C4 Therapeutics, Inc. (CCCC) Earnings Call Transcript & Summary

Good afternoon. Welcome to the C4 Therapeutics AACR Investor Call on CFT7455 Clinical Data. My name is Vanessa, and I will be your operator for today's call. [Operator Instructions] I will now turn the call over to Kendra Adams, Senior Vice President, Communications and Investor Relations.

Good afternoon, everyone, and thank you for joining our call to discuss the clinical data for CFT7455 being presented at AACR. We will be making forward-looking statements today, and Slide 2 contains our legal disclaimer on this matter. Joining me on the call this afternoon are Andrew Hirsch, our President and CEO; Adam Crystal, our CMO; and Dr. Lonial, an investigator for the CFT7455 Phase I/II trial. Dr. Lonial is a Professor and the Chair of Department of Hematology and Medical Oncology at the Winship Cancer Institute at Emory University. Stew Fisher, our CSO, will also join for the Q&A portion of the call. I'll turn the call over to Andrew for some introductory remarks.

Thanks, Kendra, and thank you all for joining our call today. As you know, we have a broad pipeline of oncology programs, and that's shown here on Slide 4. And today, we're sharing clinical data from Cohort A of the ongoing Phase I/II trial of CFT7455, our IKZF1/3 degrader in multiple myeloma and non-Hodgkin's lymphoma. CFT7455 was designed with an enhanced PK profile and the early clinical data suggests that the markedly improved in vivo single-agent activity observed preclinically translates to the clinical setting. We've not seen single-agent clinical activity at such low doses with other approved or investigational IKZF1/3 degrader molecules. We're encouraged by the results from Cohort A and look forward to data from Cohort B1 and C, as we progress to the recommended Phase II dose. While I know most of your interest is on the clinical data, and that's the focus of today's call, I'd like to remind you of several preclinical presentations that our colleagues will deliver over the next few days in New Orleans that really demonstrate the power and capability of our TORPEDO platform for discovering and developing highly potent targeted protein degraders. These are outlined on Slide 5. I hope you have the opportunity to join these sessions either in person or virtually. Before I turn the call over to Adam and Dr. Lonial to discuss the clinical data, I wanted to remind you that we have several important milestones to achieve over the balance of the year, which are shown on Slide 6, including dosing our first patient with our BRD9 degrader, CFT8634; submitting an IND and initiating our Phase I study with our BRAF degrader, CFT1946; and completing our IND-enabling work on our EGFR degrader, CFT8919; and also continuing to advance the next wave of our research programs. We look forward to sharing updates throughout the year as we execute against our plans. Now I'll turn the call over to Adam Crystal, our Chief Medical Officer.

Thanks, Andrew. I'll start with a reminder on the role of IKZF1/3 here on Slide 7. IKZF1 and IKZF3 are transcription factors required for cancer cell growth and survival in multiple myeloma as well as non-Hodgkin's lymphoma, and they are the canonical targets of the IMiD and CELMoD class of molecules. Approved IMiDs, lenalidomide and pomalidomide, are widely used in multiple myeloma treatment and are IKZF1/3 degraders. They remain backbones of therapy in most lines of multiple myeloma. Though treatment has advanced considerably, most patients with multiple myeloma die of their disease. C4 Therapeutics' goal is to develop a best-in-class IKZF1/3 MonoDAC with increased clinical activity enabled by a differentiated PK profile together with catalytic activity, selectivity and potency. Together, these features could overcome resistance to IMiDs seen in later lines of therapy and improve patient outcomes in earlier lines of therapy. In short, CFT7455 catalyzes the cereblon-mediated degradation of IKZF1 and IKZF3, which results in the death of myeloma cells. Slide 8 shows the features of CFT7455, which result in potent in vitro activity. On the left, the binding affinity of CFT7455 to cereblon is assessed and an 800-fold improvement versus pomalidomide is demonstrated. The middle panel demonstrates the depth of degradation achieved by CFT7455 in comparison to other molecules of this class. CFT7455 has a high degree of catalytic activity, which is to say it's fast, degrading 80% of IKZF1 in 2 hours at a concentration of 1 nanomole. In comparison, pomalidomide has no activity at this dose. As shown on the right, these features together translated to a growth IC50 of 70 picomolar in H929 multiple myeloma cells. This represents a greater than 1,000-fold improvement in potency versus pomalidomide. The next Slide shows that CFT7455 demonstrates superior efficacy in the NCI-H929 xenograft model. 30 micrograms per kilogram results in robust tumor regression, while the efficacy of pomalidomide is modest at the clinically translatable dose. CFT7455 is as active as CC-92480 at [ 1/100th ] the dose. As the benchmark, based on preclinical data, we expected the 10 microgram per kilogram dose shown here to translate to a clinical dose of approximately 50 micrograms daily. On the right, from the same experiment at a dose of 100 micrograms per kilogram, you can see that after dosing is held on day 21, the observed complete regression is durably maintained for several weeks. Turning to Slide 10. We present a model of systemic multiple myeloma, MM1S. CFT7455 is as effective here as it is in the H929 xenograft model. The efficacy observed in this bone marrow-based myeloma model suggests that the consistently observed increases in in vivo potency in comparison to pomalidomide and CC-92480 is not an artifact of xenograft characteristics, and therefore, this potency is more likely to be clinically translatable. Slide 11 shows preclinical PK/PD results, which demonstrate a key differentiator for CFT7455. On the left, after a single dose, CFT7455 maintains concentrations above the DC80, which is the concentration required to degrade 80% of the target protein for all or nearly all of the 24-hour dosing period. In contrast, CC-92480 is undetectable at 24 hours. On the right, it's shown that both molecules achieved 100% degradation of target at the doses used, but CFT7455 is more effective in maintaining target degradation over time. I'll now turn the presentation over to Dr. Sagar Lonial to discuss the clinical data from Cohort A.

Thank you, Adam. The design of our first-in-human study for CFT7455 is shown here on Slide 13. This design facilitates the identification of a discrete recommended Phase II dose, as a single agent and in combination with dexamethasone in myeloma. Additionally, a recommended Phase II dose of single agent in lymphoma will also be identified. Today, we are presenting data from the now complete Cohort A. The starting dose in this cohort was 50 micrograms per day on a 3-week on, 1 week off schedule. 4 patients began treatment at the 50 microgram dose based on recommendations from the Safety Review Committee, the fifth patient in cohort A initiated treatment at 25 micrograms per day. The key enrollment criteria for these patients with relapsed/refractory multiple myeloma included greater than or equal to 3 prior lines of therapy, disease progression on or within 60 days of last anti-myeloma therapy refractory to both lenalidomide and pomalidomide, PI, glucocorticoid and CD38 monoclonal antibody. 5 patients enrolled, all with myeloma. On the following slides, I'll be walking through the data from Cohort A. The tables on Slide 14 show the baseline patient and disease characteristics, Cohort A enrolled 5 patients, all with multiple myeloma. As required for protocol, these patients are heavily pretreated with all patients having previously received both approved IMiD, PI and a CD38 antibody. Notably, 2 patients had also received prior CAR T cell. Prior lines of therapy range from 4 to 14 with a median of 5. 3 patients had plasmacytomas at baseline. PK profiles of the 4 patients initiated at the 50 microgram dose are presented on Slide 15. Preliminarily, Cmax occurred at about 4 hours and the half-life of approximately 2 days was observed. Importantly, between day 1 and day 15, a 3x to 4x accumulation was observed. In the setting of this accumulation, day 15 exposure achieved were comparable to those observed at the 10 microgram per kilogram dose in the H929 models. Target IKZF1 and IKZF3 degradation as assessed in PBMCs by mass spec is presented on Slide 16 for all patients in which samples were successfully collected and analyzed. As seen in both patients, who started dosing at 50 micrograms, as well as the patient, who started at 25 micrograms, 24 hours after the first dose, deep and sustained degradation of IKZF1and 3 was achieved. Observed degradation of IKZF3 at 50 microgram was deeper than the 70% degradation that had been predicted by preclinical modeling. On the next slide, we present serum free light chain data for 3 patients, all patients for whom data was available. One patient, patient 5 did not have a serum free light assessment after baseline, thus, change cannot be plotted. Patient 4 did not have PK collected on cycle 1 day 15, thus, AUC could also not be plotted. Here, you see that in addition to deep and durable degradation of IKZF1and 3, CFT7455 is also showing meaningful decrease in serum free light chains. The 3 patients, who started single-agent CFT7455 dosing at 50 micrograms achieved exposures of approximately 1 to 3 nanograms hour per ml and were observed to have meaningful decreases in the serum free light chain in the range of 41% to 78%. This is compared to CC-92480, another investigational IKZF1/3 degrader. Patients who dosed at 100 micrograms of this degrader, notably in combination with dexamethasone had comparable exposures, but no reduction in serum free light chain was observed. Comparable reductions with CC-92480 in combination with dexamethasone were observed at much higher exposures. This early data for CFT7455 indicates that the preclinical data demonstrating increased single-agent activity in in vivo models appears to be translating to the clinical setting. Slide 18 demonstrates the best responses and duration of treatment among the initial dosing cohort. Across the 5 patients treated, a best response of stable disease was observed. 3 patients achieved stable disease and 2 patients had progression of disease. Patient 2 achieved a free light chain difference of 78%. However, this did not achieve PR status due to the presence of a radiographically stable plasmacytoma. Slide 19 describes one patient's experience on single-agent CFT7455. This patient is a 60-year-old female who is diagnosed with Stage III myeloma in January of 2017 and enrolled on CFT7455 in June of 2021. This patient was treated at 50 micrograms daily for 21 days on and 7 days off for 5 cycles. The patient was heavily pretreated and had extramedullary disease. She had received 5 prior lines of therapy, including multiple IMiDs, proteasome inhibitors, stem cell transplant and a bispecific antibody. Notably, the patient's fourth regimen, the third regimen in the relapsed/refractory setting was a combination of pomalidomide with dara, carfilzomib and dexamethasone. The best response achieved with this regimen was progressive disease. While on our study of single-agent CFT7455, this patient achieved a meaningful decrease in serum free light chain of 78% with the best response of stable disease in the setting of radiographically stable plasmacytomas. With the addition of GCSF after cycle 1, CFT7455 was well tolerated in this patient. Slide 20 presents all adverse events. Adverse events were remarkable for grade 3 -- grade 4 neutropenias observed in 3 of 5 patients, as well as grade 3 thrombocytenia in one patient. No febrile neutropenia was noted. There were no SAEs reported, and no AEs resulted in treatment discontinuation or in death. Beyond the discussed cytopenias, there were no other safety signals. The next slide presents the trend of neutropenia observed in cycle 1. Neutropenia consistently worsened following day 15 and recovery was incomplete during the 7-day drug holiday. Due to the pattern of neutropenia and recovery, the mechanism is considered to be an on-target effect of degrading IKZF1, resulting in the downstream decrease in PU.1, resulting -- causing transient neutrophil maturation arrest. Two DLTs were observed at the 50 microgram a day dose. The first DLT in patient 3 was Grade 4 neutropenia lasting more than 5 days. The second DLT in patient 4 resulted from investigator decision to delay initiation of cycle 2 for greater than 7 days, 14 days in the setting of persistent grade 3 neutropenia. I'll now turn the call back to Adam.

Thank you, Dr. Lonial. To summarize, our early clinical data demonstrate that we were successful in developing a highly potent IKZF1/3 degrader that has the potential to be used as a dexamethasone-sparing agent. However, together, the potency and differentiated PK profile result in neutropenia due to the unanticipated depth and durability of target degradation seen at this dosing regimen. Other than cytopenias, no other safety signal was observed. On the left of Slide 22, we present modeling data demonstrating the impact of the extended exposure achieved by CFT7455. In this setting, with a 3 week on, 1 week off schedule, target degradation remains deep, even during the 7 day recovery period. Thus, insufficient time is permitted for neutrophil maturation. In contrast, the figure on the right shows that a 2 week on, 2 week off schedule would result in slow recovery of target, such that only during week 4, target levels will have recovered to greater than 50%. It's also worth noting that grade 4 neutropenia was only observed in patients, who had received 3 consecutive weeks of CFT7455. The 2 week on, 2 week off schedule is likely to aggregate the emergence of clinically problematic neutropenia. As critically, by maximizing the doses of CFT7455, which can be administered in the first 2 weeks of the cycle, we expect to achieve daily doses greater than 50 micrograms daily. This regimen will maximize the durable antitumor apoptotic effect during the dosing period, and we anticipate minimal tumor recovery during the portion of the cycle when CFT7455 is held. On the next Slide, we present our conclusions. The data we presented today demonstrates that the preclinically observed activity appears to be translating into the clinical setting and more single-agent activity was observed than anticipated at the starting dose level. On-target neutropenia was observed when CFT7455 was given at 50 micrograms on a 3 week on, 1 week of schedule. The differentiated PK profile points to the opportunity to explore alternative dosing regimens, giving CFT7455 for 2 weeks followed by a 2 week off period, which may mitigate neutropenia, but preserve antitumor activity. We are now testing this regimen, as part of the ongoing trial. As you can see on Slide 25, we are currently enrolling cohorts B1 and C at a 25 microgram starting dose and the trial is progressing as planned. We have completed modeling of the Cohort A data and expect this alternative dosing regimen to increase therapeutic index. We look forward to progressing the trial to identify the Phase II -- the recommended Phase II dose for both multiple myeloma and NHL patients. We are grateful to the patients and their families, who have participated in the trial today, and thank our investigators and C4T colleagues for their continued efforts to advance CFT7455 to patients. Operator, please open the line for Q&A.

[Operator Instructions] We have our first question from Eric Joseph with JPMorgan.

This is Chuan Hong for Eric Joseph. So our question is, since you are planning to explore 14 day on, 14 day off schedule to address the neutropenia problem. However, in looking at the plasma cell kinetics, like those shown for patient 2, we're wondering whether it's likely that you could achieve and maintain the responses and myeloma suppression through those -- the 2 week holiday.

Well, thanks for the question. I'll turn it over to Adam to answer that one.

Sure. Thanks so much. It certainly is a very critical question for the program. And I think my answer is I do believe that the 2 week on, 2 week off schedule will be able to maintain the activity -- antitumor activity, which has been observed. The reason I believe that is based on what we now know is a differentiated PK profile and how that compares to, for example, CFP-92480. A lot of our thinking, a lot of our planning, a lot of our internal data analysis has benefited from the data set, which has been put together with similar molecules developed by Celgene and BMS. Some of that data looked at alternative regimens with CC-92480, including the 14 day on, 14 day off regimen, we have moved to. You might remember that in that regimen, they saw what they refer to as a sawtooth effect. Serum free light chain did recover by the end of that 14 day off period, they didn't with the 2 week on, 1 week off schedule. Because our PK profile is different, we believe that we have -- that we will be able to sustain the antitumor effect during that 14 day holiday, said most simplistically, it's because our half-life is effectively twice as long. Therefore, we will maintain antitumor effects for twice as long at CC-92480.

We have our next question from Colin Bristow with UBS.

Congrats on the data and just really incredible potency. Just a couple of quick ones. I'm curious how you're thinking about the utility of dex based on the profile that you've seen to date. Has that, in any way, changed your appetite to either pursue a dex-free regimen ultimately or now move the plan more to a dex-based one? And then I'm just curious, in terms of the anticipated timing for the next steps, where would you foresee having the sort of critical massive data at the 14 on, 14 off schedule?

Yes. Thanks, Colin. This is Andrew. So I'll answer that. I think in terms of dex, I think it actually gives us a little bit more optimism that we may be able to do. It's a dex-sparing agent. I think if you look at similar data presented by others, they don't see anywhere near the reductions in serum free light chains in patients -- in combination with dex that we see as a single agent, I think that's important to remember that all this data we presented today as a single agent, not in combination with dex. So certainly, I think the goal will be to escalate from here at the new schedule. And I think that's where we think we could potentially still have it as a dex-sparing agent. We're not opposed to using dex. But I think right now, we're really excited about what we're seeing as a single agent. In terms of timing, we're not giving any guidance today on sort of next steps and update. I think we need to get into the -- as we're into cohorts B1 and C, we'll see how those progress. And as we get more visibility, as you know, in a Phase I, as you escalate, it's not always clear when you're going to get there. And so we're not providing any guidance on that today.

We have our next question from Etzer Darout with BMO Capital Markets.

Just maybe a couple. Do you have maybe any kind of ongoing hypothesis or thought around patient 4 that had the increase in serum free light chain. Any thoughts there? I know that the exposure data is not yet available? And then just secondly, if you could provide a little bit more color on the patient with the high degree of serum free light chain. I think it was what 78% or so, but that did not translate into response? And maybe a little bit color around that as well.

Yes. So I'll actually ask Dr. Lonial, if you could address those questions.

Can you restate the first one -- the first part again?

Yes. So on the exposure, the patient that had the increase in free light chain of 56%, and I know that we don't have the exposure data yet, but maybe kind of any sort of thought around why we saw an increase, if you will, of serum free light chain in that patient. I think it was patient 4.

Yes. I'm trying to think that -- I mean, that indicates lack of response, as -- so that patient may simply not have been sensitive to the drug. I don't have the exposure data in front of me for that individual patient. In terms of the descriptors around the patient that did have the 78% reduction, I think -- there are a number of things that really strike me as being important about that patient. First is they clearly were IMiD-resistant in a number of different lines of therapy. And from what we know about adverse events tolerated the treatment actually quite well. And so to see responses in an early Phase I study is certainly very encouraging, and I think speaks to the fact that this is a very potent mechanism of action that is able through its longer half-life able to overcome the resistance of prior exposure to IMiD class agents.

Our next question is from Tyler Van Buren with Cowen and Company.

I want to ask both on safety and efficacy. First on safety. So to be clear, since all grade 4 neutropenia events occurred at day 21, if you do the 14 day on, 14 day off schedule, do you believe that those grade 4 events would not have occurred and that the neutrophils would return to at or near baseline by day 28 and before you start the next cycle? And then on efficacy, once you figure out the proper dosing schedule, how do you plan to escalate and related to your qualitative comparison to 92480 serum free light chain reductions at these doses. Can you elaborate on how close you believe you are to generating responses based on when [ 92480 ] first saw them?

Sure. So I'm happy to comment on that. This is Adam. In terms of the degree of neutropenia that we anticipate seeing with the new schedule, I think of 2 benefits of the new schedule, which are obviously related, but separate. The first is, it's worth noting that the only patients, who achieved grade 4 when it was achieved, it was achieved after 3 consecutive weeks of dosing. So which is to say that by dosing for 2 weeks only one would expect that the depth of problematic neutropenia seen after 3 weeks would be less because they're not going to be getting drug on that third week. I think the second benefit is that to the degree that neutropenia is observed, whether it's worse on day 14 or worse on day 21, we'll see, but the patients will have more time to recover. So there's a double benefit here, right? One, the maximal degree of neutropenia will be lessened; and so two, will be the patient's ability to recover from that trough of neutropenia prior to beginning the next dose level. As for the second part of the question, which I think boils down to how are you thinking about escalating and when can you achieve more -- and when do you think you'll be able to achieve efficacious doses. The intent is to go down to goal. What do I mean by that? We're going to be giving drug on a 2 week on, 2 week off schedule. We're going to be giving 25 micrograms with the expectation that we will be able to escalate from there, and the clinical data will give us as to what doses we can reach. In terms of what dose level, I think will be efficacious in terms of observing responses. I think there it's wise to wait until the data flows in. You see the responses we had. We had 3 stable diseases and -- when we have more patients, we will see whether we get some responses along with that. My expectation would be the higher we go, the more responses we'll see. But rather than speculate at which dose level, I think we'll see objective responses. I think it's wise to wait until we have more patients dosed more objective data and take a look then.

We have our next question from Chi Fong with Bank of America.

I guess the first one is sort of the next step, dose exploration. I'm curious if you have any thought -- what's the current thinking about whether you would explore just the 14 day on, 14 day off? Or is there any thought process into whether you would explore more dosing regimen on top of that as you evaluate Cohort B1 and Cohort C? And I guess, I also have a follow-up question on sort of the correlation between the reduction of the serum free light chain, and it looks like you're getting into that 40% to 80% reduction, but you're not seeing response. So I just want to get incremental color. Are these patients getting dosed down or not getting sort of like a continuous treatment to see a benefit? Or is it just that because you run into DLT, you're not getting to as high of a dose or as high as our serum free light chain reduction for you to get to that response?

Well, so I can field that. Two parts to your question. The first was what regimens will you be exploring. The protocol is enabled and -- is enabled to explore alternative dose regimen, not just the 2 week on, 2 week off schedule. We're beginning with the 2 week on, 2 week off schedule for 2 reasons. One, it's the regimen we believe is most likely to be successful based on our understanding of the data and our subsequent modeling and analysis, but we will go where the data takes us. And within the existing protocol have the flexibility to do that. Those decisions will be made by looking at the data and discussing it with our investigators, including Dr. Lonial. In terms of serum free light chains, if you are curious in understanding how much drug was delivered to this patient, you can read that off of the swimmer plot on the poster, which is now available. We indicated when drug was given. I think that it is a function of the underlying biology of the patients with 5 patients. There is variability. There is variability in response. And I think it's a function of the drug being given at a less than ideal schedule and a less than ideal dose at that schedule, which is to say, I don't think it was necessarily a function of drug being held in the setting of adverse events. I think it was a function of the patients who we treated and the way they were treated.

Our next question is from Colin Bristow with UBS.

Just a quick follow-up for Dr. Lonial, really just high level. In -- how valuable and translatable do you view these early serum free light chain data? Just would love to get your thoughts there?

So I think seeing any hint of a response in the first dose cohort of a new Phase I study is always incredibly encouraging as an investigator and certainly, from a patient's perspective as well. I think the fact that the PK modeling and PD modeling is consistent with some of the preclinical data also gives me hopes, and that I think this data will be translatable to other doses and schedules as we get -- as we go through the Phase I portion of the study.

And we have our next question from Kelly Shi with Jefferies.

Okay. Can you hear me?

Yes. We can hear you.

Okay. So my first question is, could you actually comment on other heme toxicities beyond neutropenia that also have been associated with other IMiDs, such as thrombocytopenia and anemia? And based on like onsite -- onset time and severity, would you expect any differentiation from other next-gen IMiDs from your program? That's the first question. And the second question is BMS actually advanced 2 different next-gen IMiDs for HCL and multiple myeloma development and assuming based on different selection criteria. So I'm wondering what is the rationale that 7455 could be ideal therapy candidate that fits for both indications.

Sure. This is Adam. I can speak to that. On our table of adverse events, you can see that one patient did have -- go ahead -- did have a grade 3 thrombocytopenia. This is, I would say, consistent with expectations. It is the same underlying mechanism of action. Ikaros degradation does prompt thrombocytopenia through a similar mechanism. So the point that I would make is that to the extent that we are successful aggregating neutropenia-related toxicity with the new dosing schedule, we'll also be successful in doing so for thrombocytopenia. Anemia with this data set does not appear to be particularly problematic. And I think I'll stop my comments in terms of anemia.

And Stew, do you want to take the second half of that -- second question.

Yes. So thanks, and I think it's a good question. I think you're referring to in the BMS pipeline, there's -- as you know, CC-92480 is going for multiple myeloma and then you have this newer agent, 99282, which they're targeting towards lymphoma. Things are very interesting compare and contrast between these 2 molecules. 92480 has the potency in terms of degradation that we see in CFT7455. But as we've highlighted, the PK on that is relatively restricted to the blood compartment and relatively quick. In contrast, as I reviewed the data for 99282, that molecule has weaker activity around the ranges, I would benchmark it to iberdomide CC-220 in terms of its degradation potency. But interestingly, it does have PK that is at least on -- from what they've reported in a recent poster to be closer to what we see with CFT7455. So it has deeper tissue penetration and more extended half-life. And it's interesting to note that in their most recent poster, they did highlight that they're going to an alternative dosing schedule, as well to cover in lymphoma. Many of the questions that we're trying to answer here is how to manage efficacy over a longer-term duration related to this enhanced PK to leverage their activity. I think when you put those 2 together, you see that CFT7455 has actually the best elements of both enhanced catalytic activity and the enhanced PK. And so that's why we believe it's actually with this altered schedule going to make great impact on both multiple myeloma and lymphoma.

Our next question comes from Brad Canino with Stifel.

Could you, Adam, repeat what preclinical dose correlated with the 50 microgram human dose we started at? And then I guess, just stepping back, can you remind us the rationale for starting out at this dose instead of staging into it over a few lower cohorts [ sorting ] some alternative schedules like Bristol had done in some of their developments for the CELMoD.

Absolutely. So the achieved exposure at 50 micrograms was approximately what we achieved in mice at 10 micrograms per kilogram. That's the dose, which we show on the H929 xenograft achieved activity comparable to CC-92480 at 100x the dose or 1,000 micrograms per kilogram and is effectively stasis in that model. It's worth noting that, that is a quite an active activity to shoot for, and we're just looking at how it compares to pom, for example, at the clinical dose, which results in a modest tumor growth inhibition. In terms of why we began at 50, and why we began at 3 week on, 1 week off, our GLP tox enabled the starting dose of up to 100 micrograms daily. We chose to have that dose and begin at 50 micrograms. We anticipated that we would see activity, and that we would see -- that we would see activity, but not to the extent that we saw it. So one could argue, it started too high, maybe you should have started lower. I think that given the data in hand, it was a wise decision to start where we were. In terms of why we began on a 3 week on, 1 week off schedule and not others, I think it's fair to say we considered alternative dosing [ giving ] our understanding of the molecules properties. But really, we're weighed by the depth of data with other molecules, including 92480, which had explored other schedules and found 3 week on, 1 week off to be the best. I think using the retrospectoscope using the data we now have in hand, clinically, one could say it may have been advantageous to start elsewhere. But with the data we had in hand at the time, I think it was a reasonable decision.

[Operator Instructions] We have our next question from Christopher Liu with SVB Leerink.

With the CC-92480 data that we've seen so far, we saw some immunomodulatory impacts to T cells, for example, as well as NK cell proliferation. How important do you think that is for the CELMoD agent and for your asset?

Sure. This is Adam. I'm happy to field that question. It's an important question. I think worth pointing out that in the xenograft models we demonstrate or we provide there is no effective immune modulation of T cell activation. These are [ renewed ] models. So what's read out there is that cell autonomous killing that results in tumor depletion. That said, I believe the literature and the literature supports that there is an immunomodulatory effect of this class of molecules, T cell activation, and that contributes to antitumor effect. To what degree, I think it's fair to say is an open debate and difficult to conclude. Now that said, the immunomodulatory effect of this class of molecules is driven by the same mechanism, meaning it's driven by Ikaros. When you deplete Ikaros, it results in upregulation of T cell activation. So to the extent that we have demonstrated upregulate -- increased potency and Ikaros degradation, one would expect effectively linear increase in T cell activation on a dose-by-dose basis.

Got it. And then for the patients, who were dose reduced, when the time line were they dose reduced?

So there -- of the 5 patients -- the fifth patient dose began at 25 micrograms based on the recommendation of the SRC having seen neutropenias in the other patients. Of this -- there were 2 dose reductions, patients who started at 50 and dose reduced to 25. One was dose reduced after 8 days of dosing during cycle 1. That was also based on the recommendation of the SRC rather than a change made on the observation of toxicity in that particular patient. And you can see how that read out, for example, on the poster [ and the PD ] for Ikaros, where we document the time of dosing change and the impact that [ half dex ] was had on pharmacodynamics. And the third patient, who dose reduced from 50 to 25, I believe, did so during cycle 2, and did well on 25 from a perspective of neutropenia.

Yes. I'd just like to -- this is Stew. I just want to return to that immuno activation question. I think it's a great point. And I just want to confirm that we have demonstrated in-house, not have -- we haven't yet published it, but we've confirmed in-house using in vitro models that CFT7455 does, in fact, potently activate T cells, and it does it strongly correlating at the potencies we see with degradation. So I'm just reinforcing Adam's point, not only is it theoretical, but it's actually been observed in our own internal studies here. So we will publish that in time. But I just want to make sure that you're aware that we've confirmed that effect.

And thank you so much. We have no further questions at this time. I would now like to turn the call over to our presenters for closing remarks.

Great. I just want to thank, everyone for all your attention today. As you can see, we believe we have a differentiated IKZF1/3 degrader that has the potential to improve patient outcomes. We look forward to completing cohorts B1 and C, as well as initiating Cohort B2, and we look forward to updating you in the future. Thanks, everyone. Have a great weekend.

And thank you. Ladies and gentlemen, this concludes our conference. We thank you for participating. You may now disconnect. Speakers, please stand by. Goodbye.