C4 Therapeutics, Inc. ($CCCC)

Good morning, everyone. Welcome to Barclays 28th Annual Global Healthcare Conference. I'm Etzer Darout, Senior Biotech Analyst at Barclays. It's my pleasure to have C4 Therapeutics with us this morning to kick us off. I have Andrew Hirsch, CEO; Len Reyno, Chief Medical Officer from C4 Therapeutics. And Andrew, maybe you can just get us going with just an overview of C4 Therapeutics and then the upcoming milestones that you think are key and are worth noting to investors?

Yes, absolutely, and thanks for having us. It's great to be here. So for those of you who are not familiar with C4, C4 is a targeted protein degradation company. And we use our degradation platform with the goal of developing medicines in areas of high unmet need. We have 2 programs currently in the clinic. Our most advanced is Cemsidomide, and I'm sure we'll spend some time talking about that today. That is an IKZF1/3 degrader, that's targeting in development for multiple myeloma. Last year, we completed a Phase I study, and we've now started the next phase of development. We started a Phase II study called MOMENTUM. We started dosing patients last month, and that's underway and enrolling. And then we expect to start in Q2, a Phase Ib study in combination with elranatamab, which is the BiTE from Pfizer, and we're excited to get that underway. And so that forms the basis of what we think is an exciting and differentiated registrational path. The other program we have in the clinic is a CFT8919 that's an EGFR L858R degrader for non-small cell lung cancer, that's in a Phase I study in China run by our partner, Betta Pharmaceuticals. And we expect to have data this month that will enable us to make a decision on the path forward for that program. In addition, we have a robust discovery effort that combines both internal programs as well as collaboration programs. Our internal programs are really focused now on an area sort of outside oncology, we're focused on inflammation, neuroinflammation, neurodegeneration, we call out INN, and we're excited that really leverages some of the key elements of our platform as well as 10 years of learnings of degraders and what degraders can and can't do. And then in addition, we have collaboration partners. We're working with Roche, with Merck KGaA and with Biogen on developing degraders against targets of interest for them and more recently, Biogen has 2 molecules in Phase I that we've delivered as part of that collaboration. And then we have a strong balance sheet. We ended the year with just under $300 million, which provides us runway through the end of 2028, which should get us though a number of important milestones, including an early look at data from the MOMENTUM study, which will be in the second half of 2027. And then through the Phase Ib and start-up of a potential Phase III with the BiTE combination. So lots of exciting milestones coming up is really a key year of execution as we get these studies underway and launch the cemsidomide development plan as well as pursuing our Discovery targets.

Great. Lots going on in multiple myeloma, obviously, even yesterday, we saw an update success 2 trial from Bristol-Myers Squibb. Just maybe give us some projective in terms of what cemsidomide could deliver to sort of the multiple myeloma disease armamentarium and what you believe is achievable with that molecule? And maybe highlight as well some of the data that you've generated to date there as well?

Yes. Maybe I'll start at a quick high level and Len get into some of the data. Look, I think the IKZF1/3 pathway for multiple myeloma is foundational. I think that's lost on a lot of people because these are targets that have been drugged through the IMiD class, which we've had for a long time. But if you remember, the IMiD class are not optimized degraders. In fact, when they were discovered we didn't know that they were degraders. And now that we've learned that they were degraders, we're able to develop and optimized degrader. And so we think that cemsidomide has a potential best-in-class profile based on the data that we shared last year. And that's based on the fact that we've really optimized both the catalytic activity as well as the selectivity and PK of the molecule. I think it gets lost on people that we're dosing in micrograms. People seem to forget that, which is incredible to me that we're able to do that. Len, I don't know if you want to...

Yes, I don't know if I could build on that because, obviously, people are interested in the evolution of the myeloma space and it's undergone a fundamental disruption with the advent and the penetration of immune-based strategies. But it's a really important part to map back to what Andrew just said. IKZF1/3 degradation remains a fundamental mechanism of action. And it's really important to think about what that actually means in practice. And in that regard, our first-in-human study is incredibly informative because what we show in that study where we had patients who had a median of 7 lines of prior therapy. In fact, 75% who have been exposed either to CAR-Ts or T cell engagers or both. We showed that at our highest exposure, we still had a 53% response rate. Why does that matter? It matters because what it tells you is notwithstanding all the other things the patient has been through, there remains a foundational role for targeting these transcription factors, mapping back to IRF4. So that's sort of the top line summary of the trial, but why are we positioned for success is, I think, really important to both patients and investors. What's unique about our data set is that we were able to show really very elegantly that at every dose level we tested with dexamethasone, we had meaningful anti-myeloma responses with a very manageable and class-leading potentially safety profile. Why maps back to what Andrew just said, we were able to optimize the PK/PD relationships. We're differentiated in the class because we have a 48-hour half-life. That 48-hour half-life with the potency, we're the most potent drug in the class, more potent preclinically than Mezigdomide is with that 48-hour half-life we're able to achieve anti-myeloma effects over a range of doses, clearly goes up as you increase exposure, but we're able to release the break in time to allow for neutrophil recovery. And so taken together, we have a data set that I would refer to as a broad permission slip that cemsidomide can be developed in really in the future in any line of myeloma care. And our plan moving forward is a very efficient plan to address 2 parts of that spectrum with MOMENTUM, late line, fourth line plus. And with the 1B BiTE anticipating further development in the Phase III earlier lines of therapy pivoting on the move to immune-based strategy.

Right. Great. Maybe with that, talk a little bit more about MOMENTUM of the trial, maybe the trial design there. And then maybe some of the nuances to relative to the Phase I/II, right, in a highly refractory population, if you can kind of talk...

Yes. So in some respects, the MOMENTUM trial mirrors almost exactly what we did in the Phase I first-in-human study with some important changes. One is simply operationally now that's going to be a study that we conduct both in the U.S. and Western Europe. So that increases us because obviously, in the end, cemsidomide should be and will be a global asset. That will affect the population we recruit. So I told you a few minutes ago that we had 7 prior lines of therapy. The eligibility criteria is fourth line plus. What that will map because of the 2 continents is that probably in the U.S., there'll be relatively more prior lines of therapy with more patients who have actually progressed after T cell directed therapy. And in Western Europe, we anticipate they may have had relatively fewer lines of therapy. That's an important premise because, in fact, one of the things that we don't want to do is pigeonhole that patients have to have failed everything and anything to get value. Patients don't take [ end-line ] therapy that's approved for various reasons, including access. So it will find kind of trial on the high level. But I don't anticipate at the end that the median prior lines of therapy will necessarily still be 7. The other thing, of course, that's different is now we've really understood how to give the drug, and so we can manage the drug in terms of dosing and decision-making vis-a-vis optimizing safety and opportunity for efficacy in a programmatic way, consistent with driving the drug forward for potential accelerated approval. And that's the other difference is the trial will be conducted with what I would describe as regulatory intent. Really, the main issue is we always follow the protocol, but we will follow the protocol and in addition, have the indices of safety and efficacy reviewed by an independent committee. And that will increase the potential rigor of the data set that we anticipate will support ideally an accelerated approval discussion.

Great. I guess with that, can you talk about what you view as sort of a hurdle rate for response rate for that, again, highly refractory population? And also maybe sort of coming to sort of quorum with the FDA around what sort of that bar, if you will, could be for success?

Yes. I think the FDA is always very cautious in trying to -- and giving an arbitrary bar for what success will be, especially if you are having a discussion regarding accelerated approval. And contextually, it's always how does the data look in the context of what else is happening in the space at the time you present the data, that's it. There are some principles that I think are reliable that we can think about. And one is we know from experience, most accelerated approval drugs are going to have to have a meaningful response rate with meaningful duration and also safety that's acceptable, manifested in particular, by not having patients come off drug for safety issues. So we've modeled the study that with 100 patients we can reliably detect a response rate of 40% or greater. And we anticipate that the duration of that response benefit will be at least 6 months, more being better. We're higher than that in our IMS presentation and that the drug will be safe. And there, again, where we're really proud of and happy about from the first-in-human study, we have almost no discontinuations of cemsidomide for any safety-related events. So that's the sort of context of the study. Historically, it's compared against what the background rate of an effect might be. And we know that no off-label use in various lines is active. But typically, we statistically modeled that, that signal wouldn't be greater than about 25%. And with 100 patients we can distinguish between those 2.

Got it. Great. And I guess with the increasing use of anti-BCMA therapy, maybe you can also speak to how important is that post-BCMA activity we're observing with cemsidomide especially put in the context where the comparator IKZF1/3 degraders really didn't have that sort of -- that hurdle that you guys have with the anti-BCMA therapy. So can you speak to that...

It's a great question and an important observation that people obviously are always making comparisons with us in terms of emerging the class of BMS is calling CELMoDs, which are essentially optimized degrader. And that's a really important distinction. CELMoDs are nothing different in terms of mechanism of action than cemsidomide. What they are, are potent optimized degraders. And the difference is that when people talk about what folks have seen with those drugs, those drugs were developed. It's not a question of they didn't offer to include those patients. Those patients didn't exist. And in fact, when I joined the company 3 years ago, I had initial conversations with some investors saying, does this MOA even matter anymore? And what our data just resoundingly showed that it does matter, that patients who get state-of-the-art care still progress and they still show up seeking disease-modifying care. And we are the only drug in the class that is actually articulated and defined and really impressive response rate with that exposure history.

Yes, I think that patient population is growing because as the CAR-Ts and the BiTEs move into earlier lines of treatment, what happens is patients are living longer, but they're still progressing. So if you look at the CARVYKTI data, I think 2/3 of patients kind of relapse around within 5-year mark. So for 1/3 of patients, it's close to a functional cure, but there are still 2/3 of patients who now have a great treatment option that can prolong keeping their disease in check, but they will progress too. And that just expands the number of patients available in this late-line setting as we see that migration of these newer therapies to earlier more immunocompetent patients.

Great. And between now and when you sort of get to the response rate, duration of response endpoint, are there any interim updates that you could provide on that trial before we get to that? Or is it just sort of heads down, if you will, until we get to that response rate?

No. I mean, so as Len said, we're conducting it for regulatory intent. And so we're blinded to the data. That's why we have the independent safety data monitoring committee. So we're trying to be as clean as possible. We don't want to bias the outcome of the study at all. And so we're not going to see anything so we won't really be able to provide an update until, as I mentioned, really that second half of '27, where we'll be able to share an investigator-assessed response rate. The regulatory endpoint will be that centrally assessed as well as some indices of durability, and that really won't happen until about mid-28, and we'll have that data set. But the first look that we'll be able to see and potentially share would be that second half of '27.

Got it. Great. Maybe we can shift to the second-line plus setting in combination with T-cell engagers. We've obviously seen data from Bristol there, from Iberdomide as well as mezigdomide. Maybe first, just your thoughts around where cemsidomide could differentiate from those combinations and I guess, relative to what...

Yes, it's easy. It's going to differentiate by being more effective. But you really want to know is what's the evidence for that. And I think it's important to think about why you're doing the combination in the first place. So you're doing the combination in the first place because we know that BiTE-directed therapy suffers from T cell exhaustion as well as lack of optimized T cell effect that does 2 things. It contributes to relapse, but it also reduces the depth of the response. So if you think about the data we presented in our first-in-human study, there are 2 buckets that data that are important. One, we already talked about, and that is that we have the most active compound of the class. And then the second piece that we didn't spend any time on yet is that we also know from our translational data in that study that at every dose level we study. We have a beneficial effect on the T cell population and the concomitant related effect on cytokines that are associated with immune activity. So taken together, the promise of that combination is the following: that because we have at every dose level and every dose level that we have has anti-myeloma effects as well, we're hoping that we can both augment the anti-myeloma effects, which will appear very early in the first 2 to 4 cycles of therapy, and that would manifest with hopefully, higher quality, i.e., more CRs, deeper CRs, more MRD-negative CRs. And then at the end, that will also manifest as prolonged progression-free survival and ultimately survival. Unique differences from the data that's already been presented for us. If you look at the data that was presented at ASH for Iberdomide combination with [ ELRA ] which is our combination partner. We benefit from that data because when that trial was started, the sponsor Pfizer was still figuring out how to give a BiTE with the combination and dosing schedule, as well as how to define the safety events and the response to the safety events. We have the luxury of learning from that and actually making sure that as we incorporate our combination strategy, that we're only really focused on the dose of cemsidomide and that we have appropriate indices of both safety and efficacy. And in addition, that we have optimized the support of care because, as you know, with BiTEs, there is a very real issue. The good news is it's manageable, but it needs to be optimally managed. So we benefit from that data. Another key difference though is when I talked about the data that we had from our first-in-human study, that signature with the immune enhancement is with dexamethasone. So if you look at the Iber data from ASH, that was not with dexamethasone. And I think partly that's simply because the data to generate that hypothesis was lacking. So that's another key difference because we know dexamethasone does has augmented anti-myeloma effect, it will also reduce the side effects, risk of CRs. It also has an augmented safety benefit in terms of supporting neutrophil counts, especially in the first 2 cycles. So there's a lot of key differences. We're excited about the data that was presented though because the data that was presented, notwithstanding, we think it's not the optimal combo is it did show a beneficial effect on a higher response rate. It really is a very small study and really doesn't have the ability to drill down into quality of CRs, et cetera. But as an out-of-the-gate data set, really supportive of our hypothesis and the design we have. So we're super excited about it, and it really enables us, I think, to move quickly because obviously, we need to be agile, and we need to move fast to get these trials done to get the data to the environment we need to get ultimately to design a Phase III in this instance.

And I think some people sort of looked at that data and said, well, like the bar is higher for C4. But actually, to Len's point, sort of derisked our hypothesis around can these classes of drugs be combined and managed safety? And the answer was yes. And you saw the increased ORR that really put it on par with CAR-Ts. But what it didn't do is increase the sort of CR and greater rate to be able to put that. And that's really the name of the game in myeloma today. It's not necessarily ORR because we think with these new combinations and these novel immune directed agents, you can get close to 100% response rate. It's really how you drive that MRD negative depth of response, and that's the opportunity for cemsidomide, which is, again, we think best-in-class in terms of both potency and tolerability. And so we think that the potency of cemsidomide can actually drive that CR+ rate higher and maybe we haven't seen the MRD-negative rate for that study. And I don't know if they're going to present it at some point, but -- and then hopefully have a quality MRD negativity as well. So that's really the opportunity that, that data set opened for us.

Yes. And so as you think about the Phase Ib study that you're going to be this year? Is it really more around sort of the safety of the combination? Or are you going to sort of embed the ability to look at sort of the deepening of responses, the durability within that study?

So of course, by definition, it's safety, but obviously, it's got to be efficacious. And it's not going to be statistically powered to actually have a reported reliable response rate. But we will obviously look at and share the quality of response, the depth of response. And we'll be looking at that data and making decisions vis-a-vis how to design Phase III trial. So we anticipate that the regimen will be safe because we think we have the optimized drug vis-a-vis safety. It will be clearly very active. We won't be in a position to have 100 patients at a dose of interest quickly, but we will get data as quickly as possible at relevant doses. And in that regard, I think what's really important to note we're starting with our starting dose of 75 micrograms of cemsidomide. A great question is why? And that reflects our confidence in the safety signal. We know the drug is safe across a range of doses. If we look at the data from our first-in-human study, we have a modest side effect signal at 75 purely manageable. When we look at the effect on neutrophils as well as the supportive care that would be administered with a BiTE, we're cautiously optimistic that, that dose will be clear safety hurdle. And that will do 2 things based on the design of our trial. It will allow us to go higher. We're not -- we have to define whether 100 is the right dose when you're using a combo partner that's not just [ Dex ]. But will also allow us to expand the 75 level and if need be an interest to look at 50. So again, our job is to obviously do right by patients and to do safe regimens. But our job is also to bring efficacy to patients as fast as possible, and then, therefore, to bring data to who we need, which is our investor audience to give confidence that our plan is working and on our time line that's efficient to get the drug to market.

Yes. Great. I think one point I think that sort of maybe missed on folks to is sort of the innovation around the 14 days on, 14 days off that you ended up implementing for that versus sort of the legacy 21/7. Is that a moat, you think, in terms of for this molecule for this program? Is this something others can try to replicate? Or do you think that it's really the quality of the molecule that allowed you to do that?

They can. For a drug with a 24-hour half-life, you can give sort of a lower thing. But the question is I think I would frame back is our 14-day on, 14-day off schedule is pharmacologically optimized for this drug. And for a drug with a 24-hour half-life that won't -- anything less than the 21/7 if you're looking for the anti-myeloma effect, it's not going to be an optimal regimen. It will likely be safe and tolerable. But if you ask a different question, would it likely optimize the anti-myeloma effect, I think the answer would be it doesn't make sense. It wouldn't based on the understanding of how the drug actually works.

Right. Great. Maybe lastly on CFT8919, just your lung cancer program. And just the opportunity there and maybe the progress that the program is making currently?

Yes. So when we set out with this program, I think that we observed that when you look at osimertinib, which is a fantastic drug. There was really a gap in efficacy from [ DL19 ] versus LR patients. And we thought making a degrader against selectively against the LR segment, was going to lead to improved outcomes for patients with that LR driver mutation. And so that was the goal of the program, and we started a Phase I study in China with our partner, Betta. So we'll have the data -- some of the data from that Phase I study this quarter. And that will enable us to look at what does that mean and then kind of plug that back into our market assumptions the same. There's been certainly some advances in that space that has shrunken the gap between the [ osimertinib ] data and in terms of [ DL19 ] versus LR. And then we will also, as we always do, will evaluate what does the development path look like to really capture the opportunity. The bulk of the opportunity we believe is in the frontline setting, and that will go into the calculus of what does that look like? How complex is that? And is that a study for us to do assuming the data supports it? Or is that something that may be better suited for a partner. And so we'll put all that together and make a decision internally this month and we'll communicate at the right time, but we're on track with that.

Right? So we're up on our time. Andrew, Len, thank you so much for this discussion. And then we'll be back with our next session. Thank you.

Great. Thank you.

Thank you.