Great. Thank you for coming today to listen to C4 Therapeutics. I'm Brendan from TD Cowen, and today I have the pleasure of introducing C4 CEO Andrew Hirsch, who will be leading the presentation. With that, I'll turn it over to the company.
Great. Thank you, Brendan, and thanks to TD Cowen for having us. Really excited to share all the exciting work that's going on at C4 with you today. Before we do, I just wanted to mention that I'll be making forward-looking statements today as part of my remarks. This slide here contains our legal disclaimer on this matter. C4's mission really is to deliver on the promise of targeted protein degradation science to create new medicines that can transform patients' lives. To do that, we've assembled a portfolio of degraders that we think have the ability to have a huge impact on patients by leveraging the unique advantages of targeted protein degradation. I'll walk through each of these.
In addition, we have a robust internal discovery effort going on, evaluating targets with high unmet need, but all in places where there is a strong degrader rationale. We always ask ourselves the question, what can a degrader do that other modalities can't? That helps us identify where we think to take the platform. Turning to our portfolio here on the pipeline slide, as I mentioned, we have three programs in the clinic. Cemsidomide is our most advanced program. That's a degrader of a transcription factor called IKZF1 and 3. We recently presented two presentations at ASH, both based on the phase one data set from the myeloma and NHL arms. That data supported cemsidomide's potential to be a best-in-class degrader of IKZF1 and 3. In a moment, I'll walk through highlights of the data that support that and outline the plan for.
We're excited to announce at ASH that we're going to advance this program to the next phase of development, and I'll walk through the details of what that looks like. Our next most advanced program is CFT1946. That's a degrader of BRAF V600 mutations, and we're developing that. It's currently in a phase one study. We presented some data at ESMO last year that highlighted its potential to show first proof of mechanism and then some early indications of proof of concept. I'll also walk through that data. Our most recent entrant in the clinic is CFT8919. That's a degrader of EGFR L858R for non-small cell lung cancer. That study is being operationalized by our partner in China, Betta Pharmaceuticals. That phase one started in November and continues to progress with our support.
In addition to our own proprietary pipeline, we have a number of discovery collaborations where we're working with large pharma partners to leverage the benefits of targeted protein degradation in different ways. I'll start highlighting the Biogen collaboration. The discovery phase of that is completed, and last year we announced that we delivered two development candidates to Biogen for their portfolio, which we expect them to advance into the clinic. We continue to work across our three ongoing discovery collaborations with Roche, Merck KGaA, and Merck in the US, the first two being more traditional degrader approaches going after targets of interest to the partner. The Merck collaboration is unique in the sense that we're leveraging some of the benefits of degraders as payloads for antibody- drug conjugates. We're very excited about the potential here.
As many of you know, antibody- drug conjugates have been limited in terms of the payloads because you can only hang a certain number of molecules off of an antibody in order for it to be successful. By leveraging the catalytic nature and the potency of degraders, we can really expand the intracellular targets that are available for this exciting modality. We are excited about that potential for a new addition to how degraders can be used. 2025 is really teed up to be an exciting year for the company, really across our portfolio. As I mentioned, our focus with cemsidomide is enabling the next set of studies, which we hope to start patient dosing in early 2026.
In addition, we'll be completing the phase one dose escalation and hope to share that data in the second half of the year, and also expanding into PTCL expansion cohorts. For 1946, we are expecting to complete the dose escalation. Most importantly, as you'll see, we're enrolling some cohorts of tumor-specific cohorts at various doses, and we expect to complete those. That data is going to be important in informing the future development path in terms of indications and what the competitive profile of this drug looks like. As I mentioned, we saw very promising signs of proof of concept at ESMO, but we need to enroll these tumor-specific cohorts to get a real read on what that activity and safety looks like. The plan will be to present data in the second half of the year.
For 8919, no data readouts coming externally, at least. That is going to be guided by Betta as they are running the study. For us, we see that data in collaboration with them, and the emerging data is really going to help us inform what the next steps in clinical development are for the program. I will highlight later in the presentation what potential next steps may look like. Obviously, we will make data-driven decisions. From our discovery portfolio, we plan to present work that we have done on our internal pipeline over the course of the year, both in presentations and manuscripts, but also we plan to really aggressively advance the collaborations that I just highlighted. Let me turn to cemsidomide, and we will go into some of the data highlights of the data that we presented at ASH and talk about our development plans and path forward.
I thought I would start first by just reminding everyone of the biology here, because the biology and understanding of it is fundamental to really understanding its role in the treatment landscape and the emerging treatment landscape in multiple myeloma. IKZF1/3 is a transcription factor that's upstream of IRF4. IRF4 is important in the differentiation into lymphoma and myeloma cells. By blocking and downregulating IKZF1 and 3, the goal is to block the creation of the cancer cells and limit the disease. There's also a consequence of degrading IKZF1/3, which is the on-target toxicity of neutropenia that's also responsible for neutrophil and platelet differentiation. That's why all drugs in this class are dosed with a pulsing cycle where there's an on period and an off treatment period. That's to enable neutrophils to recover so that there's no unsustainable neutropenia.
All the drugs in the class have this characteristic of on-target neutropenia along with efficacy. Just to highlight where we are in the phase one study, the study had really three major arms: a monotherapy arm in multiple myeloma, a combination with dexamethasone arm in multiple myeloma, and a monotherapy arm in NHL. Where we are today in the program is the monotherapy arm is completed, and we have presented data in December 2023 on that arm. I will share one slide of data that is important for how we think about future development. In addition, at ASH we presented data up to 75 micrograms. We are currently evaluating 100 micrograms, and we have not yet reached or exceeded the maximum tolerated dose. In monotherapy in NHL, we recently announced we have escalated from 75 micrograms to 87.5 micrograms in that arm of the study.
Again, similar to the myeloma arm, we've not yet exceeded the MTD. When we think about the role for cemsidomide in multiple myeloma, there are a number of important advances that have happened in the last several years in myeloma, including the advent of immune-based treatments. Those have really made an important benefit to patients in this disease. As you can see here, these medicines are used really across all lines of therapy. What's important is the biology that I just mentioned earlier, that's relevant across all lines of therapy. That's why you see degraders of IKZF1 and 3 used in combination regimens across multiple lines of therapy from upfront to last-line therapy. That's why we think a huge opportunity for cemsidomide to become the backbone therapy of choice based on its potential to be a best-in-class degrader of these medicines.
Importantly, we also see that last-line patient population growing as we see newer therapies moving into earlier lines of treatment and providing benefit to patients. Those patients are living longer, but as you'll see from the patients we enrolled in the phase one study, they continue to progress and they continue to need treatments. We think that population is only going to grow over time as newer therapies take more and more share of the earlier lines of treatment. This slide contains one snapshot of the monotherapy data that we presented in 2023. It is really important for how we think about future development. In addition to the myeloma cell kill mechanism that I shared with you earlier, the other benefit of degrading IKZF1 and 3 is that it leads to activating immune cells.
This is data from the monotherapy across 25 micrograms, 50, and 75 micrograms that show meaningful increases in T cell activation. We think this is important because as we think about T cell engager therapy, one of the limitations that we see is T cell exhaustion. We think a combination regimen with a therapy that activates T cells can help address that and improve responses. This data, and we saw this activity at very well-tolerated doses, which is important as we think about combination therapy and potential for overlapping toxicities. Now, turning to the data that we shared at ASH, which is the, and that was monotherapy, just to be clear. The data we shared at ASH is in combination with dexamethasone, as many of these drugs are used in the class. What we demonstrated was a very, very competitive efficacy profile.
You can see here in the panel on the left, where at the highest dose presented at 75 micrograms, we had a 36% response rate in the 11 patients that were efficacy available. There were additional three patients that were safety available at the time, not efficacy available. We do not have an update on that today. Also, what we see on the right panel that we demonstrated was a much improved safety profile versus the most advanced medicines in BMS. With all the caveats of cross-trial comparisons, you can see here in the panel on the right, comparing the cemsidomide data from ASH to the phase one experience from mezigdomide, which is BMS's most potent degrader of IKZF1/3.
What you can see is lower rates of neutropenia, but most importantly, meaningfully lower rates of neutropenia complications, grade 3+ infections and grade 3 plus febrile neutropenia. Again, that's critically important as we think about cemsidomide's role and IKZF1/3 degraders broadly role as backbone therapies given the biology that I thought that I just mentioned. We want to make sure that we can minimize the toxicity while maximizing the activity as we think about different combination regimens. We think this data taken together supports its profile as a best-in-class degrader of IKZF1 and 3. With that data, we've embarked on, we think, an exciting path for the drug in terms of its next phase of development, which I'll highlight here on the next slide. Currently, we're enabling two studies in multiple myeloma.
The first, I'll start all the way on the far right, is a phase two single-arm study in multirefractory late-line lymphoma. I should mention the data that I presented, I forgot to mention this earlier, is also in 70% of those patients that I shared efficacy on are post-T cell directed therapies, both CAR-T and BCMA BiTEs, which is a relevant population. That is important because that is the population we're going to be studying here in the phase two single-arm study, which we think has the potential for accelerated approval in combination with dexamethasone. In addition, we'll be evaluating a phase one to escalation expansion study with two combination regimens. The first, cemsidomide and dexamethasone plus an anti-CD38 antibody in post-BCMA treated patients. Then also cemsidomide as a monotherapy plus a BCMA bispecific, leveraging that T cell activation data that I shared earlier with you.
That phase one to expansion will provide proof of concept for pivotal studies in both of those combination regimens and lines of therapy. Currently, the team is working on operationalizing these studies with a plan to start dosing patients in early 2026. Turning to NHL, you can see here that lenalidomide is approved across almost every subtype of B cell lymphoma in addition to being used on NCCN guidelines across all types. We think that the pathway is clearly relevant. However, we do not think it gets much use because we do not think lenalidomide is potent enough. We started to run this study to see if a highly potent degrader, like cemsidomide, could provide an opportunity here. In our phase one study, it is open to all NHLs, both B cell and T cell.
However, we happen to have, not by enrichment, but by how enrollment played out, a high number of PTCL patients, which we think reflects the unmet need for those patients that aren't CD30 positive because there are really no real treatment options directed toward them. We were quite pleased with the data that we generated in the PTCL populations. This is just the subpopulation of all the patients in the study. As I said, it's the majority where we showed about a 44% ORR with a 25% complete metabolic response rate in late-line multirefractory PTCL patients and really seeing responses across all subtypes. In addition, the data that we shared on the safety is pretty similar to the data that we saw in multiple myeloma, where very manageable incidents of on-target neutropenia, as one would expect from this mechanism.
We think the profile supports this development of this asset in PTCL and then potentially across broader NHL subtypes in the future. What we've outlined is a study that we're currently enabling, which would be a single-arm phase two study in multirefractory patients that, again, would have the potential for accelerated approval with a confirmatory study randomized to phase three versus standard of care in frontline patients. We're currently working on operationalizing that phase two single-arm study, which, again, we expect to dose patients in early 2026. Taken together, as we think about the strategy for cemsidomide and cemsidomide development, starting off in the highest unmet need patients in late line, which we think is the fastest path to a label, and then expanding into earlier lines of treatment in combination regimens.
Ultimately, in the future, really trying to explore it across multiple lines of therapy in multiple different combinations beyond the ones we outlined here, including maintenance, which we think will establish cemsidomide as the backbone therapy in multiple myeloma and NHL. Turning to 1946, this is our degrader of BRAF V600 mutants. BRAF inhibition has become quite a standard of care for patients with BRAF V600-driven cancers. However, there is a liability to inhibitors because the BRAF protein has a scaffold function. What I mean by that is if you look at the third column in the top row here on this slide, you can see that you can stop signaling through the MAPK pathway by inhibiting the BRAF monomer. That works.
If you kind of move one column to the right, what happens is that that inhibited monomer can form a dimer and then lead to continued signaling through the MAPK pathway. That is a resistance mechanism that is fundamental to the protein and leads to a shorter duration of response than one might like in this disease. If you go to the row below, we believe by degrading and completely removing the protein, not only do we stop monomer signaling, but there is no protein left to dimerize. We think we can very aggressively and quickly shut down that pathway and improve the treatment of the disease and the duration of response. In addition, because of the selectivity of a degrader, one of the liabilities of inhibitors is you get wild-type inhibition. That leads to toxicities, primarily skin toxicities that you see with BRAF inhibition.
Our degrader is highly selective for the mutant form. We wouldn't expect to see any types of toxicities associated with wild-type inhibition. In addition, because a lot of these patients have brain metastases, crossing the blood-brain barrier is important. We shared data at the TPD Summit last year that demonstrated we have the ability to cross the blood-brain barrier with KPUU values consistent with some of the most highly brain penetrant molecules that are out there. We're currently running a phase one-two study of this drug across multiple diseases that are driven by BRAF V600. We presented data from the monotherapy dose escalation at ESMO. In addition, we have expansion cohorts that are required to have pretreatment and on-treatment biopsies to really understand the PD. We're currently enrolling patients in three sort of expansion disease-specific cohorts.
Monotherapy treatment in melanoma in combination with cetuximab in CRC and melanoma in combination with trametinib. I should mention that in CRC, the resistance mechanism is somewhat different. When MAPK pathway is downregulated, it actually has an upregulation of EGFR, which is an intrinsic resistance pathway. That is why the cetuximab combination is important, because we need to add the EGFR blockade to really drive activity. To summarize the data that was presented at ESMO, in the left panel, you can see by IHC, we saw robust degradation of the target in the seven patients where we had paired biopsies up to the 320 milligram dose. In addition, we saw a really nice safety profile. We saw no DLTs. Importantly, we did not see any skin tox that might be associated with wild-type activity.
From that perspective, we believe we've demonstrated proof of mechanism. The drug we know degrades the target. It does what it's designed to do. We're starting to see some indications of proof of concept in the sense that we don't see wild-type toxicities. On the right panel, you can see the efficacy that we shared at the time of the ESMO presentation, where we showed robust tumor shrinkage. At the time, when we took the snapshot of the data, two PRs, one in a pancreas cancer patient and another one in a melanoma patient. We continue to advance this program. As I mentioned, those tumor-specific cohorts are going to inform the development path as to how we move the program forward. Really, there's two paths that we have here in melanoma.
You can see based on the data, we would expect to start in late-line patients and then quickly move into the frontline patients, hopefully in different forms. Again, we think we can have an impact on these patients by improving both the response and the durability through the degrader rationale that I walked through earlier. In colorectal cancer, we see a combination with cetuximab in late line, then ultimately moving it to earlier lines of therapy. Again, that decision will be based on the data that comes out of the monotherapy and does it show we have a competitive profile in these diseases. Now I'll quickly turn to our EGFR L858R degrader, which we're really excited about. Again, currently being run phase one study in China by our partner Betta.
8919 is a really exciting molecule because we've designed it to bind to an allosteric site that is created uniquely by the L858R mutation. What that gives the molecule is exquisite selectivity for the mutant form, for the mutant L858R. We don't expect to see any type of wild-type inhibition or degradation, which is associated with toxicities such as skin tox. We think because we're not binding to the orthosteric site, that the degrader will not fall to the secondary resistance mutations that the inhibitors do, like T790M and C797S. We think we can provide a much more durable response to that. Both address second-line patients, but also in the frontline, potentially provide a much longer and better response for patients with the LR mutation.
Additionally, when you think about the frontline, it's long been known that inhibitors, and here we're showing data in the middle here on osimertinib, that LR patients do less well than Del19 patients in terms of PFS. It's been hypothesized and presented by others that there are a number of additional co-mutations that occur early and are also driver mutations, but also render inhibitors less effective because those mutations surround the orthosteric site. We expect that we shouldn't be subject to those mutations given that we bind to an allosteric site. We should hope to have a much improved response in those LR patients. Looking at our preclinical data in the left panel, you can see here on the KYNOMAP, high selectivity for EGFR L858R.
In the right panel, we show activity in a model of osimertinib resistance where we've engineered the C797S mutation, which doesn't enable the covalent molecule to bind. You can see improved efficacy where osimertinib shows no activity. In addition, I mentioned we know the drug crosses the blood-brain barrier. In the left panel, you can see both brain and plasma concentrations. That results in what you see in the middle panel, which is in the luciferase model, impressive in vivo efficacy. Obviously, safety on the right, when we look at body weight change, we see the treated animals don't lose body weight due to tumor burden as we reduce that tumor burden. We're really excited about the potential for this molecule to really improve the outcomes for patients with EGFR L858R-driven lung cancer.
The path forward is fairly straightforward, although not easy because it's drug development. We would start in the second line, which is, we think, also the fastest path to market in patients who have lost efficacy from frontline EGFR treatment due to secondary mutations like C797S or T790M. Moving to a much larger patient opportunity in the frontline where we can potentially increase responses and durability of responses, either alone or because there's no competing binding, could also be developed in combination with an inhibitor. We will look at the data that comes out of the China study to understand that path forward. That hopefully will progress nicely over the course of the year and will enable us to make data-driven decisions around the path forward. In conclusion, really excited about the year we have ahead for C4.
We have, as I said, we're advancing cemsidomide into the next phase of development based on the exciting data that we shared at ASH and then continuing to move 1946 forward, looking to get a readout in the tumor-specific cohorts to try to get a read on a competitive efficacy profile at various doses. Continuing, as I said, to progress 8919, as well as investing in the TORPEDO platform to continue to advance it and keep it world-class, as well as evaluating early-stage targets for our preclinical pipeline. With that, I will thank you and open it up for any questions. All right. There being none, thank you and enjoy the rest of your day.