Good morning and welcome to the webcast to report and discuss clinical updates from both of Caribou's off-the-shelf CAR-T cell therapy programs. At this time, all participants are in listen-only mode. Please be aware that today's webcast is being recorded. I would now like to introduce the first speaker, Dr. Peggy Vorwald, Senior Director of Investor Relations and Corporate Communications. You may begin.
Thank you, Demini. Good morning, and thank you for joining us on today's call. Today, we issued two press releases announcing positive clinical data from both of our programs: the ANTLER phase I clinical trial for vispacabtagene regedleucel, or vispa-cel, formerly known as CB-010, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, and the CaMMouflage phase I clinical trial of CB-011 in patients with relapsed or refractory multiple myeloma. The press release and slide presentation accompanying this webcast are available on our website. On today's call, we will review the data for both programs, provide an overview of next steps for vispa-cel and CB-011, and host a discussion with lymphoma and multiple myeloma clinicians who we are honored to have with us today on today's webcast. Joining me from Caribou are Dr. Rachel Haurwitz, President and Chief Executive Officer, and Dr. Tina Albertson, Chief Medical Officer.
As a reminder, on slide two, we emphasized that we will be making forward-looking statements during this call. Forward-looking statements are subject to risk and uncertainties, including without limitation, risks inherent in the development of cell therapy products, uncertainties related to the design, funding, initiation, cost, timing, progress, and results of Caribou's current and future clinical trials, as well as other risk factors described in our 2024 annual report on Form 10-K and subsequent filings that we make with the U.S. Securities and Exchange Commission. Please note as well that information about the safety and efficacy of other immunotherapies is based on previously reported data about such therapies. Caribou has not performed any comparative analysis directly with such therapies. I would now like to turn the call over to Rachel Haurwitz to begin.
Thank you, Peggy. Good morning, and thank you for joining. Today marks an inflection point for Caribou as we report data from two programs that are delivering on the promise of allogeneic CAR-T cell therapies. These data reflect years of innovation and dedication from the Caribou team, our clinical collaborators, and, most importantly, the patients and families who have placed their trust in these programs. We're honored to be joined today by three clinicians who have been instrumental in advancing and advising on our programs. Dr. Mehdi Hamadani, Professor of Medicine and Section Chief of Hematologic Malignancies at the Medical College of Wisconsin, is an investigator on the ANTLER phase I trial evaluating vispacabtagene regedleucel in relapsed or refractory B-cell non-Hodgkin lymphoma. Dr. Hamadani will be presenting the ANTLER clinical data on today's webcast. Following the data presentation, Dr.
Albertson will provide an overview of our planned pivotal trial study design for vispacabtagene regedleucel. We are also honored to be joined by Dr. Adriana Rossi, Director of the CAR-T and Stem Cell Transplant Clinical Program at Mount Sinai, who is an investigator on the CaMMouflage phase I clinical trial. She will be presenting our first report of the clinical data set on CB-011 in relapsed or refractory multiple myeloma. Following the CB-011 data presentation, Dr. Albertson will moderate a discussion with Dr. Rossi and Dr. Joseph McGurk, Professor of Hematology Oncology and Director of Cellular Therapeutics at the University of Kansas Cancer Center. Dr. McGurk is an advisor to the company and a champion for the future clinical development of vispacabtagene regedleucel in second-line large B-cell lymphoma.
This KOL discussion will focus on the barriers to accessing autologous CAR-T cell therapies and how an allogeneic CAR-T cell therapy like vispacabtagene regedleucel or CB-011 could address some of these barriers and broaden patient access to CAR-T cell therapies. We're grateful to have these leaders with us to offer their perspectives on what these findings mean for patients and for the future of cell therapy. Before we turn to the data, I'd like to take a moment on slide four to describe the foundation that brought us here. Over the past four and a half years, Caribou has amassed one of the largest allogeneic CAR-T cell therapy clinical data sets. We've dosed more than 140 patients in multiple clinical trials, and we have leveraged those data to identify many critical factors that translate into better outcomes for patients.
Today, we're going to highlight two of them: donor age and partial HLA matching, both of which parallel learnings from the field of allogeneic stem cell transplant. We have found that young T-cell donors under the age of 30 drive improved outcomes compared to older donors. In the past, we have shared retrospective analyses showing that modest HLA matching of four or more alleles between the patient and the T-cell donor contributes to outcomes on par with approved autologous CAR-T cell therapies. Today, we are going to show you that when we combine young donor T-cells with HLA matching, an HLA matching threshold of only two HLA alleles contributes to outcomes on par with autologous CAR-T cell therapies. At the heart of our company is our proprietary CRISPR genome editing platform, which we call the chRDNA technology. The chRDNA technology enables sophisticated multiplex genome editing while maintaining genomic integrity.
We use the precision of our chRDNA technology to armor our cell therapies for functional persistence. In vispacabtagene regedleucel, we insert a CAR targeting CD19 and armor the T-cell with checkpoint disruption by knocking out PD-1. This is intended to prevent premature T-cell exhaustion and enhance anti-tumor activity. In CB-011, we insert a CAR targeting BCMA, and the cells are armored with an immune cloaking strategy designed to blunt rejection by the patient's T and NK cells. We believe that with the combination of our deep learnings from our large clinical data set and the precision editing of our chRDNA genome editing technology, we have the blueprint for allogeneic CAR-T cells. Today, we are excited to share data demonstrating that we have achieved our goal of developing an allogeneic CAR-T cell therapy for lymphoma that drives outcomes on par with the autologous CAR-T cell therapies.
We are also pleased to report the first clinical data from the dose escalation portion of the CaMMouflage phase I clinical trial, which shows CB-011 is driving deep, durable responses and that it has the potential to be the best-in-class allogeneic CAR-T cell therapy in relapsed or refractory multiple myeloma. Let's turn to slide five. vispacabtagene regedleucel is well poised to deliver on the broad promise of off-the-shelf CAR-T cell therapies. Autologous CAR-T cell therapies are remarkable products, but only for the patients who get them. Approximately 75% of second-line large B-cell lymphoma patients do not receive autologous CAR-T cell therapy. vispacabtagene regedleucel has the potential to greatly broaden access to cell therapy by addressing many of the challenges that prevent patients from receiving an autologous CAR-T cell therapy. Speed to treatment is key.
Auto-CAR-T cell therapy patients typically wait weeks to months for treatment, whereas patients treated with vispacabtagene regedleucel can begin treatment the same day they become eligible for the study. No waiting is necessary. Another advantage is scale. Our process for vispacabtagene regedleucel is commercial-ready today. Each manufacturing batch yields enough cells for 200-300 doses. Contrast that with the end-of-one per batch for autologous CAR-T cell therapies. The footprint required to achieve this scale is incredibly modest. The auto-CAR-T cell developers have invested hundreds of millions of dollars to build and operate multiple manufacturing facilities around the globe. In contrast, Caribou is using a single 500 sq ft suite at a contract manufacturing organization in the United States, and we can make up to 9,000 doses per year in that single suite.
We project vispacabtagene regedleucel cost of goods sold to be approximately 96% lower than the autologous CAR-T cell therapies at launch. I'd like to turn to slide six. As of the September 2 safety data cutoff date, the ANTLER trial has enrolled 84 patients. The efficacy data from today's presentation focuses on two cohorts. The first cohort we call the confirmatory cohort. The confirmatory cohort was designed to prospectively confirm the positive outcomes of partial HLA matching observed in earlier retrospective analyses. Twenty-two CD19 naive patients were enrolled in the confirmatory cohort and received a single dose of vispacabtagene regedleucel at the recommended phase II dose of 80 million CAR-T cells, such that each patient shared at least four HLA alleles with his or her T-cell donor.
I'll remind you that we have leveraged our large allogeneic CAR-T cell clinical data set to identify key factors linked to successful patient outcomes. We have applied these learnings to develop what we call an optimized vispacabtagene regedleucel profile. On slide seven, you'll see the optimized profile includes T-cells from donors under the age of 30 and modest partial HLA matching of two or more HLA alleles between the patient and the donor. Of the 84 patients in ANTLER, there are 35 CD19 naive large B-cell lymphoma patients who received a dose of vispacabtagene regedleucel matching this optimized profile. Thirty-two of these patients were second line, and three of these patients were third line or later. There is overlap between the confirmatory cohort and the optimized profile cohort.
Slide eight shows that 20 of the 22 patients in the confirmatory cohort were included in the optimized cohort, and as seen on slide nine, the additional 15 patients in the optimized cohort were enrolled in dose escalation or dose expansion. Turning to slide 10, we are excited to report that the vispacabtagene regedleucel efficacy and durability are on par with the outcomes achieved by the autologous CAR-T cell therapies. In the 22-patient confirmatory cohort, as of an efficacy data cutoff date of September 29, the data demonstrate that a single dose of partially matched vispacabtagene regedleucel results in efficacy on par with the approved autologous CAR-T cell therapies. Data from the 35-patient optimized cohort further confirm that the efficacy and durability of vispacabtagene regedleucel are on par with the outcomes achieved by the autologous CAR-T cell therapies.
The median follow-up for the 35-patient optimized profile cohort was 11.8 months, and the longest responding patient who completed the two-year ANTLER trial and enrolled in the long-term follow-up study is in complete response three years post-infusion. As of the September 29 data cutoff date for efficacy, the results for the optimized profile cohort include an 86% overall response rate, a 63% complete response rate, and 53% progression-free survival at 12 months. Vispacabtagene regedleucel continues to have a generally well-tolerated safety profile. We have seen no graft versus host disease in any patients treated with vispacabtagene regedleucel. In the optimized and confirmatory cohorts, we saw no grade three or greater ICANS and a single case of grade three cytokine release syndrome, and there were manageable rates of infections and prolonged cytopenias.
As you'll hear in more detail shortly, Caribou plans to conduct a randomized controlled trial in the second-line large B-cell lymphoma population of patients who are CD19 naive and who are ineligible for transplant and autologous CAR-T cell therapy. Patients randomized to the study arm would receive a single dose of vispacabtagene regedleucel at the recommended phase II dose of 80 million CAR-T cells following lymphodepletion with cyclophosphamide and fludarabine, and patients randomized to the comparator arm would be treated with the investigator's choice of standard-of-care immunochemotherapy agents such as Polatuzumab vedotin plus bendamustine and rituximab. We expect further refinement of the pivotal trial design through continued engagement with the FDA prior to the start of the pivotal trial. Turning to slide 11, it is my pleasure to turn the call over to Dr. Mehdi Hamadani, who will present the clinical update from the ANTLER phase I trial.
Hi.
Thank you, Dr. Haurwitz. Good morning to all. It's an absolute pleasure to review the data on the ANTLER phase I trial. As already alluded to, the ANTLER phase I trial evaluated the safety and efficacy of vispacabtagene regedleucel, an allogeneic CD19-directed CAR-T cell therapy product, in 84 patients with B-cell lymphomas. Slide number 12 shows the treatment design of the ANTLER phase I study. In this study, patients received what we call augmented lymphodepletion using a combination of high-dose cyclophosphamide at 60 mg per kilogram for two days, followed by fludarabine at 25 mg per meter squared for five days. The seven-day lymphodepletion was followed by a single infusion of vispacabtagene regedleucel on day zero, followed by response assessments at day 28 for the first time point.
This trial initially had a dose escalation phase that enrolled patients with relapsed refractory B-cell lymphomas, followed by a dose expansion phase focusing on patients with second-line large B-cell lymphoma using a partial HLA match strategy. Moving on to the key slide number 13, it goes over the baseline characteristics of patients enrolled in the ANTLER trial. I'll draw your attention to the column in the middle, which shows the 22 patients enrolled in the confirmatory cohort, and the column on the right side of your screen that shows the optimized cohort that enrolled 35 patients. Now, you can see that the median age of patients enrolled in the ANTLER trial was 66 years old, with the oldest patient being 86 years old, underlining the feasibility of administering high-dose lymphodepletion in these patients.
By the way, typically in outpatient settings, nearly all patients enrolled at my center received this lymphodepletion in the outpatient setting. The trial was enriched for patients with high-risk B-cell malignancies, including transformed follicular and transformed marginal zone lymphomas, as well as approximately 15%-18% of the patients with high-grade B-cell lymphomas. A recent publication from our group at CIBMTR showed that with autologous CAR-T cell therapies, the outcomes of CD19-directed autologous CAR-T cell therapies are particularly poor in patients with high-grade B-cell lymphoma not otherwise specified. Now, you can see that in the confirmatory cohort, by definition, all 22 patients received their therapy in second line.
Notably, in terms of the risk of these patients, nearly 60% of the patients enrolled had high ADE-adjusted IPI score, and 40% + patients had LDH levels that were up more than the upper limit of normal, including up to 15% of the patients that had LDH levels twice the upper limit of normal. Notably, this trial did not have any exclusion criteria to screen out patients with high-dose LDH, which is noteworthy. I will now move on to slide number 14. That gives you the opportunity to look at the efficacy and durability data. With Visticel. In blue are two columns that show efficacy data in the confirmatory and optimized cohorts, while in the gray you see data from the Zuma 7 and TRANSFORM trials for the sake of reference. Collectively, in the confirmatory and optimized cohorts, the overall response rates are 82% and 63% respectively.
Really exciting to see that the complete response rates are again 64% and 63%, numerically identical to the CR rates we see with FDA-approved autologous products. The median progression-free survival of both cohorts has not been reached yet, but at 12 months, 51% of the patients in the confirmatory cohort and 53% of the patients in the optimized cohort were progression-free, meaning they were still in remission, and these patients were alive. These numbers are again numerically identical to the numbers we expect from FDA-approved autologous products. The median duration of the response in either cohort has not been reached. Moving on to slide number 15. Shows simulated progression-free survival curves of the optimized cohort in dark blue and the confirmatory cohort in light blue.
The dotted or interrupted line is the expected median progression-free survival from axi-cel and liso-cel, and it's very clear to see, with the limitation of a cross-trial comparison in mind, that the early progression-free survival data that Visticel is producing is nearly identical to expected progression-free survival with the autologous products. Slide number 16 is a swimmer plot of patients in the optimized and in the confirmatory cohort. As a refresher, the confirmatory cohort is second-line large B-cell lymphoma patients that received a product that had an allele-level HLA match of four or more. The dark green portion of the curve represents the time point where a patient achieved a complete remission, while a light gray box indicates disease progression.
It's very clear to see that patients who achieved a complete remission at the day 90 or three-month assessment, none of these patients to date have experienced disease relapse or progression, which speaks to the durability of this off-the-shelf product. Third row in this figure demonstrates a patient who was in a partial remission at three-month time point but spontaneously converted to a complete remission at six-month time point without any additional consolidation treatment with either chemo, radiation, or immunotherapy. Slide number 17 is a similar swimmer's plot of patients in the optimized cohort. These are the patients who received a product with at least an allele-level HLA match of two or more, but these products came from young donors. Again, you see a similar theme here.
Among patients who were able to achieve a complete remission at the three-month time point, virtually all of these patients remained progression-free, with the exception of one patient who experienced disease progression at around the nine-month time point. This is a very nice visual representation of the kind of durability we are experiencing with vispacabtagene regedleucel. What's really noteworthy is that there are six patients that have reached their 24-month time point, and all of these six patients continue to enjoy very durable, very long complete remissions and are hopefully cured of their disease. Slide number 18 allows us to look at the safety profile of the vispacabtagene regedleucel product with lymphodepletion administered predominantly in the outpatient setting. Again, reference data from axi-cel and liso-cel are provided for informational purposes.
When we look at the signal of ICANS or neurotoxicity, grade three or higher neurotoxicity was not seen in any patient in the confirmatory and the optimized cohorts. The corresponding rates of grade three and higher neurotoxicity with axi-cel are 25% and with liso-cel 4%. In all cumulative vispacabtagene regedleucel patients, the rates of grade three or higher neurotoxicity was 5%. Higher grade CRS, again defined as grade three or higher CRS, was uncommon, seen in approximately 3%-5% of the patients in the confirmatory and optimized cohorts. Grade three infections were seen in approximately 18% of the patients in the confirmatory and 17% of the patients in the optimized cohort, and these numbers are comparable to expected rates of infections with autologous CAR-T cell products. Of note, despite an augmented or higher-dose lymphodepletion, prolonged cytopenias defined as presence of cytopenias beyond a one-month time point was uncommon.
These prolonged cytopenia rates are comparable to prolonged cytopenia rates seen with axi-cel and numerically lower than the rates seen with liso-cel. Slide number 19 is an opportunity to look at the CAR expansion as well as persistence kinetics in the confirmatory cohorts seen on the left side of your screen and the optimized profile on the right side of your screen. The blue expansion curve refers to patients who had a response at three-month time point and onwards, while the gray expansion curve is for patients who experienced an early disease progression. It is very clear to see from these expansion curves that patients with more durable responses not only had a higher expansion peak, but more notably, these patients also experienced better persistence of the CAR product at the one-month time point. Next, at slide number 20, we look at the immune reconstitution parameters.
On the left is the recovery of T, NK, and B cells. What I would like to point out is the relatively brisk recovery of B cells in recipients of vispacabtagene regedleucel. Post an allogeneic product administration, this B cell recovery numerically looks faster than the B cell recovery we expect in patients receiving autologous products, and it's potentially an explanation of the nice infectious disease signal we see with this product. On the right is a cumulative incidence curve that shows recovery of neutrophils and the platelets to grade two or lower. Again, it's very nicely shown here that nearly all patients, 95% of the patients, recovered their neutrophil counts and 86% of the patients, their platelet counts by two months post vispacabtagene regedleucel infusion.
This slide summarizes the take-home away messages that vispacabtagene regedleucel, being an allogeneic off-the-shelf CD19-directed CAR-T cell product, is producing an overall response rate of 86%, an impressive complete remission rate of 63%, with 53% of the patients being progression-free 12 months post infusion, and efficacy profile and a durability profile on par with rates expected with autologous CAR-T cell products. The efficacy in the confirmatory cohort demonstrates vispacabtagene regedleucel is on par with autologous CAR-T cell therapy. This CAR is generally well tolerated, a safety profile that enables utilization of vispacabtagene regedleucel in the outpatient setting and potentially in the community setting as well. Hopefully, we show convincing data that show that vispacabtagene regedleucel has the potential to be the best-in-class allogeneic CAR-T cell therapy product for large B-cell lymphoma patients. I thank you again for your kind attention.
Thank you very much, Dr.
Hamadani, for your presentation of the data. Turning to slide 22, you will see our expected phase III pivotal design that would support full approval in second-line large B-cell lymphoma. In recent interactions, the FDA has recommended the company conduct a randomized control trial in second-line large B-cell lymphoma CD19 naive patients who are ineligible for transplant and ineligible for autologous CAR-T cell therapy. In this trial, Caribou plans to evaluate approximately 250 patients. Patients randomized to the study arm would receive a single dose of vispacabtagene regedleucel at the recommended phase II dose of 80 million CAR-T cells following lymphodepletion with cyclophosphamide and fludarabine. Patients randomized to the comparator arm would be treated with the investigator's choice of standard-of-care immunochemotherapy agents such as Polatuzumab vedotin plus bendamustine and rituximab. The primary endpoint will be PFS, and an interim PFS is planned.
The PFS analysis will be event-driven and is not a landmark analysis. Secondary endpoints will include ORR, complete response rate, duration of response, duration of complete response, overall survival, quality of life, and safety. We believe this study design positions vispacabtagene regedleucel for success. Reported PFS from likely control arm agents range from four to nine months. Unlike the plateau we see with vispacabtagene regedleucel, the Kaplan-Meier curve for these agents continues to deteriorate towards baseline. Thus, we expect vispacabtagene regedleucel will perform better. In our continued engagement with the FDA, we will determine the appropriate criteria to define transplant and auto CAR-T ineligibility. We look to the precedents of the PILOT and ECHELON-3 studies. The PILOT study evaluated liso-cel in a transplant-ineligible patient population, and each patient needed to satisfy only one of six criteria, such as age of 70 or greater, to determine their transplant ineligibility.
The ECHELON-3 study evaluated brentuximab vedotin in auto CAR-T ineligible patients, and the inclusion criteria encompassed clinical factors such as certain comorbidities as well as access issues such as being unable to receive CAR-T cell therapy due to financial, geographic, insurance, or manufacturing issues. We intend to further refine the pivotal trial design through continued engagement with the FDA prior to initiation of the study. We plan to leverage our learnings about young donor T cells and HLA matching for our pivotal supply strategy. All batches of vispacabtagene regedleucel used in the pivotal study will be manufactured from young donor T cells. We plan to have 10 batches for the pivotal study, and we estimate that 98% of patients dosed with vispacabtagene regedleucel will receive a dose where the patient and donor share at least two alleles. We expect that the average number of HLA matches will be seven.
Turning to slide 23, we plan to bring vispacabtagene regedleucel closer to where patients live by leveraging sophisticated community sites in addition to academic sites within the US and globally. We've mentioned previously that only about 25% of patients receive autologous CAR-T cell therapies. That means 75% of patients are not getting these potentially curative therapies. The barriers for accessing auto CAR-T cell therapies are a combination of medical, socioeconomic, and geographic challenges that prohibit patients from getting to and being treated in the centers that provide patients with auto CAR-T cell therapies. We believe vispacabtagene regedleucel is ideally suited to address these challenges as a single-dose, off-the-shelf CAR-T cell therapy with a safety profile that allows for both outpatient administration and utility in the community. I'd like to now turn the call back to Rachel to discuss the commercial market opportunity.
Thank you, Tina.
I'll turn your attention now to slide 24, where you will see the meaningful commercial opportunity in second-line large B-cell lymphoma. There are about 10,000 second-line LBCL patients in the US. We believe that this is an underestimate of the overall opportunity since large B-cell lymphoma includes additional BNHL subtypes such as PMBCL, high-grade B-cell lymphoma, and grade 3B follicular lymphoma. We estimate that about half of all second-line patients are transplant-ineligible, and we anticipate a meaningful majority of the transplant-ineligible patients will also be auto CAR-T ineligible. The total large B-cell lymphoma market is expected to double from now until 2033, and we believe that even with modest penetration, vispacabtagene regedleucel use could lead to a meaningful market opportunity.
On slide 25, I would like to reiterate that with vispacabtagene regedleucel, we see efficacy on par with the autologous CAR-T cell therapies, safety on par with liso-cel, and favorable compared to axi-cel, and cost of goods sold that we project to be approximately 96% lower than the auto CAR-T cell therapies at the time of launch. These low COGS can be achieved with a completely different manufacturing profile compared to the autologous CAR-T cell therapies. We need only a minimal footprint. A single 500 sq ft suite can generate up to approximately 9,000 doses per year. I just told you the entire second-line LBCL patient population is 10,000 patients, so this is a very large capacity from only a small footprint. We've covered a lot on the vispacabtagene regedleucel data and future development plan, so I'd like to summarize what we've shared with you on slide 26.
Today, we have shown you data demonstrating that vispacabtagene regedleucel drives efficacy and durability on par with the outcomes of autologous CAR-T cell therapies. With a safety profile that allows for outpatient administration and use in the community setting, we are confident in our approach to bring vispacabtagene regedleucel closer to where patients live through our planned pivotal phase III randomized control trial in second-line large B-cell lymphoma patients who are CD19 naive and auto CAR-T and transplant-ineligible. We believe that what we showed you today positions vispacabtagene regedleucel as the potentially best-in-class allogeneic CAR-T cell therapy for large B-cell lymphoma. On slide 27, we will now turn to the second data readout for today. We are equally excited to share the first clinical data set from the CB-011 CaMMouflage phase I clinical trial for relapsed or refractory multiple myeloma.
Turning to slide 28, we routinely hear from treating physicians that the benchmark for success for an off-the-shelf CAR-T cell therapy is to be at least on par with the efficacy of the bispecific antibodies, the only asset class broadly and readily available to this large patient population. These positions highlight for us that the one-and-done nature of a cell therapy is attractive compared to the high treatment burden associated with the repeat dosing of the bispecifics, and in particular, the high prolonged infection risk these patients face. Moving now to slide 29, I mentioned a few minutes ago that only 25% of lymphoma patients receive auto CAR-T cell therapy. In the myeloma field, only 10% of patients receive auto CAR-T cell therapy. We believe as an off-the-shelf treatment, CB-011 has the potential to bring the benefit of cell therapy to additional patients.
It is readily available, and patients do not need to wait to access their therapy. At commercial launch, we expect our manufacturing process to yield 50-100 doses of CB-011 per manufacturing batch. This would put our projected cost of goods sold at commercial launch an estimated 80% lower than autologous CAR-T cell therapies. Moving now to slide 30, I'm excited to summarize the dose escalation data. At the recommended dose for expansion, 450 million CAR-T cells following a lymphodepletion regimen, including a 500 mg per meter squared cyclophosphamide dose, CB-011 has exceeded our bar for success by outperforming bispecific response rates and demonstrating meaningfully lower rates of grade three or greater infections than the bispecifics.
Twelve BCMA naive patients have been treated with the recommended dose for expansion, and in that cohort, we observed a 92% overall response rate, with 75% of patients achieving a complete response or stringent complete response. Nearly all evaluable patients, 91%, achieved MRD negativity, a strong indicator of the depth of response. Importantly, with a median follow-up of 8.3 months, seven of the twelve patients achieved a very good partial response or better at six months or longer, demonstrating encouraging signs of durability in a high-risk, heavily pretreated population. The safety profile has been manageable, with no graft versus host disease, no colitis, no Parkinsonism, and no cranial nerve palsy observed at any dose level. These dose escalation data showcase CB-011's potential to be the best-in-class off-the-shelf CAR-T cell therapy for patients with relapsed or refractory multiple myeloma. I am now honored to turn the call over to Dr.
Adriana Rossi, who will share the dose escalation data from our CaMMouflage phase I clinical trial of CB-011 in patients with relapsed or refractory multiple myeloma.
Thank you so much. It is my pleasure to share some of our experience with the CaMMouflage trial. To date, we have 48 patients dosed with CB-011 during our dose escalation in the phase I trial. These were patients with three or more prior lines of therapy, including a PI, an IMID, and an anti-CD38 antibody, and specifically excluding prior CAR-T cell therapy or patients with prior BCMA-targeted therapy within the last three months. We used a three-by-three dose escalation. We started with a lymphodepletion regimen of 300 mg per meter squared and evaluated cell dose levels of 50, 150, and 450 million cells.
We then evaluated a lymphodepletion regimen at 500 mg per meter squared of Cytoxan at dose levels 150, 300, 450, and 800 million cells, specifically looking at best HLA matching for class two, as we've seen that we essentially have a six out of six for class one match. Slide 32, focusing on the dose expansion. As mentioned, the cell dose will be of 450 million cells with a 500 of Cytoxan lymphodepletion. On slide 34, we see that we've really had robust enrollment. As mentioned, a lot of excitement from the investigators, noting that all 16 sites have access to multiple bispecific options and approved auto CAR-T cell therapies.
During a survey at a prior annual meeting, some of our key reasons for enthusiasm are the one-and-done treatment with an off-the-shelf product for patients with myeloma, the lack of manufacturing wait time preventing any clinical deterioration in our patients between apheresis and infusion, and the promising deep and durable responses we've observed as the trial has progressed. Slide 35 shows us about our high-risk, heavily pretreated patients. With an average age of 68 and a half, these patients span from 49 to 84 years of age, again highlighting the high tolerability and safety of this product across a wide age range of patients. We did have an impressive over half of the patients showing high-risk cytogenetics, and over a third of them having extramedullary disease. Prior lines of therapy were on average four, ranging from three up to 11 prior lines of therapy.
Slide 36, we look at the responses, again starting at 48 patients dosed, 35 of whom received the selected lymphodepletion with 500 mg per meter squared of Cytoxan and 30 mg per meter squared of fludarabine dosed daily for three days. Of the six patients dosed at 150 million dose level, four were BCMA naive. Of 13 at 300 million cells, 11 were BCMA naive. Of 13 at the 450, 12 were BCMA naive, and all three patients dosed at the 800 million dose level were BCMA naive. We saw a range of response rates, but focusing specifically on the dose expansion, overall response rate, as we've seen, of 92%. An impressive 75% being CR or better, and 83% being at a VGPR or better. Remarkably, all but one patient achieving an MRD negative rate.
Slide 37 shows us the summer spot, again highlighting the impressive depth of response that we've reached. I highlight on the left hand that all but one patient did reach MRD negativity. We see that 7 out of 12 remain at a VGPR or greater at six months and beyond, with our longest patient having exceeded 15 months. Also on the left-hand side, the patients with extramedullary disease have been very well represented, being able to achieve not only these very deep, but similarly durable responses. Slide 38, turning our attention to the toxicities, we really had a very manageable, notable AEs. The expected infections, I would say, lower than any other experience we have had, the CRS at the selected dose, four patients, only one of which was grade three or higher. Similarly, with the ICANS, a single patient that I will highlight, and the prolonged cytopenias.
By definition, being a high-grade toxicity. I'd like to take a moment to go over the high-grade toxicities. We did have a single case of a grade five ICANS at day 90. This was a patient with prolonged cytopenias and a bumpy course who ultimately withdrew care and so died a few days later. One grade five pneumonia. This patient presented to his primary care physician with two days of cough, was not noted to have any hypoxia, never had a fever. No tachycardia, had an uneventful workup, including a chest X-ray, and was sent home. The patient lay down to rest and did not wake up. On further evaluation of the X-ray, there was atelectasis versus consolidation, so it was attributed to a pneumonia, but no autopsy was done.
Lastly, we did have a grade four Guillain-Barré syndrome out at day 129, ultimately requiring ventilation support and ICU level of care, but the patient has since improved, recovered, spent some time in rehab, and is currently home recovering. I would mention one event that happened at the 300 million dose level. This was an 82-year-old patient who had presented with increasing hypoxia and oxygen requirement. He did receive antibiotics and IVIG, but the family declined escalation of care. He did not receive directed therapy and died after having withdrawal of care. We have implemented prophylactic measures for the cytopenias and infections across the board. I do not think any of these were surprising.
I would highlight on slide 39 that CB-011 expansion correlated with responses at our selected lymphodepletion, and we see the error bars are quite tight, showing a consistent level of expansion with the T max at day 14 in responders. Impressively, we did see recovery of the endogenous T and NK cells. Patients, as we have seen, had successful depletion of their T cells, enabling the CAR-T expansion. Here we see a very fast recovery of T and NK cells, reinstating their natural immunity and contributing to this impressively favorable safety profile we have seen. Balancing this activity with a rapid recovery is really a unique profile that we see with the Caribou AlloCAR-T programs. I did want to take a moment to compare to bispecifics, being the other off-the-shelf option. With bispecifics, we do require repeat dosing.
While we may see limited or no B cell recovery, we are soon to redose and re-offend the system. Whereas with the AlloCAR-T, a single dose allows for this rapid immune cell reconstitution with no further insults and thus much less infection seen. In conclusion, in slide 42, we see deep and durable responses observed in this very heavily pretreated population, an overall response rate of 92% with a CR or greater of 75%. Having 91% of patients reaching MRD negativity and having 7 out of 12 being at greater than a VGPR at six months or longer for the recommended dose for expansion. The manageable safety profile with no GVHD, no colitis, no Parkinsonism, and no cranial nerve palsy observed really gives us a potential to expand access and bring this meaningful benefit to patients who urgently need a readily available single dose option. Thank you so much.
Thank you, Dr. Rossi. We are very grateful to be able to benefit from the extensive experience that you have in multiple myeloma and with clinical trials for cell therapies, as well as bispecific antibodies. We are also grateful to be joined today by Dr. Joseph McGurk. I would like to ask both Dr. Rossi and McGurk a few questions. Dr. McGurk, I will start with you. Although you are not currently an investigator on the phase I Antler trial, you have been a champion of the vispa-cel program. Based on the dataset we just saw, you informed us of your eagerness to participate in our pivotal trial and have shared your enthusiasm for the community centers within your network in the Midwest to participate in our pivotal trial as well.
Can you tell us more about the needs you are seeing in your hospital and the surrounding community hospitals when it comes to accessing auto CAR-T cells? What needs are not being met?
Absolutely. Thank you very much, Tina, and thank all of you for being here today. At the University of Kansas Cancer Center, where I practice, we've treated a very large volume of patients with CAR-Ts due to our broad catchment area across several states in the Midwest. However, as my colleagues and I have published earlier this year, only 25% of second-line large B cell lymphoma patients are actually receiving CAR-T cell therapy, and we must do better than this. This is a potentially curative therapy for patients, and the access issue is abysmal.
There's a clear lack of uptake of CAR-T, predominantly in patients treated in the community setting due to geographic, financial, socioeconomic barriers, as well as patients with rapidly progressing disease who require immediate treatment. Further efforts are needed to improve earlier patient identification, logistical support, and referral systems to address the current gap in CAR-T access. As you know, Tina, we've built a strong network with the local hematologists over the years in the Midwestern part of our nation and have confidence that these sophisticated community centers can safely administer an allogeneic CAR-T like vispa-cel to their patients on this pivotal trial. In this context, we leverage the Midwest Cancer Alliance, which is a research network where we take research studies out to community sites. This is NIH-supported. It's very large and captures a several-state area. The best way to improve patient outcomes is first, improve patient access.
For goodness' sakes, when you look at the associated challenges with CAR-T cell therapy, not everybody responds, not everybody who responds stays in remission. We contend within our patients' CRS and ICANS, as was mentioned, although vispa-cel with a very favorable profile in this respect. And we have cytopenias and associated infectious complications, as have been mentioned. But when you put all those issues together, in my estimation, they do not equate to the major problem that we have, and that is the overwhelming majority of patients who might benefit by CAR-T therapy never have a chance at it. There's a national initiative, as you know, to increase patient access by 50% to CAR-T by 2030. This is the CAR-T vision effort through our national organizations, and I'm a member and head the access committee. And vispa-cel will increase our chances of reaching this goal.
Thank you, Dr. McGurk.
What is it about the safety and efficacy of vispa-cel that makes you want to participate in this pivotal trial?
Absolutely. As Dr. Hamadani detailed very carefully and thoughtfully, 84 patients were treated with vispa-cel using the same lymphodepletion in all patients and demonstrated a favorable benefit to risk profile. This lends itself to safe administration in community sites. In terms of safety, very low rates of severe CRS and ICANS were observed, with the majority of patients recovering from prolonged cytopenias by 60 days. It is also important to note the rapid immune reconstitution of T, B, and NK cells, which is likely contributing to the favorable safety profile. In terms of efficacy, the overall and complete response rates are on par with the approved auto CAR-Ts, as you demonstrated. It is very encouraging that the median progression-free survival has not been reached with the optimized vispa-cel product.
Several patients are also in long-term response, which speaks to the durability of this product.
Why do you believe vispa-cel may be a solution to broaden patient access for second-line LBCL patients, both at your site and, importantly, within the community network of sites in your region?
Absolutely. I think that it is very straightforward. It is a one-time off-the-shelf treatment that can be administered safely at both large academic centers as well as community sites, based on that risk-benefit profile. Efficacy. There is no apheresis required, with no manufacturing delays or failures. It is like a drug. We can have it the next day when ordered. Ability to initiate lymphodepletion right away, followed by vispa-cel, and avoiding the need for bridging chemotherapy or immunotherapy strategies while we are waiting for manufacturing of an autologous CAR-T construct.
Vispa-cel's efficacy is clearly on par with approved autologous CAR-T cells, with a manageable safety profile that supports outpatient administration. This has the potential to be a national game changer and address this unacceptable issue of lack of access for the overwhelming majority of patients, again, for a potentially curative therapy.
Thank you very much, Dr. McGurk, for your thoughtful responses, but especially your passion for patients and for getting CAR-T cells to more patients. Thank you for participating in today's webcast. Dr. Rossi, I would like to turn to you. I would like to ask you some questions about how the multiple myeloma landscape and your thoughts on the CB-011 data to date. Let's start with enrollment for CaMMouflage. All of the CaMMouflage sites had access to auto CAR-T and bispecifics, as you mentioned earlier, but we often had a waitlist of patients for enrollment. Dr.
Rossi, as a hematologist practicing at a large academic center, can you explain why patients chose to receive CB-011 versus other treatment modalities?
Absolutely, Tina. Whenever we present options to patients, and one of the reasons to be at an academic center is the number of options we have, in giving alternatives to participating in the trial, our options are either a bispecific, which offers an off-the-shelf option, or an autologous CAR-T, which could be a one-and-done. The availability of something that is both one-and-done and off-the-shelf is really incredibly attractive, both to physicians and for patients. As was mentioned with the lymphoma product, the lack of manufacturing delays and failures in itself is incredible, and the ability to have it available for the patient right away, I think, will really broaden access, just as we've heard in lymphoma.
Diving a bit deeper into the data you presented today, do you believe CB-011 has a favorable benefit-risk profile at the recommended dose for expansion?
Absolutely. I've been really, really impressed. At our center, all BCMA-directed therapies, be they the autologous CAR-Ts or the bispecifics, have a requirement for quite a bit of supportive care, including monthly IVIG. In bispecifics potentially for years while they're on therapy, and in our CAR-T program, usually for at least 12 months, often more than that. This rapid immune reconstitution we are seeing is really unprecedented. We're seeing response rates on par with the auto CARs and much beyond what we're seeing with the bispecifics targeting BCMA, while seeing so much less toxicity. I think the less inflammatory events and lesser rates of infection have really made it a remarkable benefit-risk profile.
How do you see an alloCAR-T therapy like CB-011 fitting into the future landscape for multiple myeloma treatment?
I welcome it very much for all of the above reasons. We love the one-and-done. Having an off-the-shelf, removing the requirement for apheresis will also reach so many more of our patients. As was mentioned, only one in ten eligible patients actually will make it to a center such as ours. For the vast majority of patients who, for medical, logistical, financial reasons, are unable to benefit from these great new therapies, now we potentially would have an option that will reach them wherever they are in the country and the world. With a lower toxicity profile, I think, it will also make it much more manageable for a greater number of physicians and centers.
Thank you, Drs. Rossi and McGurk, for your insights, your expertise, your time today. Dr.
Haurwitz, handing the call back to you.
Thank you, Dr. Albertson. Thank you again, Dr. Rossi and Dr. McGurk, for taking the time today to share your experiences and your perspectives on the front lines of treating patients. Turning to slide 44, we are incredibly proud to share these datasets and plans for next steps with these programs today. We plan to initiate dose expansion with CB-011 by the end of this year, and we expect to provide a data readout on dose expansion and longer follow-up on dose escalation in 2026. We look forward to continued engagement with the FDA ahead of initiating the randomized control phase III pivotal trial for vispacabtagene regedleucel in second-line large B cell lymphoma. Before moving to Q&A, I want to highlight an upcoming Caribou event.
We are very much looking forward to hosting a panel on the sidelines of the 2025 ASH annual meeting, where a group of lymphoma clinicians from sophisticated community hospitals will join us to discuss CAR-T cell therapy access challenges for their patients and how an allogeneic CAR-T cell therapy like vispacabtagene regedleucel could transform the treatment paradigm for the patients they serve. We expect many of the voices you will hear from to be involved in enrolling patients in our planned vispacabtagene regedleucel pivotal trial. That panel will be available via our events page when the details become available. I'll hand the call back to the operator for the Q&A session.
Thank you. As a reminder, to ask a question, you will need to press star then the number one on your telephone keypad. If you would like to withdraw your question, press star one again.
We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Yigal Nochomovitz with Citi. Your line is open.
Hi, great. Thank you very much for taking the questions, and congrats on all the very good data. I have one for Dr. Hamadani, if I may. I'm just curious if you could talk a bit about the pent-up demand at your center. Specifically, what fraction of your lymphoma patients that are not eligible for the auto CAR-T or transplant would you be putting on vispacabtagene regedleucel today, assuming it were available? Also, what are those patients getting today in the way of chemoimmunotherapy? Thank you.
Yigal, yeah, Yigal, thank you so much for your question. Unfortunately, Dr. Hamadani had to drop for some clinical work this morning. Maybe Dr.
McGurk, I could put you on the spot and ask if you could reflect on that question.
Yes, absolutely. A critically important question. I think, first and foremost, it's important to understand that the major unmet need are patients who never make it to the University of Kansas or University of Wisconsin in Dr. Hamadani's case. We know that they're out there because we look at patient-level data through entities like the Flatiron Health Research Database, and we've reported on that, and other such reports. Several of which, if you look at the literature, you'll see our center has contributed to, and I think Dr. Hamadani has as well. We know that those patients are out there, but we never get to see them. The vispacabtagene regedleucel potentially addresses those patients by taking it out to the community because they're not in our center.
They, by definition, don't meet eligibility for CAR-T or autologous stem cell transplant, as their treatment-referring physicians or the patient has decided. Based, as I mentioned earlier, on socioeconomic factors, geographic issues. We've got ranchers and farmers out in western Kansas. It's a 10-hour drive out to the Colorado border. And they'll simply say, "We're not going into Kansas City." Some people. Going to Kansas City is gas money versus grocery money. And that's a potential barrier. The bottom line is that the majority of patients aren't coming. If you look at, as Tina mentioned earlier, the Echelon 3 data and the other data presented in the literature, the pilot trial, the definition of CAR-T in the Echelon data set, for example, and auto transplant ineligibility was geographic.
Restrictions for patient population, socioeconomic drivers, financial drivers, as well as comorbidities and advanced age, that is 70 years of age and greater. I think it's when the patient does make it to us, if they're willing to stay with us, we can generally get them to CAR-T, unless their disease is rapidly advancing and patients, even though they got to us, will have progressive disease, become too infirm to receive CAR-T, or progress and die before the CAR-T are manufactured. That does occur in our centers. As a matter of fact, Fred LaMeder's team and Sarah Cannon, they're a big national network of CAR-T centers, and they published just several months ago in Blood Advances on the lack of ability to deliver CAR-T to 45% of the patients that they take care of because they had disease that was rapidly advancing and they didn't have time for manufacturing.
It's that population of patients who do make it to the cancer center, that minority, 25%, who then would not be eligible for CAR-T. Patients with significant comorbidities, patients of advanced age, historically for autologous stem cell transplant being set at 70, and manufacturing failures, rapidly progressing disease, etc. I hope that addresses your question.
Yeah, no, thank you very, very much. Is there time to ask Dr. Rossi a question, or should we?
Nope, I'm here.
Oh, hi. Thank you. Obviously, you made a lot of very important points related to the bispecifics. Also, as you pointed out and the other Carols pointed out, a lot of the allo products which Caribou are developing may be appropriate in the community center as opposed to just into the academic centers.
That being said, I'm wondering if the CB-011 profile, as we've seen now, holds up in later stage studies, could you just talk about what would you preclude in terms of continuing to use bispecifics at your institution, given what you point out to be some very significant improvements, both on the efficacy and the safety side for CB-011?
Yeah, absolutely. I think, again, our enthusiasm even for auto CARs, this concept of one-and-done is, I think, more remarkable than as physicians we necessarily recognize. I was very happy to share in the auto CARs, these five years. Progression-free, treatment-free reality that is kind of coming into the world of myeloma.
But I've had patients who've had six months of treatment-free post-CAR and come to me when I'm apologizing to say, "Doc, you don't realize this was the best six months of my life since I was diagnosed 11 years ago." So absolutely, the one-and-done is a desirable just life experience, not only medically but psychologically. The ability to reach these older patients who will always have more toxicity and difficulty tolerating continuous therapy. The need to come to a center, even if we're moving away from academic centers, bispecifics can be given increasingly. But many of us are still using inpatient admissions for step-up dosing. There's no, I don't think we're having to pay anything for a much greater win. In the, as we showed, this immune reconstitution, I think, is remarkable. So it's not even that it's not repeat dosing.
They also don't need the level of care and attention such as IV infusions that we're using with the CARs. I think it would be a huge step forward.
Great. Thank you very much.
Question comes from the line of Alec Stranahan with Bank of America. Your line is open.
Hey, guys. Thanks for taking our questions and congrats on the really exceptional data here. First, maybe for the company on PFS, it looks like you're seeing the expected curve shapes versus auto CAR-T. The patients that respond really well respond for a while and those that don't progress pretty quickly. I guess if the pivotal study goes through, as you outlined, how should we be thinking about PFS on the comparator arm?
And maybe you could just walk us through what the event-driven interim would look like and sort of the alpha that we should feel from the final readout.
Yeah, great question. Tina, over to you.
Thank you, Alec, for the question. So right now, obviously, we're still discussing the final details with the FDA over the next few months. But as we model this trial design and we think about things like Polatuzumab vedotin plus bendamustine and rituximab or R-GemOx as the control arm, those are agents that really don't have curative potential. When you think about their PFS curve, they continue to decline to the baseline. Whereas, of course, with CAR-T cells and as you saw today with our PFS curve, you see a shelf or a plateau of patients that stay in remission. That's really where the benefit comes from.
As we model our trial design, it's really the difference between the vispacabtagene regedleucel that we assume will maintain that plateau and the control arm, which have published median PFS of four to nine months, depending on what regimen you're looking at. When we think about an event-driven endpoint like PFS, we are modeling doing an interim at 70% of the events and then, again, at the 100% of events. The alpha when we. Model doing an interim would be very small amounts, something in the range of 0.007. Of course, this is all of our planning and estimates right now. Then we'd use the rest of the alpha at the final analysis.
Okay, great. Maybe one for the doctors on the call.
I appreciate you come from fairly large academic centers, but maybe you could just talk whether there was a learning curve as you got comfortable with the therapy and if you see any potential hurdles or points that smaller community practices might need to come up the curve on. Thank you.
Yeah, Alec, thank you. Go ahead.
I'll address this from our perspective. We are a large center, and we do over 200 CAR-T on a yearly basis here in Kansas City. Our catchment area is principally rural, and even out to wilderness areas out on the Colorado border, half of Missouri, a little bit of Nebraska, Iowa, Oklahoma, and Arkansas. We have a network, as I mentioned, Midwest Cancer Alliance, with a large swath of that area of community hospitals. We've chosen very wisely, I think, centers that have, obviously, an ICU, have a champion, local champion.
We have been in the process of meeting with this group of folks in this large swath of area, docs. They want to do this. Their teams want to do these therapies. These docs will be provided with 24/7 access to treatment experts. For that unusual patient who does have more advanced CRS or ICANS, for example, where they need to get further guidance or actually transfer the patient, that will all be arranged and set up. We're used to this in our network because we have one of the largest acute leukemia programs in the nation. 24/7, these folks don't do 9- 5 when they have onset of acute leukemia. We're a yes-sir, yes-ma'am right away. We get them on a helicopter, and we have them up here from Oklahoma or from way out in the state of Kansas, etc. We will be leveraging that.
Obviously, intensive education, algorithms of care that we provide for our patients, the understanding of grading, understanding therapy for the grading, the side effects of therapy, etc. There's a very intensive effort already underway to do this.
I agree. Whereas New York City is definitely a very different geography, we similarly, originally with autologous transplants, have a lot of partners in the community with the auto CARs and the bispecifics. Similarly, we've been doing a lot of the step-ups for the bispecifics and certainly the first weeks of CAR-Ts. We do have a growing community or partnership with our community partners. We've educated them and shared our learning experience on the products we already have. This would just be adding a layer to this existing network. They have 24-hour access to me and my partners. The infrastructure of sharing the learning is already there.
I think the learning curve is a lot less steep than it has been with our current standards of T-cell redirection.
Okay. That is very helpful. Thank you so much.
Next question comes from the line of Mani Foroohar with Leerink Partners. Your line is open.
Thanks for taking the question. I want to dive in a little bit on timing and status of regulatory conversation. Recognizing that is a little bit looking forward beyond the conversation we are having today. When should we, as investors and analysts, expect feedback regarding your next interaction with the FDA? What is the timing in which we can get more clarity, recognizing that some of this morning's news has sort of introduced more nervousness into investors around predictability of FDA feedback, etc.?
Mani, thanks for the question. I assume you are referring to the news of a top departure at the FDA.
Of course, that is not the part of the FDA that oversees this. I will just say in terms of the blocking and tackling with the FDA, for us, it has actually been quite routine. There has been very high consistency in terms of the review team we have engaged with repeatedly over the past few years, which we are very pleased to see. In terms of timing for answering some of these questions about the pivotal design, we anticipate in just the next few months, we will be in a position to get clarity on some of these topics, including, for example, how best to think about inclusion and exclusion criteria for transplant and auto CAR-T ineligible patients, as well as nailing down the complete list of agents within the control arm.
Great.
If I could hop off to a separate unrelated question, a little bit, I guess, a little bit also off the immediate set of our conversation. More about CB-011 and separate disclosures that you guys have also had. How should we think about the expected dose response for an allo CAR-T? Recognizing this is a relatively small absolute patient population in terms of n, how should we expect the tempo of dose response across that population to emerge? How should we think about analyzing that in future disclosures?
That is a great question, Mani. I will hand it to Tina to begin on that.
Thank you, Mani.
When we look at our dose escalation data, probably the two dose levels where we have the most data to look for a dose response is the 300 million and the 450 million cells. There are really just too few patients at 150 and 800 to understand true dose relationship. When you look at 300 and 450, those are the patients you can see a dose response for efficacy. We did not show it today, but we do see trends of better expansion of the cells at 450 million cells as well. Moving forward, we are expanding at 450 million cells. That is the regimen we're moving forward. When we disclose in the future, those are the data that will get added to. The other dose levels, we do not plan to further evaluate at this time.
Thanks. That's really helpful. Congrats again, guys.
Next question comes from the line of Asthika Goonewardene with Truist Securities. Your line is open.
Hi. Good morning, folks, and thanks for taking my questions. I'll also offer my congratulations on this positive update here. Tina, just to start us off, the vispacabtagene regedleucel cohort had patients with some pretty poor prognostic features. Can you maybe also give us some clarity on what proportion of the patients treated with vispacabtagene regedleucel in the optimized profile or the confirmed profile would have been deemed transplant ineligible? And how did these patients perform versus the others?
That's a great question. What we can tell from our database right now is about a third of our patients would have reached one of the auto transplant ineligible criteria. In this study, all of them, kind of by definition, would have met the auto CAR-T ineligibility.
These are patients that could not wait or could not access the auto CAR-T. They have very similar outcomes. About half of those patients have long-term responses.
Okay. That's encouraging to know that. Maybe it's a question for Dr. Rossi. In a similar vein here, it's interesting to note that CB-011 was administered at centers, all of which, if we do our checks, suggest that auto CAR-T was commercially available. We know that approved auto CAR-T, like CAR-T, may have a long vein-to-vein time. Maybe for Dr. Rossi, I could ask this question. I know it's hard to maybe glean this out of the baseline characteristics, but could you give us an estimate of what proportion of the patients treated with CB-011 would have been also deemed ineligible for auto CAR-T? Maybe they had rapidly progressing disease. Can you maybe talk to us a little bit about that?
I'm just wondering if this cohort might have recruited some of those patients who were just not fit enough and had rapidly progressing disease who did not get to wait around long enough to get that auto CAR-T.
Yeah, that's actually a very interesting question because we're very used to, in our practice, patients who are eligible to go on study. We will offer a study, and they'll usually be excited to have that option. The patients we take to commercial CAR tend to be the ones who are ineligible for study. I don't think I've ever thought of it the other way around. In general, these were patients with high burden of disease. I think sometimes the predictability would have been one thing, the manufacturing delays. The other is just the time commitment for a patient and a caregiver.
I don't think that many of our patients could not have made it to a CAR-VicT type experience. It would be the more elderly. We had a lot of octogenarians, I think more than we do in our CAR-VicT commercial experience. It is the fact that they were able to get it within a couple of weeks and not, say, six months down the road through maneuvers to try to get them under control. Generally, I would say if I have it available commercially, we would reach even more patients because of the restrictions of the clinical trial eligibility.
Okay. Thanks for taking my questions.
Next question comes from the line of Jonathan Miller with Evercore ISI. Your line is open.
Hi, guys. Thanks for taking my question and congrats on all the data.
I'd like to dive in a little bit deeper into the different ways that somebody could be CAR-T ineligible for the proposed phase III definition. I mean, we've heard a lot about these patients in academic centers who are ineligible for a variety of reasons. There is also this other population that some of the KOLs were referring to that are ineligible in the community because they can't travel or they don't want to leave their local center to go to an academic center where auto CAR might be available. Presumably, these patients have different baselines and different expected response to CAR-T. Can you talk a little bit about what proportion of the phase III population you might expect to be "geographically ineligible" versus more strictly ineligible and how you might stratify for those characteristics?
Yeah, John, thank you for the thoughtful question.
Tina, if I could ask you to answer this one, please.
Of course. As Dr. McGurk mentioned, we're already talking to many sophisticated community centers with the hopes that half or more of our sites have that kind of footprint, which means a significant portion of our patients may meet more this geographic or financial criteria for auto CAR-T ineligibility, where the other types of ineligibility might be medical or low lymphocyte counts where they are high risk for manufacturing failure. There are a couple of different ways we're thinking about stratifying, either on the type of site they're being treated at or whether or not the site has access to auto CAR-T. We are thinking about that because I think you are correct. The type of patient and their ability to respond and have durable responses to CAR-T, particularly vispacabtagene regedleucel, may be different.
To control for that, we are discussing having stratification factors that should take that into account.
May I just comment, Tina?
Oh, please.
Yeah. I mentioned earlier Flatiron Health Research database, patient-level data, we looked at over 500 patients. Of those who were clearly eligible, so they had an ECOG performance score of 0 or 1 and no significant comorbidities, it was that population that only 25% of presented to us. The percentage for patients who had more advanced comorbidities and worse ECOG scores 2 or greater. That was abysmal. That was in the single percentages. For those who are clearly eligible, should be eligible based on that patient-level data across the nation, 25%. That is what we are looking at. It is multifactorial, right? As the education of our referring physician population, optimized communication. The geography really matters to a lot of people in this part of the country.
Makes sense. Makes sense. Makes sense. Thank you. One other question I have is on cell persistence, the durability of the cell signal, which I know you guys have armored your CARs and you have gone to some trouble to try and extend cell viability and persistence in vivo. It does not look like, at least in the CD19, it does not look like you are getting cell persistence that is dramatically extended, certainly, versus the auto CARs. Granted, the efficacy data you have is very competitive, but do you expect that that cell persistence is going to be meaningful to an allo product in the way that it is to an auto product? Should the bars there be the same?
Yeah, that is a really great question, Jon. I will take a small piece of it and then hand it to Tina for the rest of the answer. I will just start by noting that the armoring strategy we use for vispacabtagene regedleucel is a PD-1 knockout. That is actually not intended to alter PK. We do not think the PD-1 knockout would extend persistence of the circulating allo CAR-T cells. Instead, it is intended to prevent premature CAR-T cell exhaustion so that during that defined window of time where you have circulating allo CAR-Ts, they are not becoming exhausted and they are packing kind of as much anti-tumor punch as possible. We do believe that that is contributing to the auto-like efficacy that we are seeing with these cells. Tina, I will hand it to you for kind of broader thoughts on the role of persistence.
Yeah, thank you, Rachel. Thanks for the question. I have actually been in the auto CAR-T field for a long time, and we have always wondered how much persistence you needed. I knew you probably did not need a year, but wondered if you needed three or six months for long-term durability. I think with allo, we are seeing that you do not even need three months when you have young donor T cells that are healthy and maybe for vispacabtagene regedleucel armored with a checkpoint disruption or with CB-011 or cloaked from the immune system. You need maybe one to two months as long as those cells are healthy and can do their job. Of course, we are only measuring persistence in the peripheral blood right now. They disappear from blood, but they may still be working for longer at the site of disease.
I think this is really exciting to actually maybe show how low that bar is for expansion and persistence when you have healthy CAR-T cells around doing their job.
Makes sense. Thank you so much.
Again, everyone, if you would like to ask a question, press star one on your telephone keypad. Next question comes from the line of Luca Issi with RBC Capital Markets. Your line is open.
Oh, great. Thanks so much for taking my question and congrats on the data. Maybe if I can circle back on the powering assumption, it looks like your trial is obviously 250 patients, which is actually a little bit smaller than Zuma 7. You just maybe talk about that. Is that because you anticipate the control arm to underperform what you've seen historically from Zuma 7, or are there any other drivers that actually can explain the difference?
Again, any comment there? Much appreciated. Then maybe on manufacturing, quickly, can you just expand a little bit more on manufacturing? I find it remarkable that the FDA published 200 CRLs, and close to half of them are actually related to manufacturing. Can you just talk about what capabilities you have with your partner and then maybe talk about whether any part of the supply chain or XUS? Thanks so much.
Yeah, Luca, thank you. That's a lot of ground to cover. We'll try to get it all. Tina, I'll hand the first part to you.
Yeah, it's a great question. With Zuma 7 and TRANSFORM, those were event-driven studies, very different. Time to event versus progression-free survival. With a different patient population.
When you look at the published data for transplant ineligible patients versus transplant eligible, which are in those other studies, there are just different assumptions for outcomes in the control arm. As I mentioned, we're still in discussions with the agency around the control arm. Right now, we're just modeling size and depending—and we think we're being conservative in our assumptions of the control arm median PFS as we do the sizing modeling of the study.
Luca, maybe just for reference, the TRANSFORM trial that Tina just mentioned actually enrolled fewer patients. It was about 184 patients randomized between the two arms. With respect to manufacturing, look, fantastic question. Our cell therapy manufacturing happens at a contract manufacturer here in the U.S. We've not disclosed which one, simply that it's here in the U.S.
We've disclosed in prior filings that the vast majority of our drug supply comes from U.S.-based suppliers. I believe there's one component that is manufactured XUS in Europe, not in China, for those who are thinking about geographic constraints. We believe that our supply chain is incredibly well situated to take advantage of the very well-skilled manufacturing process that we have today. The partner we are working with in terms of the cell therapy manufacturing has quite a lot of experience and expertise with a variety of cell and gene therapy approaches. We're pleased with the capabilities that they have, and we think they're well suited not only to support us for the planned pivotal study but for commercial as well.
Thanks so much, guys.
I see no more questions at this time. The lines are now closed, and I will hand the presentation back to Dr. Haurwitz.
Thank you all for your time and your questions. Turning to slide 46, we will conclude today with gratitude. None of the exciting data we shared today would be possible without the patients, caregivers, and investigators who have participated in the ANTLER and CaMMouflage trials. We are grateful to everyone involved and are truly humbled by the patients who have enrolled. These patients inspire us as we continue to execute on our mission to develop transformative therapies for patients with devastating diseases through novel genome editing. Thank you all so much for joining us today.
This concludes today's conference call and webcast. Thank you for participating. You may now disconnect.