Good day and welcome to the C4 Therapeutics Phase I trial data of Cimcitamide in multiple myeloma presented at IMS 2025 conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your touch-tone phone, and to withdraw your question, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Ms. Courtney Solberg, Associate Director of Investor Relations. Please go ahead, ma'am.
Good afternoon and thank you for joining our call to discuss our Phase I data of Cimcitamide in multiple myeloma. These data were presented at the IMS 2025 annual meeting earlier today. We will be making forward-looking statements today, and slide two contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO, and Leonard M. J. Reyno, our Chief Medical Officer. We will begin with opening remarks and then walk you through the clinical data for Cimcitamide in multiple myeloma and next steps in clinical development. We will end today's call with a Q&A session. This will include Kendra Adams, our CFO, as well as Dr. Benoit Dacal, a clinical investigator for multiple myeloma. Dr. Dacal presented the Phase I clinical results at IMS 2025 earlier today. I will now turn the call over to Andrew Hirsch for some introductory remarks.
Thank you, Courtney. The focus of today's call is on the Phase I data for Cimcitamide in multiple myeloma and the next steps in development. I wanted to take a few moments to highlight key elements of our strategy to create a new generation of medicines that transforms patients' lives by delivering on the promise of targeted protein degradation. First is to advance our clinical stage assets through the development stages as data warrants to the commercial setting. Cimcitamide is our most advanced and de-risked program and remains our top priority. We also continue to advance CFT 8919 in collaboration with our partner, Beta Pharmaceuticals. The second pillar of our strategy is to leverage the learnings from 10 years as a leader in TBD science to advance a preclinical portfolio of degraders against novel targets in areas of high unmet need.
Under the leadership of our new Chief Scientific Officer, we've expanded beyond oncology into other indications that build upon the learnings of the early stages of this new modality. We will update you in the future as these programs advance. Lastly, we continue to advance our established collaborations in both oncology and non-oncology indications as a way to expand the application of TBD, but also achieve financial milestones that can contribute to our capital formation plan. We're excited about the recent news from Biogen that the IND for BIB-142 and an IRAK4 degrader has cleared and clinical trials will start soon. Taken together, we're excited about the potential here at C4T and look forward to updating you on our progress across all three elements of our strategy.
As I mentioned, our top priority is to quickly advance Cimcitamide through the clinical development process to targeted high-value labels that address important segments of the multiple myeloma market. While degrading IKZF1 and 3 are not new therapeutic strategies, given the biology of multiple myeloma, this therapeutic approach is fundamental to halting the disease, which is why the on-market degraders have had significant market penetration. However, it's important to remember that these are not optimized degraders, whereas Cimcitamide is, and the data we'll present today will demonstrate that Cimcitamide has a potential best-in-class profile. Based on the data and our perspective on the evolution of the multiple myeloma treatment landscape, we've identified an efficient development plan that we can execute with a differentiated label-enabling strategy than other next-generation IKZF1/3 degraders are pursuing.
That strategy leads to potential $2.5 to $4 billion peak revenue opportunity across two market segments in combination with a BCMA-BITE in second line or later, and in combination with dexamethasone in fourth line or later. As some of the new immune-directed therapies move to earlier lines of treatment, multiple myeloma patients will live longer, but since these therapies are not cures, there will ultimately be a growing late line multi-refractory patient population, similar to the one we studied in the Phase I. Additionally, while the efficacy of new immune-directed treatments has been impressive, there's an opportunity to enhance both the rate and depth of response by boosting T cell activity through the addition of a highly selective IKZF1/3 degrader with class-leading tolerability. Everyone at C4 Therapeutics is excited about the potential for Cimcitamide, and we're in execution mode to begin the next set of studies in early 2026.
Now I'll turn it over to Len to share more detail about the Cimcitamide data and the path forward.
Thank you, Andrew. I want to start off by emphasizing the importance of Ikaros and Aiolos, also known as IKZF1 and IKZF3, respectively. As Andrew mentioned, these targets are central to multiple myeloma biology and are well established in the treatment landscape. IKZF1 and 3 are transcription factors essential to cancer cell growth and regulate the activity of IRF4, another transcription factor that multiple myeloma is dependent upon for survival. As a result, multiple myeloma has strong dependencies on IKZF1 and 3, and degrading these targets leads to plasma cell death. Neutropenia is an inevitable consequence because IKZF1 and 3 play a role in early neutrophil maturation, and neutropenia is observed with this class of medicine because of reduced replenishment of neutrophil populations over time rather than a direct effect on neutrophil cell viability. Incorporating a dosing holiday period allows us to balance both cell kill and neutrophil replenishment.
With Cimcitamide's half-life of approximately two days, the 14 days on, 14 days off dosing regimen is optimal. As seen on the right graph, IKZF1/3 degradation also stimulates the immune system by activating fully differentiated T cells and preventing T cell exhaustion. This is an important concept as we think about combinations, especially with bispecific antibodies. With a potentially best-in-class profile, Cimcitamide is well positioned to be a backbone therapy in multiple myeloma across multiple lines. To orient ourselves, this slide describes the progress we've made and where we are going. This data enabled us to advance to the next phase of development. With Cimcitamide dose escalation complete and the data presented at the IMS today demonstrating class-leading anti-myeloma activity, a differentiated safety profile, as well as compelling evidence of immune activation.
To that end, we are on track to initiate a Phase II evaluating Cimcitamide plus dexamethasone in a fourth line or later setting with the potential for accelerated approval. We are also on track to initiate the Phase IB trial in combination with a BCMA-BITE in the second line or later. If the Phase IB trial is supportive, we would trigger a Phase III trial for Cimcitamide in combination with a BCMA-BITE. This Phase III trial has potential for accelerated approval and will serve as a confirmatory trial for both combinations. This slide demonstrates all of the comprehensive dose escalation work we have completed to get us to this path. Based on the data generated to date, the 14 days on, 14 days off schedule remains the optimal dosing schedule for Cimcitamide.
We have escalated up through five dose levels with the 100 microgram dose level declared safe and is the maximum administered dose. Based on our discussions with investigators, we believe if we dose escalated higher, we would have exceeded the MTD, making further dose escalation not warranted. It should be noted that dose escalation and subsequent dose level expansion decisions use the BLRM methodology. Safety was initially determined in cohorts of three to nine patients, and then dose levels were expanded to include up to 20 patients. Also, as a reminder, during cycle one, routine GCSF use was not permitted in the escalation cohorts determining safety, but could be used at investigator discretion in all subsequent cycles. There was no restriction on GCSF use in any cycle for patients enrolled during dose level expansion.
On this slide, we describe the characteristics of the multiple myeloma patients enrolled on the Phase I trial of Cimcitamide in combination with dexamethasone. The median age of patients enrolled was 67, which is typical for relapsed refractory multiple myeloma with an age range of 39 to 90 years. 32% of patients have extramedullary disease, a marker of more difficult to treat disease. Importantly, all of these patients are heavily pretreated. Indeed, patients had a median of seven prior therapies ranging from 3 to 22, and 79% of patients were pentaclast exposed. Note in the green boxes, the population treated in this trial also included patients who had progressed despite prior CAR-T or T cell engager therapy. 75% of the patients had one or the other therapies, including 75% with prior BCMA therapy, 47% with prior GPRC5D therapy, and 29% who had both CAR-T or T cell engager therapy.
Despite the success of these novel therapies, as the enrollment data from our trial shows, these patients are still progressing and continue to need more treatment options representing the current high unmet need. Let's now examine the safety and tolerability profile of Cimcitamide plus dexamethasone. To summarize, Cimcitamide plus dexamethasone demonstrated a differentiated safety and tolerability profile in a highly refractory late line population. This supports late line development as well as the possible combination with other anti-myeloma agents. Notably, neutropenia was manageable, supported by no discontinuations related to Cimcitamide and minimal treatment-emergent adverse events that led to dose reductions. This is important for two reasons. First, the number one reason patients came off of this study was due to progressive disease and not due to safety. This supports the fact that Cimcitamide is well tolerated for those that derive benefit, and this bodes well for full development.
Secondarily, this is a key differentiator compared to other IKZF1/3 degraders in the clinic. In addition, we'd like to highlight the risk of neutropenia did not increase over time, and we observed limited GCSF use, which again supports the minimal impact of neutropenia on the patient experience. I will now walk you through the Cimcitamide plus dexamethasone safety data in more detail. As expected for all drugs in this class, the most common adverse event was neutropenia. 61% of patients experienced all grade neutropenia; however, only 33% of patients experienced grade 4 neutropenia across all doses. Febrile neutropenia occurred in only 6% of patients. Only 19% of patients experienced thrombocytopenia of any grade, with 4% reported as grade 4. Importantly, only 6% of patients had dose reductions due to treatment-emergent adverse events, and there were no discontinuations related to Cimcitamide safety.
This data continued to demonstrate Cimcitamide's well-tolerated profile and that patients are not coming off treatment due to safety events. Let's now examine the common and important side effects across the individual dose levels tested. In general, rates of grade 3 and 4 neutropenia were remarkably consistent across each dose level. We do note the 75 microgram dose level has a numerically higher neutropenia rate, an outlier from the other dose levels. It's important to note, however, that 95% of the patients enrolled at this dose level had received prior stem cell transplant, which is known to increase the risk of neutropenia to any given myelosuppressive agent. Regardless of the rate of neutropenia at any given dose level, the more significant question is what are the clinical consequences of neutropenia, bacterial infections, and febrile neutropenia.
In this regard, you can see the rate of grade 3 or greater infections across all dose levels was only 25% and, in fact, is a mixture of both bacterial and viral etiology and did not increase as dose level increased. Finally, the incidence of febrile neutropenia was also low, with no dose level having more than one patient with febrile neutropenia. On this next slide, we break down the incidence of myelosuppressive side effects, including the use of growth factor support and significant infections across multiple cycles of treatment. It is remarkable to note that the majority of myelosuppressive-related side effects occur in the first two treatment cycles. The risk of neutropenia does not, in fact, significantly increase over time, with only 6% of patients experiencing grade 3 or 4 neutropenia for the first time after cycle two.
This bodes well for further success in late-stage development and, again, supports the notion that patients do not come off of therapy because of treatment-related side effects. As you can see from the green bars, the pattern of stable and modest myelosuppression is also not the result of increasing use of growth factor support. In fact, only 40% of patients received GCSF at any point during their course of therapy, and GCSF use did not increase in later cycles. Importantly, 32% of patients are still on treatment after cycle eight, consistent with clinical benefit from Cimcitamide. Taken together, this data strongly supports the differentiated safety and tolerability profile of Cimcitamide in combination with dexamethasone in this highly refractory population. Now let's turn to the evidence of class-leading anti-myeloma activity. As summarized on this slide, IMWG objective responses were achieved across all dose levels.
Patients enrolled at the highest dose levels, 75 and 100 micrograms, respectively, achieved a 40% and 50% objective response rate. This includes a patient who achieved an MRD negative CR at the 100 microgram dose level. Importantly, these responses were durable. The median duration of response across all dose levels was 9.3 months at the time of the data cutoffs, with the median duration of response not yet reached at the two highest dose levels where a number of patients continue on therapy. While we observed compelling activity across multiple dose levels, it's clear there is a dose-related response at our highest dose level of 100 micrograms. Now let's examine how pharmacokinetic and pharmacodynamic data further support optimal therapeutic outcomes at the two highest dose levels. As a reminder, Cimcitamide in combination with dexamethasone, when given over a 14-day dosing schedule, shows dose proportional increases at each dose level.
The half-life is approximately two days. On the right-hand side of this slide, at all dose levels tested, you see degradation of IKZF1 and 3 is observed. If we specifically look at IKZF3, which is the most cited in relationship to myeloma control, there is deepened and prolonged duration at 75 and 100 microgram dose level. This data further supports that Cimcitamide is a highly potent degrader and at the two highest dose levels is associated with durable and meaningful degradation, which, in fact, persists over 21 days of the 28-day cycle. In addition to deep degradation, secondary pharmacodynamics such as CD8 positive T cell activation were observed at all dose levels treated, as measured by significant elevation of cells with HLA-DR and CD38 markers after 7 and 14 days of doses. These activated T cells persist until day 21 of cycle one.
This T cell activation, as expected, is associated with IL-2 elevation. It's important to note this immune enhancement is actually seen across all dose levels tested. This is an important concept as we think about the combination with BCMA-BITE. Bispecific antibodies exhaust T cells, which limits the durability of response. As a result, we believe with Cimcitamide's immune enhancement profile that we can increase the quality of BITE response and durability. To better understand the relationship between Cimcitamide exposure and objective evidence of anti-myeloma activity, a population pharmacokinetic analysis was conducted. On this slide, we plot the decrease of serum-free light chain in individual patients against the population PK-derived AUC for that same patient. It's clear that the higher AUCs are associated with more predictable light chain reductions, which are a prerequisite for IMWG responses.
In this regard, patients who achieved AUC in the highest exposure quartile achieved a 52% reduction in serum-free light chains. The likelihood of achieving this level of exposure is optimized at 100 micrograms, which we'll show on the next slide. Here on this slide, we plot the reductions of serum-free light chains as a pharmacodynamic parameter across each individual dose level. If you focus your attention on the blue and purple bars, which represent 70 and 100 micrograms respectively, it is easy to tell that these two dose levels have the greatest reductions. Importantly, over all doses tested, 73% of patients demonstrated decrease in light chains, and 50% of patients with elevated light chains achieved at least a 50% decrease in serum-free light chains. Finally, as expected, this reduction in light chains predicts evidence of objective responses using IMWG criteria.
Here, the data demonstrates that Cimcitamide is highly active at a range of doses, achieving a 34% overall response rate across all the doses tested. There's also clear evidence that higher doses are associated with more predictable and deeper responses as seen at the 75 and 100 microgram dose level. We achieved a 40% overall response rate at the 75 microgram dose level and a 50% overall response rate at the 100 microgram dose level, including one patient at 100 who achieved an MRD negative CR. We should also note that as of September 5, which is after the data cutoff, one patient at the 100 microgram dose level who is not reflected on the graph became efficacy evaluable and achieved a PR. Additionally, one patient who was included in the graph as a VGPR converted to a CR.
Taken together, these data show, in fact, that Cimcitamide plus dexamethasone has a class-leading anti-myeloma effect. Now let's turn to examine durability. The median duration of response across all dose levels is 9.3 months. At the two highest dose levels, we've not yet reached the median duration of response because 67% of patients here who achieved a PR or better remain on therapy as of the cutoff date. Together, these data points demonstrate that patients who responded experienced a durable and clinically meaningful benefit. We recognize the importance of viewing the Cimcitamide data set in context with other drugs that are in development in the class. We must caveat that there are inherent limitations in cross-trial comparisons, especially in Phase I study populations, and the data shown here is provided only as a benchmark for relative comparison. No head-to-head trials have been run.
Demographically, our patient population is quite different from the Zignamide and Ibrutamide Phase I populations. Our Cimcitamide trial patients were the most heavily pretreated, especially as it relates to having previously received the BCMA-directed therapy. Our trial highlights the fact that despite novel treatments used in earlier lines of therapy, patients are still progressing. In fact, 75% of our patients had prior BCMA-directed therapy. While Ibrutinib's Phase I trial did not report patients progressing on BCMA-directed therapy, these therapies had not been approved when this trial was enrolling. Also, only 59% of their patients were triple class exposed. When we look at Mesigdomide's dose escalation, 12% of patients had received prior BCMA-directed therapy, and only 56% were triple class exposed. Against this backdrop, Cimcitamide has potential to be best in class based on both its safety and anti-myeloma characteristics.
As it relates to safety, our clinical data supports a differentiated safety profile compared to the other degraders in development. If we examine neutropenia across all three trials, there were similar levels of grade 3 neutropenia. As a reminder, grade 3 neutropenia, while measurable, is rarely of clinical consequence. Grade 4 neutropenia, which is associated with clinical complications, favors Cimcitamide versus Mesigdomide. In comparison to Mesigdomide and Ibrutinib, Cimcitamide demonstrated minimal disruptive events and had significantly fewer dose reductions due to adverse events in a cross-trial comparison. The safety signal supports the ability to give Cimcitamide with manageable safety consequences and to give it at the intended dose across multiple cycles. Now let's turn to the anti-myeloma activity observed. Cimcitamide demonstrated compelling activity across all dose levels and especially at the two highest dose levels with durable responses that are ongoing.
Taken together, we believe this profile differentiates Cimcitamide from other IKZF1/3 degraders in the clinic, especially against the backdrop of a highly refractory population presenting for disease-modifying care in 2025. The next two slides further illustrate this point in two patient vignettes. This first case relates to a 42-year-old male who achieved an MRD negative CR response after three cycles at 100 micrograms. Prior to achieving this response, the patient had a four-year history of multiple myeloma with extramedullary disease and prior to our trial had, in fact, received 17 prior therapies. In the month prior to enrollment, the patient had progressed after therapy with talquetamab, a BITE antibody directed against GPRC5D. At the time of the data cutoff, this patient remains in CR after eight cycles. The second case demonstrates and describes the activity in a 90-year-old woman who was enrolled with light chain disease after five prior therapies.
Her last prior therapy, in fact, was tocilizumab with the best response of progressive disease. She has tolerated therapy well and, in fact, had a VGPR after two cycles, which continues after the data cutoff, currently post cycle four. Summarized, Cimcitamide has demonstrated class-leading anti-myeloma activity, a differentiated safety profile, and immune enhancement, which de-risk its development in the next phases. With this data, along with feedback from the agency, we now have a clear and efficient path forward. On the next few slides, I will describe this path in more detail. We acknowledge that the multiple myeloma treatment landscape includes a multitude of currently approved options. Importantly, targeting IKZF1/3 is biologically relevant in any line of therapy due to its importance as a primary mechanism to inhibit plasma cell proliferation.
Commercially, this is manifested by the inclusion of the drug class in multiple lines of therapy and regimens, which you can see on this slide marked by orange boxes. Our all-oral regimen with Cimcitamide has the potential to be used across multiple lines of therapy as a result, and C4T has identified two distinct near-term development opportunities. The first is Cimcitamide plus dexamethasone in the fourth line plus setting, and the second is Cimcitamide in combination with the BCMA-BITE in the second line plus setting. If we achieve labels for these two regimens, we project peak revenue opportunity in the range of $2.5 to $4 billion. The Cimcitamide plus dex strategy in the fourth line or later is supported by the fact that despite high response rates of recently approved later line assets and regimens, patients continue to progress, including after receiving BCMA-BITEs and CAR-T.
While many patients are living longer, the median survival of quad or penta-class refractory patients is less than a year, with a range of approximately 5.6 to 9 months. The next slide describes the rationale for Cimcitamide plus BCMA in the second line or later. T cell directed therapies currently are an important segment of the multiple myeloma market and include both BITEs and CAR-Ts. While CAR-Ts have a higher response rate, their widespread adoption is more challenging due to technical operations and clinical administration issues than BCMA-BITEs. The use of BCMA-BITEs may therefore be an even more attractive option if both the response rate and the quality of response could be increased. It is now accepted in the literature that T cell exhaustion limits the ultimate effectiveness of BITEs.
We and others have demonstrated that degradation of IKZF1 and 3 can reverse or limit T cell exhaustion and thus enhance therapeutic cytokine production. That is why we believe with Cimcitamide's ability to activate T cells and with a potential best-in-class safety profile, the combination could increase the effectiveness of this T cell directed strategy with the opportunity to pick up a portion of the CAR-T market share and a growing segment of the BITE adoption in practice. Based on this rationale, we've outlined a strategic and efficient development plan to registration to take advantage of the growing multiple myeloma population, as well as changes in the treatment paradigms for this disease. First is a non-randomized Phase II trial in the fourth line plus population evaluating Cimcitamide plus dexamethasone, which we believe has been de-risked by the data set we shared today.
Second is a Phase IB trial in combination with a BITE, which aims to characterize the safety and quality of responses. If the data from the Phase IB trial supports it, we would then trigger a Phase III trial of Cimcitamide plus a BITE with the opportunity to use ORR from this trial for accelerated approval. The Phase III trial is designed to support full approval for both the second line or later combination with a BITE and the fourth line and later combination with dexamethasone, where full approval would be triggered by a time-to-event endpoint. We're on track to initiate the single-arm Phase II trial of Cimcitamide plus dexamethasone in the first quarter of 2026 with a targeted enrollment of 100 patients. The RPGD for this trial will be finalized by year-end in consultation with the agency.
We expect to share the initial ORR data resulting from this trial in the second half of 2027. The Phase IB trial with the BCMA-BITE is on track to initiate in Q2 2026, with the goal to characterize safety and quality of the response in the combination and establish an optimal dose for Cimcitamide. Doses of 50, 75, and 100 micrograms of Cimcitamide will be tested starting at 75 and, depending if it's declared safe, we would evaluate then simultaneously doses of 50 and 100 micrograms. The first part of this trial is expected to enroll between 30 and 50 patients, and we expect to share data from the Phase IB trial in the second half of 2027. To conclude, today we have reviewed data that supports our thesis that Cimcitamide has the potential to be a best-in-class IKZF1/3 degrader in the growing multiple myeloma market.
Our clinical trial has demonstrated class-leading safety and anti-myeloma profile in a heavily pretreated population. The data supports the differentiated development path we've outlined, which is designed to capture a significant portion of the growing commercial multiple myeloma marketplace. We're on track to declare the RPGD by the end of the year and initiate the Phase II trial in combination with dexamethasone in Q1 2026 and the Phase IB trial in combination with the BCMA-BITE in Q2 2026. The operational path to achieving these goals is clear, and we've initiated all the appropriate activities to ensure we continue advancing Cimcitamide towards value creation for both patients and our stakeholders. Operator, please open the lines for Q&A.
Thank you. We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you are using a speaker phone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we'll pause momentarily to assemble our roster. The first question will come from Sudan Loganathan with Stevens. Please go ahead.
Hi, good afternoon, Andrew and C4T. Thank you in advance for taking my questions and congrats on achieving this crucial milestone with a very positive outlook for the Cimcitamide program. My first question is regarding the upcoming Cimcitamide plus BCMA-BITE specific trial. What magnitude of efficacy are you hoping to see to justify moving directly into a Phase III? Is the bar currently the BCMA-directed therapy monotherapy outcomes of approximately 60% or are to be met or exceeded to justify green lighting a Phase III combo study? Additionally, can you share which BCMA-BITE you may plan to use, if it will be another agent and why if it's another agent? I may have some follow-ups after.
Yes, Pat, thanks for your question. I'll turn over to Len to answer some of the technical design questions. At this point, we've not decided the BCMA-BITE that we'll be going with. We're currently evaluating that now, and we'll hopefully update you when we've made that conclusion.
The second part, or actually the first part of your question, but a super important part, I want to speak to the strategy here. We do think that regardless of which BCMA-BITE we study, there is an opportunity to improve both the magnitude of the response, but actually increasingly importantly, the quality of the response. What we'll be looking at is not just response rate, but actually obviously the CR rate and in fact the MRD negative CR rate. In terms of predefining what those differences might be, we need two things. We need to then characterize it on the BITE we're actually using, and we need to get a read of the initial data in small cohorts for qualitative decision making.
The assessment of the difference, though, will require randomization, and we think within the first three dose levels, we'll be able to get enough information in groups of patients that are around 15 or so at each dose level to make that qualitative decision and plan the Phase III trial. How big that trial is and what the eventual sample size is and the statistics around that, of course, will depend on data that we don't have yet in hand. We think it's a viable strategy and in fact provides an opportunity, as we said in the deck, for a second accelerated approval.
I'll remind you in that regard, an early predefined look at the CR rate in particular on a BITE randomization trial provides an opportunity to go to the agency to discuss that for accelerated approval and then to use the data from the same trial on a time-to-event endpoint for full approval.
Great. I appreciate the color there. If I can squeeze in a follow-up on the regulatory side, is the FDA expecting confirmatory data from the BITE combo Phase III to serve as a confirmation for the monotherapy accelerated approval, or will there be maybe two separate confirmatory strategies to be required? Lastly, could you share what the median follow-up time was at the July 2025 cutoff and how should we think about the maturity of the DOR signal, especially since it wasn't reached yet at the higher doses? Thanks again for all the answers.
Okay, I will tackle that in two parts. In the regulatory part, the randomized time-to-event endpoint for full approval for the BCMA-BITE would also serve for full approval for the non-randomized indication. It would be one randomized trial that ultimately could drive full approval in two indications. To answer your second question, the median duration of therapy, I'm not sure if I have that number up top. I turn it up, Dr. Dacal. Yes, I'm sorry.
This is Dr. Dacal. The median duration of follow-up for PFS is about seven months, seven and a half months, and for the DOR is about four to five months. It's still pretty early. As you know, if you recall the data, about at 75 or 100, a lot of patients are still on treatment, 67% of the patients. We're anticipating the median DOR is going to be much longer than the median DOR of 9.3 months. That will continue to follow up with the patient.
Gotcha. Also, the median follow-up time, was there the July 2025 cutoff? Was there kind of a range for that as well?
I would say the median follow-up is over seven months.
Okay. Awesome. Thank you so much. Again, congrats on the completion of this style with the positive outlook for Cimcitamide's program. Thank you.
The next question will come from Brad Canino with Guggenheim. Please go ahead.
Hey, thanks for the question and great to see this comprehensive data in the forward path outlined. The immediate question that comes to mind is how you're thinking about the right dose for the fourth line dexamethasone combo. You see great efficacy at 75. That improves at 100, but the DLTs also start to emerge at 100. It would be helpful to understand why those DLTs don't immediately invalidate that dose and how you think this is, with the optimized degrader still having a therapeutic index across the dose range that you've presented here today. Thank you.
Thanks for the question, Brad. I'm going to answer part of it, and then I'm going to ask Dr. Dacal to speak to it as well. In terms of dose selection for the Phase II, our guidance that we're working on is that we do believe that 100 is the optimal dose, notwithstanding the observations you made from the data set. First, with respect to the number of DLTs at 100, that's in nine patients in a BLRM model. That actually does not exceed the MTD per the statistics of the trial. Actually, per those statistical modeling, it recommended actual further dose escalation. I think to your point, there is a sense that there is more evidence of complications, if you will, at a higher dose. However, what's important to note is those patients did not come off therapy. They continued on therapy.
I'm going to hand it over to Dr. Dacal to speak to this more broadly.
Yeah, I think what we have seen here in this one is when you look at this deal, this specific neutropenia is more kind of prevalent in the first cycle. After the first to second cycle, the patients really maintain the counts pretty well. I can tell you for sure, for a lot of patients being treated in this program, including all dose levels, not only on this and all those levels, there are very few patients after cycle two where we have to either reduce the dose or discontinue the dose because of grade 4 neutropenia. I think, as Len said, in that 100 microgram, that didn't exceed the DLT based on the BLR methodology. I think that is the right dose, in our opinion, that we can expand the Phase II for the efficacy and safety.
To follow on from that, however, Brad, when you go into Phase II with efficacy seeking trial, you need to have a recommended starting dose and obviously a dose reduction strategy. What I think is really important for successful development here is what you've already pointed out, that we actually have compelling efficacy at 75 as well. Drawing on what Dr. Dacal is saying, these are patients with late line relapse refractory disease and no really viable options. Getting their disease under control with the highest dose possible, we think makes the most sense. We do have obviously a rational dose reduction strategy, and our data collectively fully supports that. Obviously higher exposure is associated with deeper degradation of the targets, and ultimately we think higher quality long-term responses.
I'll just add, recall in the protocol, GCSF use is not allowed during the DLT evaluation period. To me, more relevant is what's the grade 3 or 4 neutropenia rate across all the doses, including all the patients, including the expansion, because that's more relevant of what you would see in clinical practice as the dose is going to be used, and we wouldn't have that restriction in the Phase II and in future studies.
Got it. Maybe if I can just ask you to expand upon this a little bit, I think additional commentary would be helpful about why you might not be seeing the sequelae of neutropenia like fevers and infections as much as you might see with other neutropenic agents, even Bristol's Mesignamide. Another way of asking the question is why the clinical consequences seem to be decoupled from the rates of high-grade neutropenia that you're reporting on the safety table.
I'm going to speak first, and then again I'm going to hand it over to Dr. Dacal. I think one of the issues that we benefit from is the 14 days on, 14 days off schedule, and what I see, one of the theories is if you look at those degradation curves as it relates to IKZF3, you can see from day 14 to day 21 you get a gentle rise, and then you get continued to day 28. At some point, we're able, I think, to get it, release the brake enough to get neutrophil recovery. The actual consequences are limited, and the 14 days off really helps us. Dr. Dacal, please.
Yeah, no, I agree. I think, you know, when you look at the Mesignamide, you know, three weeks on, one week off, so it's a little bit long duration in my opinion. The beauty of this schedule of 14 days on, 14 days off, what I have observed in doing that 14 days off, sometimes we see that we check the labs of these patients and they have nicely recovered by the, you know, by third week, they've already, most of them have nicely recovered the neutrophil count. I think it has to do mainly with the schedule. We know that it's a class effect of delayed neutropenia, you know, having neutropenia because of delayed granulocyte maturation. I think giving the scheduled break really, you know, helps us the neutrophils to recover and so that doesn't compromise the subsequent cycles. At least that's what we saw in the clinical trial.
As Andrew mentioned, in terms of GCSF use, you know, it's not that very high. It's only 40% despite not letting cycle one GCSF use into the escalation. If you allow that liberally from the in the Phase II, I think that number is going to be much lower.
Appreciate the context. Thanks again.
The next question will come from Etta Durrell with Barclays. Please go ahead.
Thank you for the updates and thank you for taking the questions. First one for me is, you noted alignment with the FDA by year-end on the recommended Phase II dose. Just curious if you've had any initial discussions on sort of the fourth line plus trial and sort of endpoints. Just a follow-up, if you could maybe give some guideposts around the potential cost of the Phase II for accelerated approval, as well as the Phase IB in combination with BCMA therapy, whatever color you could provide. Thank you.
Yeah, Len, you can start with the regulatory, then Kendra, you can wait to weigh in on the cost side.
Yeah, so from a regulatory perspective, you know, we just had a really robust and productive discussion at a Type C meeting earlier this summer. During that discussion, we discussed our plans to interrogate late line, and we also discussed our plans to combine with a BCMA-BITE. We got feedback on both. As it relates to the late line, we got specific feedback to not limit it simply to people who were post T cell engager or CAR-Ts, and that fourth line plus was the appropriate population to interrogate because of the lack of full penetration of those mechanisms of action to all patients. That was the first thing. The second thing was agreement that in terms of selecting the dose for that trial, we would come back to them by year-end, but we agreed on the methodology of how we would recommend the dose.
In fact, many of the analyses the FDA asked for are actually in this deck, which will be presented in a robust way before the end of the year, along with the Phase II protocol, which has actually already been written. Did I miss part of your question? I just want you to remind me if there was another part.
No cost.
Yeah, Kendra will go. I'll ask Kendra to speak to cost.
No worries. A couple of things to know, right? Generally speaking, the Phase II is going to be more expensive than the Phase IB just because it's going to be a higher number of patients. The team has done a really nice job sort of mapping out our clinical trial sites, and of course, we'll try to be as efficient as possible utilizing the same trial sites potentially for both studies. The other thing that I just want to remind you all, Andrew noted it, but we are currently exploring supply agreements for the cost of the BCMA or for use in the BCMA study, which would obviously help us to offset some cost.
Thank you. The next question will come from Derek Arcilla with Wells Fargo. Please go ahead.
Hey, good afternoon, and thanks for taking the questions. Great data. Just two from us. First, just in terms of potential partnering strategy, how is that influencing potentially the BCMA-BITE you'll use in the combo trial? Just remind us, you're looking at potentially three doses to use in combination, just thoughts on overlapping tox and what we should think there in terms of the three doses that you've selected.
Yeah, Derek, thanks. I'll take the first part. Our focus right now is advancing the program as we've outlined in the slides and in our presentation. Certainly, we think this is a development plan that we can execute, and we're planning to do that in ways that Kendra outlined. I think the profile is really exciting around this program, and I think there's a lot more we'd like to do, and that's really where a partner comes in. Given the profile, I could see this used in a post-CAR-T maintenance and a post-transplant maintenance, given the activity and safety, but those are trials that as a small company we're not going to do. I think any partnering strategy would really be around how do we expand the opportunity beyond what we've outlined here today.
To tackle your question with respect to overlapping toxicity with the BCMA-BITE, obviously a crucial issue, which we've thought a lot about. I'll call your attention to the part of the slide presentation where we talked about the immune enhancement. One of the exciting things about the immune enhancement is it occurred at every dose level that we studied. We think we have some latitude in terms of what dose we will select. In terms of how to do that, clearly the most important overlapping toxicity potentially is neutropenia. We think with the three dose levels we've identified that we'll have a grade 4 neutropenia level that's low enough that won't interrupt the BITE therapy. That said, we have to show that with data. We're trying to show that as quickly as possible by interrogating the three dose levels as close as statistics will allow. Maybe I'll ask Dr. Dacal to just comment on the dosing with a BITE and your concerns.
Yeah, there are some trials that are already happening if you are aware that they're combining BCMA-BITE with the, you know, with the regimen or whatever is already being tested in the trial. I have some experience of using Cimcitamide with another BCMA-BITE. I must say that, you know, the overlapping toxicities are not that major concern. I mean, I would say the main thing that you worry about is the cytopenia, but if you allow, you know, kind of a close watching of this number, at least in the cycle two onwards, I think the cytopenia doesn't become a major concern. I feel that this is going to be even less of a concern with the rates of grade 4 neutropenia that we're seeing here, you know, with the combination.
Actually, I forgot in my answer that because of the step-up dosing and issues in cycle one, we wouldn't introduce Cimcitamide to cycle two. That way, we get through that loading of the BCMA-BITE before you introduce it to simplify.
Yeah, and if cytopenia are most common in the BCMA-BITE specific in the first cycle, yeah, after the second cycle, it becomes less common.
Got it. Understood. Thank you so much.
The next question will come from Ian Zhu with Jefferies. Please go ahead.
Hi, this is Ian. Thank you for taking my question and congratulations on the data. First question on the durability. I found that the DOR seems much more compelling compared to BMY's IKZF degraders while the PFS, median PFS, falls short. I'm wondering if you can elaborate on why these two durability measurements have some divergence. Second question is that do you see better or worse efficacy among patients post-BCMA, CAR-T, or T cell engager? Thank you.
I think it's premature to conclude that we have final estimates on either PFS or duration. Both of them are still evolving, especially with the later enrollment of the two highest dose levels. That said, the 3.7 months PFS in all patients, all dose levels to date, is actually approaching four months, which is very similar to what has been reported for other agents in a relapsed refractory population. We think that data is just not quite mature yet to draw that conclusion. We're confident, you know, really what's driving the duration of response in particular, we think, is the deep degradation of the targets combined with the fact that the patients do not have to come off drug for safety, in fact, and don't have dose reductions.
No, I agree. I think if you look at the Cimcitamide, I think what we're looking at is the whole patient population of 100-something patients. If you look at it, the patients, again, we're doing the cross-trial comparison, you know, that is probably a little bit limited in that regard. The patients treated in this trial, I must say that it's more heavily treated. At the same time, we also don't have the full follow-up of the 7,500 micrograms. I think that will probably, you know, once we have a little bit more longer follow-up, I think that will give a more idea about. If you just look at the duration of response, I think that looks quite promising.
I think your other question was, do we see a difference in responses based on prior therapy? I think we're sort of, you know, the answer is no when we slice it. I think, you know, we're really stretching in terms of ends by doing that. We don't see that when we do slice the data. Again, it's a pretty small data set, so it's hard to really draw meaningful conclusions at this point. Thank you and congratulations on the data again.
Great. Thank you.
Thank you.
The next question will come from Terrence Flynn with Morgan Stanley. Please go ahead.
Hi guys, this is Alex with Terrence. Congrats on the data. We just have a quick one for the Cimcitamide and Phase II trial in the fourth line settings. What is ORR and PFS bars required for accelerated approval? If you can comment here, that would be nice. Thanks.
Yeah, so there's never a predefined overall response rate for accelerated approval really for any indication. It's always driven by what's contextually the prevailing treatments and expectations of the time. However, what's important to say is, you know, we have to realistically plan a trial statistically that will detect a meaningful effect. We anticipate being able to achieve a 40% response rate and that that would be statistically different from the background expectation of off-label use of other treatments. As it relates to duration, we know that typically for late line multi-refractory indications of any type, you're going to want a duration of at least six months. That's why, in fact, our current duration at nine months, we're really optimistic about because it may well end up being higher than that. We already have a really compelling response rate in really the most difficult to treat patients with meaningful duration.
We think we can translate that into Phase II and ultimately have a discussion of both the response rate, the duration of therapy, and the safety in due course with the agency to have an accelerated discussion.
Great, thank you.
This concludes our question and answer session. I would like to turn the conference back over to Mr. Andrew Hirsch for any closing remarks. Please go ahead, sir.
Thank you. I want to close today just by thanking you all for joining us. I also wanted to thank the patients, their families, and caregivers for participating in our study. We're very excited about Cimcitamide's potentially best-in-class profile and believe that the data shared to date has de-risked the next phase of development. As we continue to advance the program, we look forward to updating you on its progress. Thank you and have a great rest of your weekend.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.