In this founder talk, Stephen Nichtberger, CEO of Cabaletta Bio, provides a comprehensive update on the company’s mission to create curative, targeted CAR‑T cell therapies for B‑cell‑mediated autoimmune diseases. He explains the scientific platform, which repurposes a clinically validated CD19 CAR‑T design by swapping the targeting domain from an anti‑CD19 antibody fragment to disease‑specific autoantigens, thereby selectively eliminating pathogenic autoreactive B cells while preserving overall immunity. The lead program, the DSG3‑CAR‑T (DayCart) trial for mucosal pemphigus vulgaris, has completed four dose‑escalation cohorts (20 M–2.5 B cells) with no dose‑limiting toxicities and a dose‑dependent increase in CAR‑T persistence observed at the 500 M cell cohort. The fifth cohort (up to 7.5 B cells) is enrolling, with additional safety and biologic activity data expected mid‑2022. He outlines the MuSK‑CAR‑T program for MuSK myasthenia gravis, which has received IND clearance and will launch in 2022, and the PLA2R‑CAR‑T pre‑IND work for primary membranous nephropathy. Manufacturing is currently performed through partnerships with the University of Pennsylvania/Children’s Hospital of Philadelphia, WuXi, and Oxford Biomedica, with plans to build internal capacity after clinical validation. Cabaletta’s cash runway of $119 M at the end of Q3 2021 is projected to fund operations through Q1 2023. Throughout, Nichtberger emphasizes the safety advantages of targeting a small fraction of B cells, the plug‑and‑play nature of the platform, and the broader market opportunity affecting over 80,000 U.S. patients.
Chapters
I'm Stephen Nickberger, CEO of Caboleta Bio, and appreciate you taking a few minutes to get updated on Caboleta. Caboleta exists to develop and launch the first curative targeted cellular therapies for patients with autoimmune diseases. It was spun out of the University of Pennsylvania to develop highly specific CAR-T products that are designed to treat B-cell mediated autoimmune diseases. We're targeting diseases where there's a biologic opportunity for a true response, even a cure perhaps. We're leveraging a clinically validated CAR-T product design and a manufacturing process through our alliance with the University of Pennsylvania. The DayCart trial in patients with mucosal pemphigus vulgaris is ongoing. There have been no dose-limiting toxicities observed in the first 4 dosing cohorts, ranging from 20 million cells up to 2.5 billion cells. In these patients, we have not used lymphodepleting regimens, and all of the patients that we treat have soluble circulating anti-DSG3 antibodies that are thought to be the cause of the disease. There's been no clear evidence of biologic activity reported in the first two low-dose cohorts, the 20 million and 100 million cell dose cohorts, as of December 12, 2021. These are doses that are less than 2% of the currently planned maximum dose to be used in this trial. We have observed a dose-dependent increase in DSG3 CAR-T persistence during the first 28 days post-infusion in the third cohort relative to the first two cohorts. The dose escalation plan includes up to a 375-fold dose increase from 20 million up to 7.5 billion across five cohorts. We're currently initiating the fifth cohort. Our cell therapy pipeline targets diseases that affect over 80,000 patients in the US alone. The MUSK CAR for MUSK myasthenia gravis patients had an IND submitted and cleared within the routine 30-day period and is now ongoing or under— undertaking the preparations to launch the clinical study, to initiate the clinical study in 2022. FDA Fast Track designation has been granted, and it is specifically to improve activities of daily living and muscle strength in patients with myasthenia gravis, the MUSK form specifically. The PLA2R CAR, a pre-IND interaction occurred as expected in the fourth quarter of 2021 for patients with PLA2R-positive primary membranous nephropathy. Our cash runway, As of the end of 3Q21, we had $119 million in the bank, and that will last at least through the first quarter of 2023. Turning to our scientific platform, it's designed to leverage a validated CAR-T technology. When used for cancer, our platform technology would have a CD19 antibody fragment as the targeting domain. The machinery that leads to, that is activated by engagement of the targeting domain involves a co-stimulatory domain and a signaling domain that are used already and frankly are already approved in the form of Kymriah when targeting cancer with these CD19 targeting antibody fragments. Those CD19 antibody fragments will attach to the CD19 antigen on a B cell, a healthy or a cancerous one will usually have the CD19 antigen, and successful therapy will lead to elimination of the B cells completely, leaving the patient with no humoral mediated immunity. In our platform, we make only one change, a subtle but a very important change to that product design. We use the same signaling machinery, the same co-stimulatory design, but we change the targeting domain from an antibody fragment to an autoantigen. The autoantigen is subject of attack in an autoimmune disease that's B-cell mediated. That autoantigen will recognize the B-cell receptor on the pathogenic autoreactive B cells in the patient who has the disease that is being targeted.. In that case, the B cells that contain this B cell receptor that are causing a problem typically represent less than 1% of the B cell population. And as a result, successful therapy in these patients with our products is designed to leave the patient with a normal immune system, and it is designed to eliminate the very cause of the disease, the B cells that are producing the antibodies that are causing the pathology. We also believe that the safety profile of our product should be substantially better than what we see with CD19 products, because we're only killing 1% or fewer of your normal cells, and there are no cancer cells involved. Our platform is really plug-and-play architecture. It's designed to enable a full portfolio across a variety of B-cell-mediated autoimmune diseases with terrific read-through from the lead on through the portfolio. So the lead program, the DSG3 CAR-T program, we've talked about being in the clinic. The MUSK, the IND recently accepted. The PLA2R, a pre-IND meeting completed at the end of last year successfully, and so on. This is our portfolio shown based on its point in development. And so now I wanna dive into the DSG3 CAR-T program specifically. So by way of background, pemphigus vulgaris, two major forms, the DSG3 mucosal form, the DSG3 and DSG1 mucocutaneous form. Our lead program targets the DSG3 mucosal form of the disease. Both forms of the disease are treated with broad immunosuppressive agents that are modestly effective and poorly tolerated uniformly. The most recent advance in this field is with rituximab. And rituximab combined with a steroid dose of about 3,500 milligrams per year, according to their data and their label, delivers a response rate of about 40% of patients, at least transiently for 4 months, being without medicines and without disease. Most of these patients, we know from the literature, are going to have a recurrence of their disease, and many of them will have serious side effects. In their label, again, 22% annual serious side effect rate. So there's a need for better therapies, and that leads us to why we do what we do. To design our products, and this is intended to be generalized, the DSG3 protein is analyzed. We come to understand that 91% of patients who have pemphigus vulgaris will have antibodies directed to the extracellular domain 1, shown on the top left. 71% of patients will have antibodies directed to EC2, and so forth. EC5 by itself does not cause human disease, in humans, this has been documented. And so our product shown on the bottom left, and then inserted into the T cell on the right of this slide, our product does not include EC5, but it does include the antigens that would attract the antibodies that could possibly be causing this disease. So all of the known epitopes that cause the disease, cause antibody responses, are incorporated into the product.. And on the right, you see the product with the antibody and the various epitopes that would be covered by each antibody. So one product designed for all patients. The Descartes study of DSG3 CAR-T is an open-label study to determine the maximum tolerated dose and the fractionation regimen of the DSG3 CAR-T product. As I've said, the dose escalation phase, the first phase of this program, has 5 cohorts, A1 through 5. A1 through We've reported now the safety data, particularly dose-limiting toxicities were not seen in any of those first 4 cohorts. The 5th cohort is now just beginning to enroll. After we finish this, we'll go to a dose consolidation phase and an expansion phase of the study. The primary objective of the study is to evaluate the safety and tolerability of the product. But at the same time, our secondary objectives include include evaluating various measures of biologic activity and efficacy in order to determine if we have struck the right dose in order to have the sort of treatment effect that the biology suggests we should be able to deliver in the clinic. So to date, on this timeline of patient enrollment, we have not observed any DLTs in any of the first 4 cohorts.. We did, however, observe a dose-dependent increase in DSG3 CAR-T persistence in the third cohort, the 500 million cell dose cohort, versus cohorts A1 and A2. That observation, we believe, is very important because it suggests that as you go up in dose, you might begin to see a higher exposure of the patient to the product. And so we'll, we'll wait and see as we go through the next couple of cohorts. The timeline here includes particularly the infusion, and then at day 28, the DLT observation window is closed. And then by 6 months, we have to wait, we can't know the efficacy profile until we allow the patient and the data to mature to between 3 and 6 months. Before we can declare that we either do or don't have biologic activity or efficacy. And so that's the timeline here. The safety data observed to date has allowed us to move into— to initiate the fifth cohort, which goes between 5 and 7.5 billion cells per patient. Additional clinical data on the patients in cohort A3 and A4 are expected to be presented at a scientific meeting in the middle of 2022. There are many options. And we've, as a company, as a team, we've always tried to identify what could potentially go wrong and what we might do to mitigate, minimize the risk of it occurring, and then to make it course redirect after. And so what are the opportunities on the safety side? And we've reviewed this over the past 2 years in great depth. Because the safety profile has been so exceptional, we've turned our attention towards the efficacy and the biologic activity for this program. And in that domain, we think about increasing the dose, we think about retreatment options, we think about enhancing the manufacturing of the product that we are making. And specifically, it's not that something is wrong or inadequate about the current manufacturing, rather, we see in our patients the central memory cells that we believe are the central actor, the active component, if you will, after infusion of our product. We see that in the patients using our current manufacturing process. So if we're trying to get to maximize the efficacy of the product in patients using the lowest dose of cells that we can use, we would want to enhance the manufacturing process in a way that increases the number of activated cells that we will see, those central memory cells, that we will see after infusion into a patient. And that is the opportunity to enhance the phenotype of our CAR T cells. There are various preconditioning strategies, whether it's with IVIG or other means to modify the circulating soluble antibody or with cytotoxic chemotherapeutic type of preconditioning regimens. All are opportunities to maximize efficacy in these patients as we need. We are committed to first increasing the dose, second, enhancing the phenotype through enhanced manufacturing, and we are open to, and the protocol allows for, retreatment to be done in these patients. And so with these options to enhance or to realize full maximum efficacy, we look forward to presenting additional data in the middle of this year and beyond as the data matures in each cohort in the program. Let me turn my attention very briefly to the MuSK CAR-T programs for patients with MuSK myasthenia gravis. And I'll reiterate, the IND for this product was accepted by FDA within the 30-day window. And we are now moving ahead to prepare to launch the study, to initiate the study in 2022. The study design has benefited tremendously. Upfront, I said, you know, there's a lot of read-through from the lead to the next and to the next portfolio program. So the benefits in this must-cart trial of the DayCart experience are as follows: similar design, open label to determine the maximum tolerated dose and to evaluate safety of the must-cart T product. However, we're not starting with a 20 million cell dose, we're starting with 100 million cell dose. We're not starting with a fractionated regimen of 4 infusions over the period of a week or so in each patient. We're starting with a single dose infusion. And then finally, rather than have a 3x3 design where 3 patients are treated, and if there are no side effects that are dose limiting, you can move to the next cohort, we're using 2 patients by 4, which means if we treat 2 and there are no dose limiting toxicities, we move to the next dose cohort. If there are dose limiting toxicities, we expand by an additional 4 patients in that cohort. And so we proposed, and FDA has agreed and given us the acceptance to move into this clinical trial. We've got physicians enthusiastically engaged. We're starting to work with sites. And as I've said, we expect to open this trial initiated in, in this year. Our manufacturing strategy has always been incredibly capital efficient compared to the alternatives. So we have a 3-stage manufacturing plan. First was to partner with Penn and with Children's Hospital of Philadelphia on both vector and cell manufacturing. That has been a terrific partnership for us, very capital efficient, very high quality, and sufficient capacity to meet all of our needs, despite the fact that our trial is enrolling with both more patients than anticipated initially and faster than anticipated by us initially.. And so that's been a terrific partnership and it continues. In addition to that, we have last year announced a partnership with WuXi as well as with Oxford Biomedica on the vector and the cell therapy manufacturing aspects of our programs, particularly WuXi will be manufacturing the product for the Muscart trial. And then third, once we see sufficient clinical data, we will both lease and build out our own manufacturing capabilities in-house, but we won't take on that additional expenditure until we have visibility into the clinical profile and the path forward. So in summary, we've got multiple potential data catalysts and within the lead program, the second program initiating its clinical trial this year. And very specifically, in the middle of this year, we expect to be able to present Cohort 3 the 500 million, as well as the 2.5 billion cell dose cohort biologic activity and clinical data, and, and the 28-day safety data for Cohort A5 as well in the middle of 2022. We have an expanding network. I didn't mention the sites continue to come on board and continue to enthusiastically initiate enrollment of yet more patients in the DayCardt trial. And we appreciate both the patients who invest themselves in, in becoming enrolled in the trial, as well as the investigators who have partnered with us on advancing this completely novel and potentially transformative therapy. So with that, I thank you for your time and look forward to hearing from you if there's interest for more information.
