetious. When you actually go forward with a proposal to get accelerated approval on a non-randomized trial, that data is by definition interpreted in the context of what the prevailing outcomes are expected to be for that type of patient at the time you present it. By definition, if we present this data to the agency in 2028 or beyond, or probably 2028, then what is the efficacy bar? Well, when we originally started talking about this, we had people saying, "Well, you have to beat the CAR-T." No, you do not, because those things are not late-line drugs anymore. They are actually migrated back appropriately into second line, if not sometimes first line. We will be judged by our contemporaneous peers.
Now, what is clear, that judgment will include a recognition that, in fact, off-label use of lines of therapy is always going to be associated with a response rate. For argument's purposes, we have assumed that that response rate would be at least as high as 25%, and we need to get an efficacy signal that is interesting beyond that background. We have targeted at least 40%, but we are hoping to get more. But it is important that response rate alone is not the bar. The other components of the accelerated approval bar are obviously duration of response, but safety, safety. In that regard, the agency will be looking for a drug that you can give without dose modification or without stopping therapy for safety.
Again, going back to when I started off by saying this is the drug with an incredibly robust proof of concept, the pieces that really drive that are not just the response rate, but the fact that we are able to give it without a lot of dose reductions, dose interruptions, and we do not have patients coming off for safety.
Right. I think you guided to presenting initial investigator-assessed data in the second half of next year. Just help us understand how substantial that update will be relative to the final investigator, the independently assessed data.
Yeah. First of all, we expect in this disease that investigator-assessed response and the independent response will relatively mirror each other. There may be some differences on the margins, but they should be pretty close. That said, the agency is only going to consider the independent response criteria, and the agency will not consider response criteria without associated safety as well as duration. By looking at investigator-assessed response, it gives us an opportunity to look at an early read of the signal, and we can look at it once the whole trial has been recruited and enough patients have been followed for the purposes of establishing a response and getting data clean to actually comment on it. That brings us into the second half.
So we think it will be a good read on whether or not the data is actually behaving in a way consistent with the a priori expectations, and bode well for us to be able to put together the full package to apply for accelerated approval consideration.
Okay, great. So as you mentioned, the combination with BCMA-targeted bispecific antibodies is obviously a unique development opportunity that, based on the profile, is perhaps something that is uniquely attractive to C4 Therapeutics. So maybe first help us understand, so there are a lot of moving parts in the myeloma landscape right now. We have seen more registration data come out on BCMA bispecific antibodies, IMiDs as well. So, where does a combination like that fit into the landscape?
So the landscape is evolving, and the evidence for that evolution of the landscape thinking is really started really with a vengeance, if you will, about almost two years ago when thought leaders started pointing out that, why are we saving our drugs that have the highest response rates and the most interesting durability things to late line? That has been pushing immune-based strategies earlier and earlier. With the advent of positive trials now in second line, and we had the Pfizer press release just last week or two weeks ago, looking at Elra in a second-line drug, there is really firm migration of BiTEs into at least second line and maybe eventually first line.
Now, that said, that is occurring, and at the same time that that's occurring, there's a lot of people making the valid point that if you look at CAR-Ts versus BiTEs, CAR-Ts, if you're able to give it, overall probably do have the highest response rate, and some people are adamant that that's the drug of choice or the modality of choice. So there's a great opportunity there to build on that conversation of second-line interest with immune-based strategies, and frankly, to make BiTEs look more competitive with CAR-Ts in that first decision-making. So how do you do that? You get the BiTE response rate up, including the MRD-negative CR rate, and that you, in the long run, you build on the durability and the depth of response.
The combination of cemsidomide with a BiTE fits that nicely, and particularly, we're uniquely positioned to benefit from the dual MOA, because as you pointed out already, we can give cemsidomide at a dose that has a 40% response rate, which has already differentiated us from mezigdomide and iberdomide in that space, and drive that to higher quality responses faster. I'll end by saying that, what we just talked about, that evolution of thinking in second line, that's really been sort of documented in changes in practice guidelines that were released last week by ASCO, and that is that second-line patients with refractory myeloma should first and foremost be considered for a BiTE-based regimen or CAR-T. So, we've been really predicting this was going to happen for a while, because we obviously didn't develop our development plan in the last three months.
We're really reassured that the field has evolved over the last year and a half to exactly where we thought it would be to give cemsidomide the best opportunity for success.
As far as I know, no one else is pursuing an IMiD-BiTE combination in a regulatory study so far. Is that correct?
At this time, we've not.
There's some phase I studies and there's a co-op group study, MELT-MM, out of South Korea. That data was very encouraging for us because it sort of, from an efficacy perspective, gave proof of concept. As I mentioned earlier, those were at MEZI doses meaningfully below the recommended phase II dose. There was definitely some safety signals in that combination.
Right. Maybe then just go back to your own study. You mentioned earlier already, you cleared the 75 microgram dose. Where are you right now with this study, and what should investors expect next year as you plan to update this?
Yeah. As we announced at IMS, we've cleared 75. We've escalated to 100 mcg in an escalation cohort and also expanded an expansion cohort at 75 mcg. We've guided to data mid-year 2027 from that study, from all the cohorts that we've evaluated.
You said you are looking at MRD negativity and MRD-negative CRs as key readout. I guess, what is a good outcome here?
Well, again, we want to be cautious about the confidence that you will have in small sample sizes and putting confidence bars on the MRD-negative signal. That said, we know that the MRD-negative signals CR rate in second line for drugs to be of interest right now need to have a MRD-negative CR rate of at least 40%. We are able to model that, and we have now the data coming out at ASH from Elra. I think it is at 47% in the abstract. So, we can model a delta on that we can achieve in a phase III study, that then should map, or not should, will map to a PFS advantage.
It is important to note that we all know that Iber got approved with a MRD-negative CR rate for accelerated approval in the summer, and we are going to ride that process for seeking in our phase III, use MRD-negative CR as predefined in the protocol for consideration of accelerated approval in that phase III. Then use time to event in the same trial to get full approval. Importantly, at least for investors to know, is that that trial would also, if we get accelerated approval with MOMENTUM, would convert MOMENTUM to full approval as well.
Right. Yeah, maybe expand on your potential registration strategy some more and how your combination would be positioned relative to the other studies.
Combination?
The-
The Elra combination?
Yeah, correct. Yeah.
Yeah. I think if you look at the other studies and the BMS studies in particular with their portfolio, they're taking a very different strategy than we are. They're developing and generating labels that effectively replace their IMiD franchise, kind of in the current treatment setting and treatment algorithms. We've taken a very different approach. As Len mentioned, we've looked at where we think the market's evolving, and that's to bring immune-directed agents into earlier lines of therapy. Our positioning of cemsidomide is in that realm, is leveraging both that anti-proliferative effect, but also the immune stimulation activation effect to augment the efficacy of those in combination, which we think is really a strategy that goes where the market's heading versus where the market was.
Makes sense. I think you're planning to start a Dara carfilzomib combination as well, next year. Maybe talk about those plans and how that might fit into the landscape.
Yeah. So we're embarking on additional phase I-B work. One of our primary thesis for cemsidomide, it's a combination partner of choice. In order to make that a reality, we need to show some combination data, and the most important bit of combination data we need is a predictable dose to combine with other agents. So, although those trials are not efficacy-seeking trial, the trial will actually begin to establish that, in fact, the safety profile and the 14-day on, 14-day off schedule provides an opportunity for an easy-to-combine drug of the potent degrader class, which, again, we feel strongly we are the best in that class. So that's really to build the overall thesis that cemsidomide is your drug of choice, and here's how to combine it.
Great. Anything that's coming up at ASH that you're particularly paying attention to as it perhaps reads through to your pipeline?
Yeah, I mean, certainly there's a combination data with elranatamab with both mezigdomide and iberdomide, and I think that's going to be an important data set. We think it'll be, at least the mezigdomide data should be consistent with the MELT-MM study that was presented at IMS. There is the Elra mono data in second line, and then the EXCALIBER data that we're looking at the full data presentation there.
Great. Then maybe in the last couple minutes, just a question on the platform capabilities, and maybe talk about how you're looking to leverage that to create value for investors.
Yeah. The platform is really important because it does two things. Obviously, it generates a future pipeline, but it also enables us to bring in non-equity dilutive capital through collaborations, and that's a mechanism we've used from the very beginning. Back when the company was founded, we had a collaboration with Roche that really helped get the company off the ground and running. That's something that's critically important. Our platform now is focused less in oncology than really, we focused it really on inflammation, neuroinflammation, and neurodegeneration, based on some work that we've done in terms of thinking about what does our platform do that's unique, and then where's the best place to leverage it.
We always look for targets where there's a strong degrader rationale, why the world needs a degrader against that target, and then how can we generate clinical proof of concept in a capital-efficient way. We're very excited about the potential and the targets we're working on. At this point, we're not ready to disclose them, but we're making great progress.
Great. Then maybe longer term, any partnering plans for Selinexor, or are you planning to take that forward on your own for now?
Yeah, I mean, look, at this point, we're focused on building value and advancing Selinexor in the clinical development path that we have identified and already created. That said, I'm always a believer that if we can do more in collaboration with someone than we can do on our own, it's something we should absolutely look at. If that opportunity presents itself, we'll certainly evaluate it. But until that does, we're very focused on advancing it in the development path that we've laid out on our own for now.
Great. Well, thank you so much. I think we will wrap up here, but looking forward to hearing more about Selinexor in the near future.
Great. Thanks for having us.
Great. Thank you.
Thanks for the questions.