GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - C4 THERAPEUTICS INC

All right, so welcome to this next Five-Side Chat with C4 Therapeutics. My name is Michael Schmidt, and I'd 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 simcitamide, and how does it differ from other cerebron-based drugs in myeloma? Yeah, thanks for having us. So first, for those of you who are unfamiliar, simcinamide, it's a cereblon-modulating protein degrader of two transcription factors, IKZF1 and 3, which are critical in multiple myeloma. In fact, they're foundational biology. And our vision for simcinomide is to become a backbone therapy for myelomacross the evolving landscape. And it's really based on the fundamental MOA, which is really, there's two mechanisms. The first mechanism is around plasma cell proliferation. It blocks that. But then the second and equally critical mechanism is immune cell expansion and activation. And that's critical in the evolving landscape. How simcinamide differs from others in the class is really around its pharmacology. It has a longer half-life. It's 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 cerebrum modulating integrators. Okay, great. So I'll get back to the landscape and how it fits in, but first just wanted to touch on the data that you've presented so far and, you know, talk about that and how much confidence it perhaps gives you in the clinical profile so far. Yeah, so Len, do you want to tackle that? Yeah, sure. So, you Know, 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. Simcidamide 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. Simcitamide was built from the ground up to be a better molecule, and the clinical data supports that thesis. So how does it support the thesis? So we can start with the top-line summary, that in a first-in-human study where we treated 72 patients with simcinamide plus dex, we have an overall response rate of 53% at the highest dose level, which is our RP2D, 100 micrograms, 40% at their next dose level. But impressively, we have a 36% response rate, regardless of what dose they saw in the study. but 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. So this is an incredibly important clinical signal in the most contemporaneously refractory population to date. That signal would be not so impressive. it was 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, neutropene-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. And in particular, we have the lowest rate of grade 4 neutropenia. We have the lowest rate of GCSF use. And 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 had very, very few dose reductions or dose delays. So in fact, you can deliver simcitamide on schedule with the lowest need for GCSF and the most modest neutropenic signal. So taken together, that's the sort of thesis for what we're building on. How we're rebuilding 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, you know, one way of describing the molecule has been sort of the efficacy of mesictomide with the safety of iberdomide, sort of having that, you know, best of both worlds combined in one molecule. Can you talk a bit about how you approach dose selection between the 100 and the 75 microgram dose? Sure. So 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 data set is we really have an incredibly powerful data set, both in terms of dose effect and outcome, but we also have a POP-PK model. And that model doesn't get much attention, but it actually was disclosed and published as a poster at the American College of Pharmacology meetings last October. What does the model show? The model shows for simcinamide unequivocally that you are going to get higher rates of anti-myeloma control with higher exposures. Well, 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, it. There's only a very modest increase of samcinamide'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 two dose, because we also don't have dose reductions and we don't Have patients coming off for safety events, we discussed and gut alignment on a dose of 100 micrograms as the dose for late-line fracturing. 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. And we've done that, and we've actually shared the top-line outcome of that with their combination with L-renatinib, a bite. What's that top- line thing that we shared? It was a press release at IMS. We cleared 75 micrograms for safety, and now we've escalated back up to 100. But the unique piece of the 75, which is already differentiating, is 75 microograms. Remember I told you that's a 40% response rate. So we've already been able to give a dose that has a 40 percent response rate in late line refractory, including bite refractory, clear it for safety, escalate it, and they're 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. Yeah, I think just to build on that, I Think what Len's referring to is if you look at the mesignamide experience in combination with L-renatumab, they've had to dose reduce, you know, 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, you know, monotherapy over the DEX combo, I guess, in lay line in the momentum study. So maybe just talk about how enrollment has been going and how perhaps how the patient characteristics compare to the phase one experience in the momentum. 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.K. 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 prescrivers 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, but we anticipate many of those patients in this trial are going to end up having been BITE-exposed and NARC-RT-expose. We didn't want to have it completely only those patients because there's a need, and this speaks to then 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 talking to community docs and knowing the penetration of drugs into the community, myelomah, at its core, is a disease of older persons, and we think there is a real need for a simple-to-give all-oral regimen as well. So 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. And the most approved myeloma drugs have achieved the 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 is it will be high enough, and I'm not being facetious. When you actually go forward with a proposal to get accelerated approval in 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. So by definition, if we present this data to the agency in 2028 or beyond, or probably 2028, then what's 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 don't, because those things are not late-line drugs anymore. They're actually migrated back appropriately into second line, if not sometimes first line. So we'll 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've assumed that that response rate would be at least as high as 25%. And we need to get an efficacy signal that's interesting beyond that background. So we've targeted at least 40%, but we're hoping to get more. but it's 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, safety. In that regard, the agency will be looking for a drug that you can give without dose modification, without stopping therapy for safety. So again, going back to when I started off by saying this is a 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're able to give it without a lot of dose reductions, dose interruptions, and we don't have patients coming off for safety. Right. And then 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, as the independently assessed data. Yeah. So, 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 cleaning to actually comment on it, and 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. And so, as you mentioned, the combination with BCMA targeted by specific antibodies is obviously a unique development opportunity that, you know, based on the profile, is perhaps something that is uniquely attractive to C4 therapeutics. And so maybe first help us understand, so there are a lot of moving parts in the myeloma landscape right now we've seen more registration data come out on BCMA by specific antibodies image as well and so where does a combination like that fit into the landscape so the landscapes evolving and the evidence for that evolution of the landscape thinking is really started really with the vengeance if you will about almost two years ago with slot 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. And 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 LRAD in a second line drug, there's really firm migration of bites into at least second line and maybe eventually first line now that said that that 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 t's versus bites car t's if you're able to give it uh overall probably do have the highest response rate and some people are adamant that that the drug of choice or the modality of choice so there's a great opportunity there to to build on that conversation of second line interest with immune-based strategies and frankly to make bites look more competitive with car t's and 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 all long run you build on the durability and the depth of response and so the combination of some cinnamide with a bite fits that nicely and particularly we're uniquely positioned to benefit from the dual mechanism of action because as we pointed out already we can give some cinamide at a dose that has a 40 response rate which has already differentiated us from the zygdomide and iberdomide in that space and drive that to higher quality responses faster and i'll end by saying that you know 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. But 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 Stamcinamide the best opportunity for success. And as far as I know, no one else is pursuing an IMiD-bite combination in a regulatory study so far. Is that correct? You guys could present? At this time, we've not. At this point, no. There are some phase one 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, but as I mentioned earlier, those were at Mezzy doses meaningfully below the recommended phase two dose, and there was definitely some safety signals in the collaboration. Right. So 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 the study, and what should investors expect next year as you plan to update this? Yeah, so as we announced at IMS, we've cleared 75. We've escalated to 100 micrograms in an escalation cohort and also expanded an expansion cohort at 75 microgramms. We've guided to data mid-year 2027 from that study, from all the cohorts that we've evaluated. And you said you're 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'll have in small sample sizes and putting confidence bars on the MRD-negative signal. That said, we know that the MRRD-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%. And we're able to model that, and we have now the data coming out of ASH from ELRA. i think it's at 47 in the abstract so we we can model a delta on that um that we can achieve in a phase three study uh that then should map on that should will map to a pfs advantage so it is important to note that that you know we all know that iber got approved with a mrd negative cr rate for accelerated approval um in this summer and and we're going to ride that that that process before seeking in our phase three, use MRD negative CR as predefined in the protocol for consideration of accelerated approval in that phase three. And then use time to event in the same trial to get full approval. But importantly, it's 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 strategies some more and how your combination would be position relative to the other studies. Combination? The ELRA combination? Yeah. Correct. Yeah. Yeah. So I think if you look at the other study and the BMS studies in particular with their portfolio, you know, they're taking a very different strategy than we are. 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 looked at where we think the market's evolving, and that's to bring immune-directed agents into earlier lines of therapy. And so our positioning of samcinamide is in that realm, is, you know, leveraging both that anti-proliferative effect, but also the immune stimulation and activation effect to 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 mark was. Makes sense. And I think you're planning to start a Dara-carfilzomib combination as well next year. Can you talk about those plans and how that might fit into the landscape? Yeah, so we're embarking on additional Phase 1b work. One of our primary thesis for simcinamide, 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. And so, although those trials are not efficacy seeking trials, the trial will actually begin to establish that, in fact, the safety profile and the 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. That's really to build the overall thesis that simcitamide 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 L-renatamab with both mesignamide and abartamide, and I think that's going to be an important data set. We think it'll be, at least the Mazignomide data should be consistent with the MELT-MM study that was presented at IMS. You know, there is the El Romano data in second line, and then the Excalibur data that we're looking at, the full data presentation there. Great. And then maybe in the last couple of 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, so the platform is really important because it does two things. Obviously, it generates a future pipeline, but it also enables us to bring in kind of non-equity dilutive capital through collaborations, and that's a mechanism we've used from the very beginning. You know, back when the company was founded, we had a collaboration with Roche that really helped get the company kind of off the ground and running. And so 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? So we're very excited about the potential and that the targets are working on. At this point, we're not ready to disclose them, but we're making great progress. Great. And then maybe longer term, any partnering plans for some cytomide, 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 some cytamide in clinical development path that we have identified and are committed. You know, 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. And so, you know, 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 on for now. Great. Well, thank you so much. I think we'll wrap up here, but I'm looking forward to hearing more about samcidamide and in the near future. Great. Thanks for having us. Thank you for the question.