Good morning, I'm Eric Joseph, Senior Biotech Analyst of J.P. Morgan, and our next presenting company this morning is C4 Therapeutics. Presenting on behalf of the company is CEO Andrew Hirsch. There's a Q&A session after the presentation. Just raise your hand, we'll bring a mic over to you, before asking a question, and for folks tuning in via the webcast, feel free to submit questions via the portal. So with that, Andrew, thanks for joining us.
Great. Thank you, Eric, and thanks to J.P. Morgan for having us here today. So before I begin, wanna just comment that I'll be making forward-looking statements today. Obviously, those are subject to various risks and uncertainties, and you should look at the risk factors section of our SEC filings to understand what those risks and uncertainties are. So for those of you new to C4, C4 is a recognized leader in the world of targeted protein degradation, in fact, one of the pioneers. We were started in 2015, coming out of Dana-Farber, Jay Bradner's lab.
Our mission is really to deliver on the promise that we see with targeted protein degradation, to come up with a new generation of medicines, to really transform patients' lives. There's really four pillars that underlie our strategy for how to do that. The first is we have a world-class degrader platform. We have a robust, proprietary portfolio of novel cereblon binders that we use in engineering all of our degraders, and we've been able to demonstrate, and you'll see that, really, orally bioavailable and highly catalytically efficient degraders, which we believe are critical to making best-in-class degraders. Secondly, we have a rigorous target selection approach. That's critical because, as we've explored this field, there are a lot of targets that we can point the platform to and degrade.
And so we focus on targets where there's a clear degrader rationale for what can a degrader do that no other modality can do, that can solve a problem, that can ultimately lead to an improved patient outcome. The third is we have a very broad degrader approach. Many companies, you know, have one or focus on one approach. We have multiple, so MonoDAC, or sometimes called molecular glues, is an approach we can take. We also have BiDAC, or known as heterobifunctionals or PROTAC, as well as a new collaboration that we did, antibody conjugates with degraders as payloads. And lastly, we have a very robust clinical pipeline against a number of high-value oncology targets that we think meet a number of high unmet needs. And this platform isn't just theoretical.
In fact, since we've been at this, we have been able to demonstrate the ability to generate degraders against three different target classes, so multiple target classes, transcription factors, chromatin modifiers, as well as kinase targets, and we've taken four programs through FDA to IND clearance. On top of that, the three that we've studied in the clinic and where we have clinical data, and you'll see some early data from the third, our BRAF program today, we've been able to generate really desirable drug-like roperties, so oral bioavailability, as well as degrading our target as our preclinical models predicted. So when I stood here a year ago at this conference, I said that 2023 was gonna be a transformative year for C4 Therapeutics, and it was.
So, this slide here, slide 5, and for those of you on the webcast, really highlights the accomplishments that we had this year that we think really position the company for success. We executed against three of our clinical programs, 7455, 1946, and 8634. And that was important 'cause that execution led us to generate clinical data, which helped us prioritize the portfolio. So as many of you saw in December, we shared some exciting data from the phase 1 study of 7455 in multiple myeloma, showing that the new schedule solved the challenges we had earlier in development, and we saw encouraging IMWG responses in the plus dex arm.
And then we dosed the first patient in the 1946, that's our BRAF V600X program. We've completed enrollment in 3 escalation cohorts, and I'll share some preliminary PK and PD data from the first 2. We also presented some exciting preclinical data showing superiority of that degrader approach to BRAF V600X over inhibitors. And then with 8634, we did, I think, a really great job executing that trial quickly and efficiently, generating the data necessary to unfortunately make the decision to stop development of that program, despite the fact that the degrader performed as expected. And then 2 partnerships that we secured last year. The first is a collaboration on our EGFR L858R degrader, CFT8919.
You know, we achieved FDA clearance of that in the U.S. as well as in China, and our partner, Betta Pharmaceuticals, is gonna run the phase 1 study in Greater China. So, that was an exciting collaboration. It's an important part of the strategy to develop that program. And then, most recently, we entered into this exciting collaboration with Merck to discover what we call DACs Degrader Antibody Conjugates, using degraders as a payload for ADC approach as opposed to highly cytotoxic payloads. And then lastly, we were able to bring in about a little more than $100 million of additional capital through the use of our ATM, the equity from the Betta collaboration, as well as the Merck upfront.
And then when you combine that with the cost savings from our restructuring, that extends our cash runway into 2027. We have a robust balance sheet to be able to execute against our plan. All those that execution in 2023 and the decisions that we made result in the prioritized pipeline that you see here on slide 6. You can see, we have three clinical programs. Two are operationalizing ourselves. The third will be in collaboration with Betta, and then a targeted number of internal programs focused on various cancers that are undisclosed, as well as three collaborations with Roche, Biogen, and the Merck one that I just talked about.
All of that positions us well for what I think is gonna be an exciting 2024 for C4, where here we've got a number of important milestones across the portfolio, starting with our IKZF1/3 degrader, CFT7455. We plan to complete dose exploration work in both the myeloma and NHL arms, and we'll be presenting data in the second half of the year from both of those arms. Well, you know, we shared some early data from the plus dex cohort in December, and we hope to complete that work and share the completed cohort there. And then we haven't yet shared data in NHL, but our plan is to do so in the second half of the year.
As we continue to move CFT1946 forward, that's our BRAF V600X degrader. In the first half of the year, at a medical meeting, we'll be presenting some additional preclinical data, and I'll tease a little bit of that here today in the presentation. Really showing some differentiated activity in melanoma, colorectal cancer, lung cancer, as well as models of brain metastases, which are critical for those indications. And then in the second half, we hope to get to a place where, with the phase 1 dose escalation, we'll be able to share data in the melanoma CRC, non-small cell lung cancer, and in other BRAF indications. So we expect to have that data in the second half of the year.
Our partners, Betta, are busy at work getting the phase one trial underway, and we plan to support that. Our activities are largely around clinical supply and CMC, but we'll do what we can with them to get that trial up and running as soon as possible, so we can start dosing patients. And then lastly, we expect to deliver a development candidate to one of our collaboration partners. So we're really excited about what's in front of us for 2024. So I'll jump into the pipeline now and start to share some of the data that, you know, mostly you saw in December for the 7455 program in myeloma. So we didn't share any NHL data, but it is in development.
I thought I'd start just with a quick refresher on degradation of these targets impacts three key areas of hematopoietic biology, and those are really important for how we think about therapeutic strategies against this target. The first, and one people are most familiar with, is that these targets are important for myeloma and NHL cell survival. So by degrading them, that leads to apoptosis and cell death, and that's obviously an important component of myeloma treatment as well as NHL treatment. The second and probably lesser known, but equally important, is degradation of these targets actually leads to T-cell activation. This is an important component of the therapeutic strategy with these drugs in this class for two reasons.
One, it enables the combination with some immune agents, but also for maintenance therapy. It's a really important component of the mechanism of degradation. And then the last consequence of degrading these targets, and something that is familiar and seen across all classes of medicine, is it does regulate hematopoietic stem cell differentiation. So the consequence of degrading these targets is you see neutropenia. Different from chemotherapies, we're not killing neutrophils in the periphery. What we're doing is we're blocking maturation of the neutrophils, and so the neutrophils don't replenish the periphery, and as a result, as the neutrophils in the periphery die off during their natural life cycle, you see reductions in neutrophils, and you see neutropenia. This is something that is critical and is important, and happens with all degraders of this class.
When you think about therapeutic strategies going after these targets, you need to balance the first two, which you really want to treat aggressively, with managing the toxicity you see with neutropenia. That's typically done with a break in dosing. So all of these drugs are dosed for a continuous period, then a break to allow neutrophil recovery. That's critical for how to think about drug development with this class of medicines. For each of these, it's unique to the unique physical chemical properties, PK properties of the drug in question.
So, we started a phase 1 study of this program, and so many of you remember, in AACR in 2022, we started off at a 21-day-on, 7-day-off schedule, which is typically how this class of medicines are dosed. That was based on the assumption that we garnered from our preclinical data that we had a 24-hour half-life. Turns out, when we got into the clinic, we had a 48-hour half-life, and so the result was that at the very first dose, we had unacceptable levels of neutropenia.
We quickly course-corrected, and based on a lot of the PK modeling that we do internally, that it's highly predictive in preclinical models, we were able to, based on the clinical PK, identify that a 14-day-on, 14-day-off schedule was more appropriate. And so we restarted the treatment arms in three here, you can see in the bottom. This is on slide 10 for those of you on the webcast. In relapse refractory myeloma as a monotherapy, and we'll go through some of that data, that cohort is now complete. We enrolled 22 patients in combination with dexamethasone, which is typically how these medicines are given. That is ongoing. We did present data, and I'll share it again from the first two escalation cohorts. And lastly is monotherapy in NHL.
That data we've not presented, but we do expect to present that this year. So this is your standard phase 1 dose escalation safety study, looking for signs of antitumor activity. So the conclusion from the data set was really encouraging for us because what it suggested was that the schedule adjustment that we did had the expected results. And what I mean by that is, we had the right safety profile. We're convinced that that is the right schedule, given the unique PK properties of the drug, and so we had a very manageable safety profile, seeing expected and manageable levels of neutropenia.
In the monotherapy arm, we saw both, anti-myeloma activity, as well as the immunomodulatory effects that we think are important for using this drug in combination with novel agents. We don't expect this drug to be developed as a monotherapy. In fact, myeloma is really not a monotherapy, treatment space. It's usually done in combination, and this data set is critical for the initiation of, combination treatments 'cause we've established the profile of the drug, as a monotherapy. And then, although early, we did see some very promising, IMWG responses in combination with dexamethasone at low doses. In fact, at half of the maximum administered dose in the monotherapy arm.
So we're very excited that the profile of this drug is starting to look like the drug we expected to see, when we put it into the clinic back in 2021. So on this slide, slide 12, you know, this is the left panel may be familiar to many of you. This is the modeling that we did when we had ran into the challenge of neutropenia, and 2 DLTs at the very first dose, where our team simulated what the degradation profile would look like based on what we know the catalytic activity of this degrader is, as well as the human PK. And that's where we landed on the 14-day on, 14-day off schedule. You can see the green line here.
You see rapid decreases in IKZF3, and really maintaining that low level or absence of target through day 14, and then you can see the recovery that we need to allow neutrophils to repopulate the periphery. We were actually very gratified when we looked at the data from the clinical study, which you see in the right panel, which almost exactly mirrors what we'd expected to see. So you can see what you're seeing here is both IKZF1 and IKZF3. We only modeled IKZF3 in the left panel, but really exactly the same profile: rapid degradation early on during the 14-day dosing period, and then recovery to 100% of kind of pre-dose levels at the end of the 28-day cycle, right before starting the second cycle.
We were really pleased to see this. It gave us a lot of confidence that we were headed in the right direction, and I think it's a real credit to the science that our team does. When I look at the monotherapy data, you know, again, as I said, we had no DLTs that resulted in discontinuations across the entire monotherapy arm. You know, all grade 3 or greater drug-related effects were as expected to be neutropenia or hematologic effects, and the safety was as expected. And we did see evidence in 20 efficacy-evaluable patients. We saw evidence of response, and that all 4 patients at the maximum administered dose had stable disease or better. This is an important slide. There's 3 panels here.
This is showing the combination, or the monotherapy arm, and showing the immune activity. So on the left, you can see evidence of T cell activation at doses that we studied in very, very safe and tolerable doses. Then on the right, you can see the enhanced cell lysis effect when we combine 7455 with a fixed dose of either daratumumab or teclistamab. This is important for future development strategy as we move into, you know, future combinations. The monotherapy arm, just as quickly, this is where we are. We've completed both 50 Monday, Wednesday, Friday, as well as 37.5 QD, and we're currently enrolling both 62.5 QD with dex, as well as an enrichment cohort in 37.5.
You can see here in this kind of modified Swimmer's plot, really robust responses at the highest dose studied, 37.5 + dex. Of the three efficacy-evaluable patients, we had two responses, including one stringent complete response, which is quite impressive to see at this low dose and at these late-stage populations. So we're excited to expand this data set and share with you later in the second half of the year. And that leads to the path forward for this drug. We think there's multiple paths forward. Certainly, in combination with dexamethasone, we think this drug can be used in late-line multi-refractory patients. And then, as I mentioned, the monotherapy data supports combination with a number of novel agents.
So turning quickly to our BRAF V600X degrader, this is a very exciting program because unlike other TKIs, resistance doesn't does not occur by a mutation in the binding pocket. There are resistance mechanisms, primarily paradoxical activation, where the monomer incorporates into a dimer and then leads to un- signaling through the MAPK pathway, which then leads to results in cancer growth. We think our orally bioavailable degrader can accomplish overcome that challenge by completely removing the protein. There are many other mechanisms of resistance, and we think by removing the protein, it addresses all of those as well.... This is a fairly complicated slide, and the biology of the MAPK pathway is quite complicated.
It's actually, the resistance mechanisms are quite different, as it pertains to certain indications. So when you look at melanoma and lung cancer, for example, this is where you see a lot of paradoxical activation. You see also splice variant amplification, places where that resistance is acquired as a result of inhibitor use. And again, by removing the protein, we think the degrader will address that. There may be a case where we want to look in combination with trametinib as a MEK inhibitor. That's a strategy used today to overcome some of those resistance mechanisms with the current class of BRAF inhibitors. In fact, they're all used with trametinib. We have the opportunity to study it as a monotherapy, but also in combination.
In addition, in colorectal cancer, there's actually a different intrinsic resistance mechanism, whereby downregulating ERK through the degradation of BRAF V600X, it'll upregulate EGFR, and that's why treatment strategies, they are all in combination with cetuximab or some other anti-EGFR antibody. Again, you can see here, I'll go quickly on this slide. This just shows you the patient population sizes across all of them, as well as we think the opportunity for improvement on the median PFS across all three of those are, and you'll note, these are all used in combination to overcome some of the resistance mechanisms that I highlighted. So this is some of the preclinical data that we'll share earlier in the year. There's a wealth more behind this.
But you can see here, that the degrader CFT1946, in some cases, as a monotherapy or in combination, with cetuximab in colorectal cancer, or with trametinib in non-small cell lung cancer and melanoma, lead to far superior responses, than standard of care alone or in combination with trametinib or cetuximab. This is data that's really gotten us excited about why we want to move this forward into the clinic. The other question that you ask about this indication here is, is it brain penetrant? And we've showed here in a model of metastatic melanoma CNS models, that we do have activity in terms of prolonging survival, and that activity is superior to what you see with the inhibitors.
So very excited to see that this will also have an impact on CNS models. It's important both in melanoma and lung cancer, where brain mets are critical. So, here's the study, started in January. We've now completed enrollment in the first three dose escalation cohorts, up to 160 milligrams BID. That we don't have the data for. We have data for the first two, 20 and 80, and I'll share some of the early PK and PD data with you. So again, you're probably used to seeing PK curves like this. What's exciting about this is this is a BiDAC degrader, quite large molecule in the 700-900 Dalton range.
And so to see really nice behaved dose, you know, drug-like properties, dose proportional increases in exposure, oral bioavailability, is something we really are excited to see and is not trivial when it comes to degraders. And then turning to slide 26, we've got two different patients here. In the left panel, we're showing degradation by IHC, and you can see on the left, BRAF, this is BRAF V600E degradation in this patient. You can see at cycle one, day 15, you know, less brown is better. And so you can see a reduction there in protein. And then the goal is to reduce ERK signaling, and you can see that in the right panel of that left slide.
In another patient, we saw rapid decreases in the variant allele frequency of the mutation, really at 15 days of dosing, at the 80 milligram dose. That was also associated with about a 7% decrease in tumor volume. And so that's good when we see clinical signs of activity that's correlated with our translational work. That means we're headed in the right direction. Obviously, we're not there yet, but we are looking forward to continuing and to share data in the second half of the year. I'll touch very briefly, 'cause I know I'm a little bit over time, on our 8919 program. This is an exciting program because it addresses a lot of the limitations of inhibition of EGFR.
With current inhibitors, we know that the L858R mutation is very poorly treated. Its PFS is a lot lower than the others, about 14.4 months. CFT8919 was designed to be able to address any mutation to the orthosteric binding pocket and spare wild type, and we've done this by creating an allosteric binder, that it binds to an allosteric site that is uniquely created by that L858R mutation. That confers lots of benefits. First, it avoids all the resistance mutations that you might see in the orthosteric site, and it has zero wild type activity, since we don't go anywhere near that site.
And then lastly, because we don't bind to the orthosteric site, it is combinable with orthosteric inhibitors, and so that's a strategy that we may use as we move the program forward. So, again, as I mentioned, our partner at Betta Pharmaceuticals will be starting the phase 1 study. We'll have to look to them for study start guidance, but we're excited to get this trial moving it into the clinic. So again, as I mentioned at the beginning, very exciting 2024 for the company. Lots of clinical data across 1946 and 7455 in the second half of the year, with some preclinical data that really tees up the promise of 1946 in the first half of the year.
So with that, I wanna thank everyone at C4 back in Watertown, who has helped us get to this point, as well as I want to thank all the patients, the caregivers, physicians who trust us to participate in our clinical studies. Without them, we wouldn't be anywhere. So thank you, and with that, I'm gonna ask Kendra Adams, our CFO, and Scott Boyle, our Chief Business Officer, to come up for the Q&A session.
... Well, great. Thanks, Andrew. And as a reminder, for those who have questions, just raise your hand, we'll get a mic over to you. But just by way of starting out, maybe with just picking up on CFT7455, and this is probably a question you get commonly. Maybe you can just sort of share thoughts on what opportunities you see for differentiation with your compound relative to BMS' mezigdomide and multiple myeloma, given that, you know, likely they're probably gonna share similar admin profiles in combination with dexamethasone.
Yeah. It's a good question, and look, I think making comparisons at this point is difficult just because of the small ends in there compared to their ends. I think, you know, there's hints, and I'll say hints that we may have a more tolerable safety profile with kind of comparable efficacy, but again, the ends are small. I think what we've seen is it's not clear. You know, they did a phase 2-phase 1 dose escalation, where they landed on 1 mg QD as their recommended phase 2 dose, and that's what they've taken into their pivotal studies, which are designed effectively to replace lenalidomide and pomalidomide in the current treatment paradigm.
But what we have noticed is they are still exploring dose and schedule in their other studies, which leads me to conclude that I'm not sure that they have the right dose and schedule. The thing we noticed is in their expansion cohort, I think their grade 3-4 neutropenia rate was something like 75%, and that's in the backdrop of allowing GCSF use right off the bat, which you do once you've established a dose and schedule. So we think there's a hint that we're gonna have a better therapeutic index and profile.
Again, we need more data, but I think that's what we've seen, and the early feedback we've gotten—again, it's small n, so I don't wanna, you know, make too much of it from some of the KOLs—is they're very excited about what the emerging profile is. So, hopefully, you know, we'll be able to answer that question more thoroughly toward the end of the year as we have a more robust data set.
I mean, so there's, I'm sure, yeah, there's a lot of focus on the relative tolerability profile, you know, you're figuring a lot—there's a lot of figuring out of optimal dose and schedule in a probably more advanced refractory patient population.
Yeah.
What do you, kind of, physicians kind of indicate where tolerability ought to go as you think about ultimately moving it up lines, up line in the treatment paradigm?
Yeah. Yeah, I mean, look, I think it's hard to just look at tolerability alone without efficacy, or you have to really look at the benefit risk. You know, if we had a 90% response rate, I think people would tolerate a much higher neutropenia rate. So I think that's a little bit hard to answer in isolation. When you look at the approved IMID class, lenalidomide and pomalidomide, their grade 3/4 rates are, you know, in the kind of 40%-50% rate. And avadomide is similar, which is, they're kinda less potent. I think the outlier, frankly, is mezigdomide, right, which has about a 75% grade 3/4 neutropenia rate.
So, you know, I think it depends again on the efficacy, but I think if you're in that range, it should be able to move forward. Again, the caveat is that when we look at our phase 1 dose escalation data, FDA requires or does not allow GCSF use in cycle one. And so, the data that we report in terms of our neutropenia rates from the phase 1 dose escalation do not include that. When you look at the broader data sets, the labels, the phase 3 data sets, the expansion cohorts, once a recommended phase 2 dose has been established, GCSF use can begin off the bat.
So you have to look at those neutropenia rates, recognizing they're on the backdrop of GCSF use, and I think, again, in the mezigdomide expansion, I think 80% of patients use GCSF.
Okay. Okay.
Maybe just one more-
Go ahead
... one more comment on sort of general physician view, right? They're used to using GCSF. They're used to neutropenia. So a lot of the feedback that you get relates to dose reductions, dose interruptions, et cetera, sort of how they manage the neutropenia. They're very comfortable managing it with all the tools, and so that will be part of, I think, the calculation in terms of these, how you use these various agents.
Got it. Got it. Well, maybe that... Yeah, you just indicated, you know, docs, you know, are flexible or are used to flexibility, or adaptable. I did wanna ask, just given that most of the approved and developing IMID regimens, you know, follow typically a 21 day on, 7 day off cycle, and right now, you're optimizing on 14, 14.
Yeah.
Does that represent a challenge, I guess, to, you know, how docs are adopting these drugs or might use them in combination?
I mean-
You know
... it's too soon to know.
Sure.
Look, I think anytime patients can take less medicine, that's better. And so, you know, we don't think that's gonna be a hurdle for adoption at all. You know, for instance, BMS has a NHL-specific degrader of IKZF1/3. They're dosing that on a 14-day on, 14 day off schedule. You know, the schedule, as I said, is really driven by the unique PK properties of the drug and the medicine. And I think that's... One of the big differentiators is that their tumor and plasma PK is the same. We have a lot more tumor residence time, which we think gives it an advantage in terms of driving improved efficacy.
Maybe just if we're looking forward to when you will next present data in the second half of the year, I guess, can you just frame expectations? I know it's early days post- post the December update, but I guess, what should we expect in terms of completed dose cohorts and perhaps patient numbers for some of the lower dose cohorts that you're looking to backfill?
... Yeah, I mean, I would say our goal is to have completed the dose exploration work for the phase 1 plus dex myeloma arm. We're unlikely to have an effective recommended phase 2 dose because in the era of Project Optimus, that's complicated, right? You need to basically find 2 doses of interest and do a little bit more exploration work.
Mm-hmm.
But we expect that our dose exploration work will be largely complete, and that's the data set that we'll share. How many patients depends on where we escalate to. Right now, with the plus dex, we're at 62.5 micrograms, plus dex. You know, question is: do we go higher?
Mm-hmm.
Assuming safety, do we bracket it and go higher? And so it really depends on-
Mm-hmm
... the data set that comes out, so it's hard to predict.
Mm-hmm.
You know, one thing that I think people sometimes are surprised at is, you know, the patient numbers are so low, and well, that's actually a good thing because when you do dose escalation, it means you haven't had a safety problem, because you're able to, you know, you only need 3-4 patients per cohort. And so, you know, we've been fortunate that, you know, we've been able to move quickly without any dose-limiting toxicities to escalate with that, the fewest number of patients.
Okay. And in terms of where you may look to present, I guess—I mean, again, early days, but—I guess, internally, how important is kind of sharing data at medical conferences perhaps or versus just giving an independent disclosure?
Look, we, we'd like to be able to present at medical conferences. I think the challenge is that, enrollment timelines don't always neatly line up with, submission deadlines, right? I mean, you know, ASH is-- It would be great to present at ASH, but I think the submission deadline is in August, for a December meeting. And so, you know, we'll have to just see where we are, what the data set looks like, and if we have to do it, we do it in December and do a company-sponsored, you know, webcast. We'll certainly do that. It's just gonna depend on the pace of enrollment when the data set's ready for, for presentation.
We expect it to be ready by the second half, but, you know, whether we'll have everything ticked and tied and ready for submission to a medical meeting, you know, that's too hard to predict, standing here in January 2024.
Okay. Okay. In December, you sort of reiterated the plan, the expectation that you'd seek a strategic partner for 7455. Is that, you know, still the case? And maybe you can just kind of help us, you know, share some of your thinking in terms of the type of collaboration structures that you're you think would be appropriate here.
Scott, you want to talk about it?
Sure. So, we see a lot of potential with this molecule, and one of the ways to unlock that potential is to get a global partner who can help us do all the studies that we need to do. On one of the slides, Andrew presented a number of combination opportunities, as well as moving earlier lines, and so certainly, that's our goal is to find a global partner who can help us unlock that value and that patient impact as quickly as possible. I think the structures will be dictated a little bit by those conversations, but we're eager to see the reaction and go forward.
And this would be, you know, for the whole molecule, and perhaps—I mean, I'm sure data will dictate, but the potential in NHL is certainly an opportunity that's exploring and could be part of those collaboration discussions, partnership discussions. Can you just kind of speak to what profile you think could be compelling in NHL and sort of your hopes there?
Yeah, I mean, it's interesting because as the first slide I showed on the in the program section, right? The mechanism really lends itself to work in NHL, but this class of medicines hasn't really been used at all, and that's really due to the sort of low efficacy. I think the response rate in the lenalidomide label is about 26%. I think it's in marginal zone or mantle cell lymphoma, one of the subsets of lymphoma. But it's just really not widely used, so I think the bar is fairly low for this. Obviously, there's a lot of development activity in NHL. You know, we've seen..
I think, you know, PTCL is an interesting subcomponent of NHL for us 'cause there really aren't great therapies, and there really is potentially an opportunity there. But I think, you know, we're gonna have to see what the data set looks like. You know, we are enrolling in the phase 1 across multiple subtypes of NHL. So it's not clear we'll have a critical mass in one or the other, you know, one specific subtype. You know, but we'll have to look at the data and see what that says, and then, you know, at that time, think about, you know, what does the landscape look like?
We know the bar for this class is quite low, just given the 26% response rate that we see within the lenalidomide label.
Same sort of criteria being able to manage for neutropenia in the NHL as it is in myeloma?
Yeah, similar.
Okay. All right. Maybe just shifting to... I'm gonna pause here for any questions. All right. Maybe just shifting to the V600X program, CFT1946. And just, you know, picking up on some of the initial PK data that you're presenting here today, from your preclinical modeling, do you expect to be in the sort of linear exposure range across the dose range you're evaluating in the phase 1 study? And I guess, really, the question is, like, where do you expect exposure to go as you enroll and evaluate the 160-milligram cohort?
Yeah. So I guess it's a question, do we expect to see PK futility at some point?
Yeah.
We didn't see that preclinically, so, you know, I think we expect to, you know, obviously. You can do all the mouse animal studies you want, until we get into human, we're not gonna know. But, you know, we expect to see it continue to increase dose proportionally. But, you know, and that, that's kind of what our-
Mm-hmm
... data set says, but we'll, we'll have to see.
And just kind of stepping back, the commercial opportunity here, is it both the clinical and commercial opportunity, I guess, with the degrader approach, is one to compete with the kinase inhibitors kind of head-on? Or is it kind of be able to also kind of-
Yeah. I mean-
Mop up in places where patients are resistant to-
Well, I'll say the way we develop, right, is we start in the last line and move forward.
Yeah.
In fact, that data that you saw, those are all in patients who are refractory and have progressed on an inhibitor right?
Okay. Yeah.
So that really speaks to the potential of, you know, first of all, using this drug to start in the second line. You know, I think certainly we think the potential and the greater rationale is there for deeper, more durable remissions in the front line. You know, that'll be a future development path that we'll have to do once we take care of the second-line opportunity. You know, and I think it's interesting just to watch the space because I think it's Pfizer is working, correct me if I'm wrong, Scott, right, on moving their inhibitor into the front-line encorafenib into the front-line setting. I think it's the Breakwater study, right?
And I think if that happens, it actually increases the opportunity in the second-line setting.
Mm-hmm.
Because of the resistance mechanisms that I outlined, we know all these patients ultimately progress.
Yeah. I mean, I think your greatest likelihood of showing activity, finding activity would be in melanoma. Can you just maybe speak to the mix of histologies that are coming into the trial and, you know, across, melanoma, Non-Small Cell Lung Cancer, and CRC?
Yeah, I mean, so this is a study that's being run, I think, at about 14 sites, both in the U.S. and in Europe, and so we are seeing a broad mix across all the, you know... We're seeing some of the smaller, but the majority of patients are in melanoma, colorectal, and lung cancer. I don't know the specifics, you know, off the top of my head, but we are getting a good number across each of those. You know, again, because it's a phase I dose escalation, largely for safety, right? We're not enriching for one or the other.
Mm-hmm.
So when we show data, you're gonna see kind of a mix, and, you know, there's a good chance we may not have a critical mass of one of those indications at, you know, what we think is the recommended phase II dose or the maximum administered dose. But we were excited to see that 'cause all, again, all these patients are, will have had to have been exposed to and progressed on a BRAF inhibitor.
Strategically, here with 1946, I guess, how should we be thinking about its, you know, how you're advancing, whether alone or would also similarly seek a partner?
Yeah. That's a good question. Part of our excitement about this program is we think it's a program that we can advance on our own. Certainly in the colorectal cancer indication, right? That's a fairly focused but large enough market, big unmet need. It's the place where BRAF inhibitors kind of have the worst performance. That's something we think is certainly doable as a development strategy, as well as commercializing on our own. You know, I think we'll have to see how the data plays out. Melanoma is obviously a little bit more complicated.
Mm-hmm.
You know, lung cancer, while complicated, you know, in a select mutation-driven population, is certainly something we could also handle on our own. So we think this is actually an exciting program, you know, for us to keep as long as, you know, it makes sense.
Okay. All right. All right, well, if there are no more questions from the floor, Andrew and Kendra, Scott, I really appreciate your time this morning, and thanks, everybody, for joining the session.
Great. Thank you, Eric.