Cabaletta Bio, Inc. (CABA) Earnings Call Transcript & Summary

Good morning, and welcome to the Cabaletta Bio Conference Call. [Operator Instructions] I will now turn the call over to the Cabaletta Bio team. Please proceed.

Good morning. This is Anup Marda, CFO of Cabaletta Bio, and welcome to our conference call to discuss our ongoing DesCAARTes Phase I clinical trial of DSG3-CAART, including new acute safety data from our first patient cohort. In addition, we will be providing a pipeline update on our new program, PLA2R-CAART for patients with membranous nephropathy. The news release became available just after 7:00 a.m. today and can be found on our website at www.cabalettabio.com. A live webcast and replay of today's call will be available on the News and Events section of our website. Before we begin, as indicated on Slide 2, we will be making forward-looking statements in this presentation, which are subject to a number of risks and uncertainties. Actual results or events could differ materially from the plans, intentions and expectations discussed here. Presenting on today's call are Dr. Steven Nichtberger, Chairman, CEO and Co-Founder of Cabaletta Bio; Dr. Russ Hall, the J. Lamar Callaway Professor of Dermatology at the Duke University School of Medicine, who will provide an overview of the pemphigus landscape. Dr. David Chang, Chief Medical Officer of Cabaletta Bio; and Dr. Gwen Binder, Executive Vice President of Science and Technology. Additionally, I will be available for Q&A at the end of the call. I'll now turn the call over to Dr. Nichtberger.

Thanks, Anup. We're thrilled to welcome you to our first company conference call to discuss the acute safety data that was released this morning from the first cohort of the DesCAARTes as well as to introduce you to PLA2R-CAART for PLA2R-positive membranous nephropathy patients. For those who are less familiar with Cabaletta, allow me to review Cabaletta today on Slide 4. We're leveraging a clinically validated CAAR T platform as a novel approach to treating autoimmune diseases, aiming to provide a deep and durable response, potentially cures, for autoimmune patients with highly specific and targeted therapy that's designed to eliminate only the pathogenic B cells. And with target engagement based on the strength of our biologic rationale, a deep understanding of translational data and many different ways to deliver on the promise for patients. We have multiple near-term clinical data catalysts with a potential for pipeline read-through on acute safety, target engagement and potential clinical responses. We have an expanding network of academic and industry partners shown here. As shown on Slide 5, the pipeline includes multiple disease targets where we believe cure is possible. I'd like to highlight a few, the DSG3-CAART program is currently progressing well in the DesCAARTes trial. The MuSK-CAART program, which is on track for an IND filing in the second half of this year for patients with the MuSk form of myasthenia gravis, and finally, the newly introduced PLA2R-CAART program, which has made consistent and rapid progress through our CABA platform on the heels of the MuSK-CAART program. We expect to request a pre-IND meeting with FDA in the second half of this year for this program. Overall, our current pipeline includes 7 programs targeting diseases that affect over 80,000 patients. As demonstrated by our expanding pipeline, shown on Slide 6, our platform is modular and highly productive. As shown on this slide, swapping out the extracellular targeting domain or autoantigen creates a new product candidate. We're using the identical signaling chain in each product. We're also using a clinically validated engineered T-cell platform as the foundational technology for our products. Slide 7 summarizes key safety data from the first cohort of the DesCAARTes trial, which was announced this morning. We believe that these initial data begin to derisk the platform. Product manufacturing has delivered a 100% success rate to date using a validated process in collaboration with Penn's CVPF manufacturing organization. The acute safety data from the first dosing cohort demonstrated no dose-limiting toxicities, nor any clinically relevant toxicities in any patient as of April 30. The next dosing cohort at 100 million cells will initiate once patient 3 completes their 28-day follow-up. Finally, we continue to believe that DSG3 antibody titers that are consistently reduced by greater than 20% over time in a patient and perhaps even in multiple patients within a cohort, would suggest target engagement and biologic activity. We would expect that the biologic activity and target engagement would be more robust with more robust DSG3 antibody declines. Once biologic activity is demonstrated, we believe there will be many variables that can be optimized to maximize target engagement. Now I'd like to turn it over to Dr. Russ Hall, who is the J. Lamar Callaway Professor of Dermatology at Duke University's School of Medicine. Russ?

Thank you, Steven. It's my pleasure to be here today to talk to you a little bit about the pathogenesis of pemphigus, some of our current understandings about how the disease is manifest and treated and some of the opportunities that we have for improving the treatment of these patients with very severe skin diseases. On this slide, the pathogenesis of pemphigus is explained. Pemphigus vulgaris and pemphigus foliaceus, our autoimmune blistering diseases, which are characterized by blistering the skin and mucus membranes. 90% of patients with pemphigus vulgaris have mucosal disease that is lesions in their oral, nasal, pharyngeal mucosa and about 25% of these patients only have mucosal disease. Shown here are patients with pemphigus vulgaris. The cutaneous manifestations are shown on the left. These lesions begin as blisters, then ulcerate and are slow to heal. If untreated, they will progress to involve large portions of the body. The middle picture shows a patient with severe oral ulcerations. These ulcerations likewise will continue to spread if untreated throughout the mouth. Pemphigus vulgaris and pemphigus foliaceus are characterized by the presence of IgG antibodies deposited in the skin and mucus membrane of patients. Shown on the far right is the direct immunofluorescence study of the mucus membranes of a patient with pemphigus vulgaris. The green chicken wire type of pattern is indicative of the antibodies bound to the surface of the individual skin cells. This is the predominant diagnostic test utilized to confirm a diagnosis of pemphigus. These antibodies that are found in the skin are directed against 2 very specific proteins, desmoglein 1 and desmoglein 3. These proteins are a normal part of human skin and are the major cell adhesion proteins that hold skin together. The binding of the auto antibodies to the skin initiates a process leading to the breaking apart and blistering of the skin and mucus membranes with a marked difficulty in healing. Pemphigus vulgaris is the most common variant of pemphigus and is characterized by the presence of antibodies against desmoglein 3, either alone, which most often occurs in patients with mucosal disease alone or together with antibodies directed against desmoglein 1, most often in patients with mucosal and skin disease. Antibodies against these desmogleins are pathogenic in animal models. That is to say when they -- antibodies are injected in animals and a disease occurs that is clinically and immunologically similar to that as seen in humans. In addition, the level of the desmoglein antibodies in the blood of patients correlates with disease activity. These findings together demonstrate the key role that antibodies against desmoglein 1 and 3 play in the pathogenesis of pemphigus. Pemphigus vulgaris is a severe disease. The oral disease is very painful with nonhealing of oral ulcers that inhibit eating and drinking. In addition, oral lesions can extend into the throat and into the upper esophagus, involved in nasal mucosa as well as the perianal and vaginal mucosa. In order to achieve control of this disease, high dose systemic corticosteroids are required. This therapy results in significant morbidity and occasional mortality in patients. In order to minimize the dosage of systemic corticosteroids utilized, additional immunosuppression is often required. And unfortunately, the disease is characterized by frequent relapses, often requiring retreatment with high dosage systemic corticosteroids as well as prolonged general immunosuppression. On the next slide is a schematic of the pathogenesis of autoimmune diseases. In thinking about how we can better treat patients with pemphigus, it is useful to consider the potential targets at different stages of the pathogenesis of the disease. The pathogenesis of autoimmune diseases, including pemphigus, rest on the presence of a genetic abnormality associated with an unknown environmental factor that together lead to the induction of an immune reaction that is misdirected against self-antigens or normal proteins in the body. In the case of pemphigus vulgaris, this immune reaction generates autoimmune T cells, which through interactions with B cells result in the autoreactive B cell. These auto reactive B cells are a small part of the total B cell population, but are critical to the formation of IgG autoantibodies directed against the self-antigens, desmoglein 3 and desmoglein 1, and thereby leading to skin disease and mucosal disease. To date, studies have been directed at many potential targets to control pemphigus vulgaris. Studies are focused on the interaction of the genetic component of the disease in order to try to stop the disease at its initiation, and these studies have proven unsuccessful. Studies are also underway at controlling the initial T cell response with the goal of interfering with the critical T cell and B cell interaction. These studies are currently underway and have no results to date. Studies have also focused on decreasing the amount of antibodies in the blood, this has occurred through either an enhancement of the normal IgG clearance of antibodies in the body or by removing them through the blood by absorbing them. These methods, however, do not stop the production of autoantibodies and in most cases, are not specific and remove all antibodies from the body and not just the pemphigus antibodies. Recently, treatment is focused on removing the autoreactive cells -- the autoreactive B cells that are critical for the development of autoantibodies. Studies are underway looking at decreasing the activity of B cells through inhibiting their signaling using BTK inhibitors. Studies have also shown that removal of B cells from patients through the use of antibodies directed against B cells have been successful in treating patients. These studies are aimed at removing all B cells in the periphery, resulting in total B cell depletion. This, however, is not a specific therapy and only a small minority of total B cells are responsible for the production of pemphigus antibodies. In addition, B cells, including disease-specific B cells are repopulated from the bone marrow and often require prolonged and repeated B cell suppression to control this disease. On the next slide is a description of what our long-term goals are in the treatment of patients with pemphigus. These include developing a therapy that can provide a long-term remission of the disease with little or no need for repeated treatments. And although we use the word guardedly, perhaps even a cure. In addition, this treatment must have minimal short-term adverse events, both minor and serious, as well as no long-term serious adverse events. Finally, we need [indiscernible] of corticosteroids both early and late in the disease. And we would hope to have, at some point in time, therapy that actually controls the disease within the first 2 weeks of starting treatment. In the next slide, is a result of a pivotal clinical trial by Dr. Pascal Joly. In this trial, a 3-year study, Dr. Joly treated patients with prednisone plus rituximab or prednisone alone. And rituximab is an anti-CD20 antibody that depletes peripheral blood B cells. These B cells return to the circulation in about 6 to 12 months. And as a result, retreatment has often been used, and in this study, Dr. Joly retreated his subjects with rituximab at 12 and 18 months. The control group was treated with prednisone alone. The results of this study show that indeed, rituximab treatment did increase the rate of complete remission off therapy at 24 months. However, it is important to note that this time to complete remission off therapy was still quite delayed, occurring 277 days in the median with a range of 177 to 751 days. In addition, patients still had to be treated with systemic corticosteroids, and many of these patients were on systemic corticosteroids for up to 277 days or even longer. In addition, 24% of the rituximab-treated patients relapsed after treatment, 9% of these patients having a severe relapse. While rituximab has markedly changed our treatment of patients with pemphigus, it is a general immunosuppressive treatment requiring long-term depletion of all peripheral B cells and is not directed against only the disease inducing desmoglein 3 specific B cells [indiscernible] pemphigus -- from centers treating pemphigus outside of clinical trials. In [indiscernible] nephropathy in 2021, they looked at approximately 108 patients with pemphigus treated with rituximab and found that 50% of their patients relapsed after the first rituximab treatment by 18 months, often requiring 2 to 6 repeated treatments, thus documenting the rituximab is not a long lasting and enduring therapy. In addition, the safety of long-term rituximab is not totally known and is best noted by the findings in the patients with rheumatoid arthritis. In this post-marketing study by van Vollenhoven and colleagues, serious infections incurred in about 3.94 per 100-patient years in patients treated with rituximab. In addition, systemic immunosuppression was noted by the low IgM level, greater than 4 months duration that occurred in 22.4% of the patients. Finally, we do not know the impact of long-term B cell depletion on patients' response to new immunizations or booster immunizations or to new viral infections. B cell depletion is considered to significantly impact the ability to develop a robust antibody response after immunization and thus represents a potential adverse event associated with long-term rituximab therapy. On the final slide, again, we have the long-term goals for our treatment of patients with pemphigus. Despite the significant advances that have occurred with the development of rituximab therapy for patients with pemphigus, we still have significant challenges to meet our long-term goals for the treatment of our patients. We would like to have a therapy that can put patients in the long-term remissions without the need for repeated therapies, especially with general immunosuppresses, including prednisone. We'd like these therapies to have minimal short-term adverse events and minimal to no long-term serious adverse events, and we must have a therapy that minimizes both the short-term and the long-term use of systemic corticosteroids. Thank you for your time, and I will be happy to answer any questions that do come up during the question-and-answer period. I will now turn the call over to Dr. David Chang, Chief Medical Officer of Cabaletta Bio.

Thank you, Dr. Hall. I am pleased to provide an update on the DesCAARTes clinical trial. Next slide, please. So DSG3-CAART cells are CAAR T cells designed to specifically target and bind pathogenic anti-DSG3 antibodies found on B cells, thereby eliminating those B cells. DSG3-CAART have been engineered to express the DSG3 protein on their surface with the EC5 domain removed since all known pathogenic autoantibodies will bind to EC1 through EC4 domains. EC5-directed autoantibodies are not known to be pathogenic. Therefore, all known pathogenic autoantibodies will be targeted by DSG3-CAART cells. Next slide. DesCAARTes is a Phase I open-label study in patients with mucosal dominant pemphigus vulgaris to determine the maximum tolerated dose and fractionation of DSG3-CAART cells. Therefore, this is primarily a safety study. Adult patients with detected disease, positive anti-DSG3 antibodies and inadequate response to at least one standard therapy are eligible, which represents a broad population. In part A, the dose escalation phase, 3 patients in each cohort will be treated with 4 split infusions on 4 separate days. To mitigate safety concerns, the first infusion will be in very small fraction of the total dose followed by increasingly larger fractions for the next 3 infusions. The first cohort received 20 million cells without preconditioning or lymphodepletion. The second cohort will be treated with 100 million cells. The next 2 cohorts will receive increasingly larger doses with the fourth cohort receiving a dose greater than what has been typically administered with oncology, CAR T therapy. Once the maximum tolerated dose has been established, part B will consolidate the 4 split infusions into a single infusion. And part C is the extension cohort to confirm the safety and tolerability of the selected dosing regimen. In part A and part B, there will be a 2 to 4-week interval between dosing of patients to ensure sufficient time has passed to observe for acute safety or dose-limiting toxicity or DLT. The definition of DLT in this study of dermatology patients is conservatively set at 1 grade lower than typical oncology studies. Any toxicities greater than grade 1 or mild severity would generally be considered DLT. Next slide. As mentioned earlier, no clinically relevant adverse events were observed during the 8-day acute safety window, including cytokine release syndrome or neurotoxicity, which is the period with highest probability of observing treatment-related toxicity. In addition, no DLTs were observed in the 2 subjects who have completed more than the full 28-day DLT monitoring period post infusion. Of note, the first patient is beyond the 5-month post infusion period, the second patient is beyond the 2 months, and the third patient is beyond 2 weeks. Next slide. The manufacturing of DSG3-CAART cells at the University of Pennsylvania was 100% successful for all 3 patients treated. In addition, the manufactured DSG3-CAART cells from the first patient were able to eliminate B cells expressing anti-DSG3 antibodies in vitro in a dose-dependent manner. The negative control is shown in the green line, where only the target B cells were present and no effector DSG3-CAART cells were present. As more DSG3-CAART cells are added in the assay, there is an increasing amount of targeted B cell cytotoxicity. This can be seen with the increased filling from the light blue line to the blue line to the dark blue line. Next slide. As noted earlier, we observed no DLTs for clinically relevant toxicities in the first 3 patients to date. There are several factors that could impact the safety data. Therefore, it is important to provide available, relevant data to help interpret the results. These safety data were observed in the context of administered dose of 20 million DSG3-CAART cells without preconditioning or lymphodepletion, and in the presence of circulating anti-DSG3 antibodies. DSG3-CAART cells was detected at low levels by quantitative PCR in both patients who have been evaluated and completed the 28-day DLT period. Once we have additional data, including top line target engagement, they will be presented on a cohort by cohort phase. Given the very low cell dose administered, target engagement in the first cohort is possible, but not expected. We anticipate reporting target engagement data in the second half of this year. Next slide. After the acute safety data at day 8, DLT window at day 28 and primary safety endpoint at 3 months, potential target engagement is expected by 6 months. We believe that a consistent decline in anti-DSG3-CAART antibody titers, of, at least, 20% would be an initial signal for target engagement, a more robust decline is expected with greater targeted engagement. Next slide. The first cohort received a very low dose of 20 million DSG3-CAART cells in the setting of pemphigus patients with a very low target cell number, representing 0.1% to 1% of the total B cell population. We are prepared with and exploring a range of strategies that can enhance target engagement if needed. Higher doses of CAAR T cells can be administered as we are doing with the subsequent cohorts in the DesCAARTes study. CAAR T cells can be expanded post infusion. Circulating autoantibodies may activate or inhibited CAAR T cells, and we can accordingly select patients or modify the autoantibody levels in the patient. The number of CAARs on each T cell surface can be increased or decreased. And the phenotype to the CAAR T cells can be modified to be more active. Next slide. With the first 3 patients tolerating treatment through at least 8 days, the DesCAARTes trial continues to gain momentum. The current 3 clinical sites at Penn, Stanford and UCDavis are very active and the dermatologists and oncologists are effectively collaborating with each other and demonstrating higher engagement in the study. Additional highly qualified sites are showing strong interest and are working to open. Also, we are expanding our relationships with patient advocacy organizations. And finally, we have established a very good collaboration with the FDA, which has already granted us with the Orphan Drug Designation and Fast Track Designation last year. In addition to providing top line data from the first cohort on target engagement by the end of the year, acute safety data for the second and third cohorts are anticipated during the third and fourth quarters, respectively. We have learned a great deal for the DSG3-CAART program and are applying those learnings to our MuSK-CAART and future programs. I will now turn it over to Dr. Gwen Binder, Executive Vice President, Science and Technology.

Thank you, David. As you've just heard, the early clinical success in our flagship program in DSG3-CAART that David just took us through, reflects the momentum in our organization that we've built in our clinical, manufacturing and translational research capabilities. And in addition, we've established our foundation in preclinical development as evidenced by steady progress in bringing our MuSK program towards IND, which is planned for the second half of this year. With these achievements in hand, today, we are ready and very pleased to tell you about our program in membranous nephropathy that is making rapid progress through our discovery pipeline. And on the next slide, I'll tell you more about this program. Membranous nephropathy, or MN, is a glomerular disease that causes nephrotic syndrome that leads to kidney failure in up to 30% of patients. MN is classified as primary or secondary, and primary MN is an autoimmune disorder that is associated with autoantibodies that bind proteins in the basement membrane of the glomeruli in the kidneys. In 75% of these patients, autoantibodies target a phospholipase A2 receptor or PLA2R, which is expressed on podocytes in the kidney. The role of PLA2R antibodies disease and their role as a predictive biomarker for clinical disease onset and remission is well established. Specifically, PLA2R antibodies are routinely measured clinically as diagnostic and prognostic markers of disease. In addition, autoantibody titers precede clinical disease by weeks or months and reduction in autoantibody titer precedes amelioration of disease. And then finally, autoantibodies are found co-localized with antigen as a site of damage in the kidney. And in autoantigen, PLA2R is an attractive CAAR target for several reasons. First, it is a single-pass transmembrane protein with distinct immunogenic regions or epitope that can be selectively engineered into a smaller construct suitable for CAAR design. Second, the epitopes targeted by autoantibodies are well defined, and the frequency with which patients develop antibodies against these epitopes is well established. In addition, the autoantibodies in this disease are of the IgG4 isotype, which avoids the possibility of complement-mediated targeting of the infused CAAR T cells. Today, we have multiple lead candidates, which contain the autoantibody epitopes. Each of these candidates can be efficiently expressed on T cells. And PLA2R-CAART cell demonstrates specific target engagement and cytolytic activity against multiple other antibody targets. So moving to the next slide. Now I'd like to tell you a bit more about the primary MN indication and the medical need in patients. Patients with PLA2R-associated primary MN fall into low, medium and high-risk groups, which are defined by the level of proteinuria, which is the main clinical assessment for the disease. As mentioned on the prior slide, PLA2R antibody levels are also a predictive biomarker for proteinuria and disease severity. For patients in the medium or high-risk categories, the risk of progression to chronic kidney disease and possibly end-stage renal disease is 50% to 75% and therefore, in these patients, immunosuppressive therapy is recommended. And recently, rituximab has been studied in primary MN and performed favorably in comparison to generalized immunosuppression. This is illustrated on the graph on the right on the slide, which is an excerpt from the MENTOR trial. Here, we can see the effect of rituximab, represented by the left columns on both PLA2R antibody titers and proteinuria, which appears superior in depth in comparison to cyclosporine, a standard of care immune suppressive therapy. Notably, you may see that reductions of PLA2R antibody levels by rituximab, shown in the top left panels, precede drops in proteinuria shown in the bottom left panel. However, despite the improvement in treatment outcomes offered by rituximab in primary MN, there remains an unmet medical need for patients due to relapse or resistance to rituximab. Resistance to rituximab appears to be secondary to disease-related renal damage and this is thought to result from the more rapid clearance of the antibody in patients with higher proteinuria. Patients with more severe disease, measured by higher levels of autoantibodies as well as autoantibodies against multiple domains of PLA2R are less likely to respond to rituximab. And up to 1/3 of patients diagnosed with primary MN ultimately progress to end-stage renal disease, depending on their clinical management. Importantly, the rapid impact of rituximab on PLA2R titers reflects that PLA2R antibodies are not produced by long-lived plasma cells, which would make the disease resistant to precision B cell targeting. And therefore, the rapid reductions in autoantibody titers after rituximab treatment supports the potential for PLA2R-CAART therapy in this disease. So to summarize on my final slide, for our PLA2R-CAART program, we have completed scientific, clinical and commercial assessment to validate the opportunity in primary MN. We have confirmed to the PLA2R epitopes involved in disease, have developed and optimize CAAR constructs containing these epitopes and have completed early preclinical testing for CAAR expression, function and specificity. We are now in the process of planning pre-IND interactions with the FDA, which will occur in the second half of this year. And with that, I would like to turn the virtual podium back over to our CEO, Steven.

Thanks, Gwen. So on Slide 28, as we wrap up, I'd like to thank Dr. Hall for joining us to discuss the standard of care and the unmet need in pemphigus vulgaris patients. The acute safety data from DesCAARTes that we announced this morning begins to derisk the CAAR T platform and sets the stage for accelerating progress into the 100 million cell dose cohort while also providing valuable insights that can inform the proposed design of the initial clinical trial for the MuSK-CAART IND, which is on track for filing in the second half of this year. The PLA2R-CAART program has been informed by learnings from the MuSK-CAART program, permitting consistent progress and rapid development through our CABA platform. We expect to discuss this program with FDA at a pre-IND meeting later this year. In summary, based on the acute safety data reported this morning, and continued progress across our platform, now more than ever, we believe that our platform and our products have the potential to provide deep and durable, perhaps curative responses in many patients with B-cell-mediated autoimmune diseases. Now I'd like to turn it over to the operator for any questions.

[Operator Instructions] Our first question comes from Matthew Harrison from Morgan Stanley.

Congrats on the data. This is [ Costas ] on for Matthew. Two questions from us on the mPV program, one on safety, one on the efficacy. On the safety side, we are wondering whether you saw any CRS or neurotox at all of any grade, and if you can provide any color around the safety you would expect in the higher doses, given what you saw in the first dose? And then a follow-up on the efficacy.

Thanks for the question, [ Costas ]. Let me turn it over to David Chang to respond.

Yes, thank you for the question. With regards to any evidence of cytokine release syndrome or neurotoxicity into 3 patients, we did not see any of those acute adverse events during the 28-day period that we discussed. So then regarding the second question, on safety of higher doses, we cannot comment on whether there will be safety or not, but that's why we're doing the study, and we hope to have that information later this year.

And on the efficacy side, I'm wondering how are you thinking about the efficacy at the low dose? And we know that safety and efficacy are correlated with CAAR T but we are trying to understand whether this is the case here or it's different?

Yes. I'm not sure that we would believe that safety and efficacy are correlated in the use of a C-A-A, CAAR T technology. And the reasons for that, if you believe they might be correlated in the treatment of cancer, the reasons for that are, as you know, we only address 1% or fewer of the B cell population if our therapy works as designed. And in the first cohort, what we know is there were no clinically meaningful adverse events reported of any sort that were clinically relevant through Friday of this past week, as we've said.

Our next question comes from Phil Nadeau from Cowen and Company.

Congrats on the progress. A few from us. So first, at several times during the presentation, you mentioned that you thought a 20% reduction in antibody levels would denote target engagement. Can you talk a bit more about how you determine that to be the threshold? What is it about 20% in particular that gives you confidence that it signals target engagement?

Yes. Phil, thanks for the question. And let me turn it over to David to respond.

Yes. So the 20% number comes from being able to determine that it is something more than beyond noise or just error in terms of measurement or variability within the measurement, and we've looked at the assay and the assay is actually quite accurate in terms of reproducibility. However, there is some degree of error that could be brought into the assay because of sampling error or just variability as, I mentioned. So 20% by looking at the various data seems to be evidence that there's something more than just variability. That's how we determined that 20%.

The -- by putting out the 20% number, what we're trying to do is offer our best thinking to investors and to the public regarding a highly sensitive measure of whether or not there is biologic activity present. Just to be sure, we don't expect that our therapy when dose is optimized and when patient-type is optimized, will achieve anything near that low level of DSG3 reduction. We ultimately believe that the platform is designed to completely eliminate the B cells that are making the antibodies. And so we would expect something much closer to complete elimination of the DSG3 antibodies.

That's very helpful. And then second question is on Slide 20, you note that target engagement in the first cohort is possible, but not expected. Again, I'm curious about the background behind that, that statement. Is that based on the levels that you detected in the first 2 patients in cohort 1? Or was that always your expectation?

Yes. So you've heard me speak often enough, and you'll recall that I've often said before we announced that the first dose in the first cohort was 20 million cells. What I routinely would say is that our starting dose, although not announced, is low enough that efficacy is possible, but not probable, not likely, that in the treatment of cancer, this dose at times has delivered some efficacy in the setting of lymphodepletion in some patients in some cancers, but it's not commonly used in the treatment of cancer. And it's on that basis that we provided the context consistently over the past year and still today, that one would not expect there to be efficacy. We don't intend to make any comment based on partial data on the efficacy front, which we've always said, between 3 and 6 months, we could expect to see a dose cohort full of data at which time we would announce the data from that cohort. I hope that makes sense.

Yes. That makes a lot of sense. And then last question is just on your term clinically relevant AE. How do you define what was clinically relevant versus not?

David here again. With regards to clinically relevant, this is something that the investigators felt was something relevant and related. So if it was not relevant according to the investigator and not related, then that was reported as not clinically relevant.

[Operator Instructions] Our next question comes from Douglas Tsao from H.C. Wainwright.

Congratulations. Steven, just curious, obviously, you sort of set out this 20% threshold as sort of an initial marker for -- you're sort of showed it in your target engagement. I'm just curious, I know the endgame is total sort of depletion of the antibody -- of the B cell antibodies. Just curious, is there sort of an in-between point when we would start to see a certain reduction in the pathogenic B cells that we would start to see some signs of clinical efficacy?

Doug, thanks for the question. I hear noise in the background. I can't speak to you.

I'm sorry. I'm trying to -- I got the webcast and my phone.

No problem. So the answer to your question is all we know and can speak to publicly is the theory, the biology, which is if our therapy works as planned, currently, we're at a starting dose of somewhere between 5% and 20% of the typical cancer dose of CAAR T therapy in CD19-directed CAAR T therapy for cancer. So at a dose that's somewhere between 5% and 20% of dose in a different disease, a different product, but we're at a very low dose in this first cohort. At this dose or at any dose in our study, when and if we are able to announce the engagement of our product with the target that is to say, the B cell, one would typically anticipate that the B cell would be destroyed, the remaining -- circulating soluble antibodies that have been produced would continue to circulate and go through their normal half-life, which is about 3 to 4 weeks. And so after about 5 half-lives, you would expect to see a pretty dramatic reduction in those antibody titers. And that's really what's behind our belief that we will see the DSG3 antibody titers reduced between 3 and 6 months, and the added time beyond 3 months, which is about 5 half-lives, is -- just in case we do see remnants of the DSG3 antibody at 3 months, we're going to want to take a look and evaluate whether those antibodies are directed only to the clinically irrelevant EC5 domain. So we'll epitope map in order to be sure that what we are seeing, we can interpret correctly as we talk about it. Regarding clinical efficacy, the -- in a given patient, the level of DSG3 antibody seems to correlate with the severity of disease. That is to say within a given patient, a higher level would be associated with more disease. If that level is reduced, it would be associated with a lower intensity of disease. And the exact timing of those 2, honestly, nobody has ever taken out the cause of the disease exclusively. We're shooting for disease suppression, not immunosuppression. And in that context, I can't answer your question until we see our data. So I do hope that's helpful, even if it's not fulfilling.

No, it is. And just curious in terms of the dosing or the trial, you obviously said 100 million cells is the next dose up. Have you determined what the dosing above that will be? Or is that going to be a little dependent on what you see in terms of target engagement with the first 2 cohorts?

We -- the trial design does include 4 dosing cohorts. We have not announced the 2 higher doses at this time, but that's the current design of the trial.

But those doses have been selected?

Yes, they have.

[Operator Instructions] And presenters at this time, I show no further questions in queue. I will now turn it back to you for closing comments.

Terrific. Thank you very much, operator. We all appreciate the time that you've invested on the call this morning. We're thrilled to have passed this milestone. And to be able to accelerate in the execution of the clinical program as well as to continue to advance the MuSK-CAART towards its IND filing later this year. And to announce the new program in membranous nephropathy, the PLA2R-CAART, which we expect to meet with FDA in order to discuss the pre-IND topics, that will allow us to then discuss our plans going forward for the PLA2R-CAART. So again, thank you for your time this morning, and have a great day.

Thank you, ladies and gentlemen. This concludes today's conference. Thank you for your participation. You may now disconnect.