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

Good morning. At this time, I would like to welcome everyone to Cabaletta Bio's conference call and webcast. [Operator Instructions] Please note that this call is being recorded and is the property of Cabaletta Bio. [Operator Instructions] I would now like to turn the call over to Will Gramig of Precision AQ.

Good morning, everyone, and thank you for joining Cabaletta Bio's conference call and webcast to discuss initial clinical data from the Phase I/II RESET-Myositis and to RESET-SLE trial that was presented at EULAR earlier today. Before we begin, I encourage everyone to go to the Investors section of our website at cabalettabio.com, where you can find the press release and slides related to today's call. I would like to remind everyone that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please review the risk factors in our SEC filings for additional details. We will begin the call with prepared remarks by Steven Nichtberger, our CEO; Iain McInnes, the Muirhead Chair of Medicine and Versus Arthritis Professor of Rheumatology at the University of Glasgow will provide an overview of the current landscape for autoimmune diseases and the unmet need. Then David Chang, our CMO, will review the results of the initial clinical data presented at EULAR in more detail. In addition to the previously mentioned speakers, Gwen Binder, our President of Science and Technology; and Anup Marda, our CFO, will join for the question-and-answer portion of the call. With that, I'll now turn the call over to Dr. Nichtberger.

Thank you, everyone, for joining us today. We're excited that we had the opportunity to share initial clinical data from our RESET-Myositis and RESET-SLE clinical trials evaluating CABA-201 earlier today at EULAR. By way of background, CABA-201 was specifically designed for patients with autoimmune diseases. It was intentionally engineered to be similar to the academic 4-1BB costimulatory domain containing CD19-CAR T evaluated by Dr. Georg Schett and his colleagues, which has generated transformative outcomes for patients with a variety of autoimmune diseases, igniting interest in the field. Not all CAR Ts are created equally. CABA-201 contains the identical signaling and 4-1BB co-stim domains as the academic construct, with a fully human CD19 targeting domain that binds to the same epitopes on the CD19 antigen as the murine FMC63 binder utilized in the academic studies with the same biologic activity. CABA-201's binder has demonstrated a favorable safety profile when evaluated in approximately 20 oncology patients as a dual-CAR with no ICANS observed and less than a 5% risk of Grade 3 CRS in cancer patients. The key questions we intend to address today include: one, is the initial safety profile of CABA-201 consistent with the academic construct, which inspired our design. Specifically, what is the incidence and severity of CRS and ICANS. And two, is the initial CAR T cell expansion and B cell elimination profile for CABA-201 as well as the serologic translational and clinical data consistent with the academic clinical data supporting the continued use of the selected dose of CABA-201, which is identical to the weight-based dose used in the academic studies. Next slide. CABA-201 is being studied across a broad range of autoimmune diseases within 5 disease-specific company-sponsored INDs in lupus, myositis, systemic sclerosis, myasthenia gravis and pemphigus vulgaris. Today, we're also pleased to announce the incorporation of the juvenile myositis cohort within the myositis IND for CABA-201, which we believe is the first company-sponsored clinical trial evaluating cell therapy in autoimmunity for a pediatric population. This builds on our previously announced success gaining a rare pediatric disease designation in juvenile dermatomyositis earlier this year. There are now 10 independent cohorts each with 6 patients able to be enrolled. Based on completed enrollment in any one cohort data permitting, we expect to engage in discussions with FDA regarding design of potentially registrational trials for one or more of the cohorts. In addition, inspired by a clinical publication from one of our scientific founders, CABA-201 is being evaluated without a preconditioning regimen in an exploratory study. The early safety and activity data from the RESET clinical program inspired us to initiate the RESET PV substudy of CABA-201 without preconditioning. Now at up to 10 active clinical sites that are considering integration of the protocol amendment to the ongoing day CAR T trial. Today's presentation focuses on initial clinical and translational data from the RESET-Myositis and the RESET-SLE trials, which we believe support a promising safety profile consistent with the academic experience as well as a promising activity profile consistent with the academic experience, supporting the use of the selected dose of CABA-201 at 1x10^6 cells per kilogram, which is the same dose used by Professor Schett's group with their similar 4-1BB containing CD19-CAR T construct. Next slide. The RESET clinical trial program currently has 18 clinical sites open for enrollment across 4 trials, lupus, myositis, systemic sclerosis and myasthenia gravis. Following a relatively modest start to the year, we are seeing enrollment ramp up with 5 patients now enrolled across the program, including 3 patients enrolled over the last 2 months. As we move into the second half of 2024, we believe the initial clinical data presented today on CABA-201, combined with an expanding network of engaged investigators with sites already opened across the country, provides the foundation for accelerated enrollment in our clinical trial program. With that, I'll turn the call over to Iain McInnes, the Muirhead Chair of Medicine and Versus Arthritis Professor of Rheumatology at the University of Glasgow to provide his perspective on the treatment landscape for autoimmune diseases.

What a pleasure it is to be joining you today. I don't know how many of you are in the virtual room up just coming across the road from the EULAR Annual Congress addressing nearly 4,000 people, in the rheumatoid arthritis preliminary session. So it's nice to sit back and relax with a convivial company. So what an exciting time it is for us in the field of immune-mediated diseases. Actually, the last time I remember this level of excitement was around the introduction of the biologic to the original TNF inhibitors a couple of decades ago. And we, of course, see so much change in that time. We've seen new medicines come along. We've seen consolidation in the field, but that does not mean that we solved the problem. Ladies and gentlemen, despite the extraordinary progress we've made we have significant unmet need. We do not achieve remission nearly often enough. And that remission once achieved has to be maintained by the ongoing therapeutics, and these are expensive therapeutics. There are also therapeutics that carry their own risk of toxicity of intolerance and frankly, the inconvenience of often young people because many people with the immune mediated diseases, we're talking about, are young. And they have a lifetime ahead of them. And of course, the other implication of that well known to you all is that young people with chronic disease impose huge health care burden costs on themselves and family, costs on society, costs from the health care providers. And so we, as a field, are rapidly seeking solutions that allow earlier interventions, if you like disease interception or in those with established disease profound interventions that allow us to reestablish a state of so-called immunologic homeostasis. That is a speak of balance in the disordered immune response. So we're thinking mainly about SLE and myositis, 2 of a number of autoimmune diseases. By the way, if you're interested, the autoimmune disease prevalence is rising, we just reported last year on 22 million people in the U.K. buyback data banks increasing prevalence of autoimmunity over 20 years. So this is a challenge that is set to grow, not diminish. These are particularly challenging disorders. Lupus, myositis, and the need here for drug-free long-term durable disease remission is absolutely imperative. Let's think, first of all, about myositis only 1 FDA-approved therapy in 1 subtype that's IVIg in dermatomyositis, think of that against the whole range of mechanisms of action we have available in rheumatoid in psoriatic arthritis and the axSpA spectrum. It's a SpA contrast. And IMNM the necrotizing considered one of the most refractory subtypes where patients are often resistant to standard of care, including off-label IVIg and/or other B cell target agents, rituximab being the most commonly applied in lupus. Systemic lupus erythematosus, the disease of multiple tissues, a disease that is devastating its impact on disadvantaged people, particularly in young people. more often women than men, 40% of people with lupus will go on and develop life-threatening target organ disease, lupus nephritis, for example but remember, it's a disease that is no respect for tissue boundaries, lungs, brain, skin, joints, reproductive possibility and then enriched life beyond them. 25% risk of death within 10 years in lupus nephritis, and sadly, incomplete response, despite the advances of immune targeted therapies in the last year or so. Take all of that together, the clinical challenge is very clear, we need durable, effective, safe therapeutics that reestablish immune tolerance at homeostasis that has alluded us thus far to eliminate the need for long-term therapy. Next slide please. So the recent academic experience from my friends and colleagues over Erlangen Georg Schett and his colleagues with CAR T therapies directed to CD19 in autoimmune disease has given a potentially transformative signal in the way in which we may treat these diseases. Academic data from the Erlangen group but has now tested over 20 patients in lupus, myositis and systemic sclerosis demonstrated the ability to deliver drug-free, complete responses that are durable and reliable in most patients with thus far a favorable safety profile. As a living therapy, CAR T cells have shown the ability to achieve deep B cell depletion in the periphery as well as in their relevant secondary lymphoid organs, where B cell drives. That's a key differentiating feature from our previous attacks to target the B cell apartment in immune disease. And achieving this systemic B cell depletion, not just in the periphery, is critical to enabling an immune system reset. So our chronic therapies such as monoclonal antibodies or even by specifics, may have the opportunity to provide benefits for patients with autoimmune disease with chronic dosing to date have not yet shown that any other modality beyond autologous CAR T treatment has the ability to deeply deplete B cells in all tissues lymph nodes, lymphoid organs, likely the tissue origins of autoimmune disease, leading to an immune system reset and a drug-free durable, reliable complete response. So excited about the initial clinical data for CABA-201 to provide a first look at the safety profile and clinical activity of the CAR T CD19 construct. So with those general remarks, it's a pleasure to turn over to David from the Cabaletta team, who will give a more detailed review of the initial data presented at EULAR. David?

Great. Thank you, Iain. Next slide, please. So our Phase I/II RESET-Myositis trial for CABA-201 in myositis is designed to evaluate a single dose of CABA-201 following preconditioning with fludarabine and cyclophosphamide at typical doses the same doses that were used in the academic studies. There are 3 independent parallel enrolling cohorts in the study, immune-mediated necrotizing myopathy, dermatomyositis and antisynthetase syndrome, each of which can dose up to and over 6 patients, in addition to the [indiscernible] cohort, which has been recently added to the study. The key inclusion, exclusion criteria are listed on the left part of the slide, the primary endpoint of the study is incidence and severity of adverse events up to 20 days post CABA-201 infusion. We are also evaluating several clinical and translational markers of disease activity as secondary endpoints in this study. Our RESET-SLE Phase I/II trial for CABA-201 in lupus is designed to be similar to our RESET-Myositis study. We aim to evaluate a single dose of CABA-201 and across the Phase I/II RESET clinical trial program without a dose escalation requirement following typical preconditioning. There are 2 independent cohorts in the lupus study the non-renal SLE and the lupus nephritis cohort, which includes biopsy confirmed Class III or Class IV lupus nephritis, each of which can dose 6 patients or more. Key inclusion and exclusive criteria are listed on the left part of the slide and the primary endpoint is similar to the myositis study, which is the incidence and severity of adverse events up to 28 days post CABA-201 infusion while also monitoring clinical and translational markers of disease activity as secondary endpoints. Next slide. Prior to dosing any patients, we provided this framework for important parameters that we believe should be examined and assessed when it comes to the evaluation of any cell therapy in autoimmune diseases. To that end, we've provided the important criteria across translational, clinical and patient experience metrics that are intended to provide clarity to the interpretation of our initial clinical data. Importantly, we plan to report on all of these parameters for the 2 patients reviewed today through the relevant follow-up period with additional insights into timing of B cell repopulation and B cell phenotyping for the first myositis patient in our study. Next slide. So in this slide, the first myositis patient on the left column, you can see that is dosed for the immune-mediated necrotizing myopathy cohort in the RESET-Myositis study. He's a 31 (sic) [ 33 ] year old male with a 2-year history of disease positive for the anti-SRP antibody and who had prior disease specific therapies that included IVIg, rituximab, methotrexate and steroids. The last dose of rituximab was approximately 8 months prior to CABA-201 infusion. On the right side, you see the first lupus patient dose is in the non-renal SLE cohort in the RESET-SLE study. He is a 26-year old male with a 6-year history of disease, positive for anti-double-stranded DNA antibody and who had prior disease-specific therapies that included cyclophosphamide, voclosporin, belimumab, tacrolimus, mycophenolate, hydroxychloroquine and steroids. Both patients were treated with a single infusion weight-based dosing regimen of CABA-201 at 1x10^6 cells per kilogram following a preconditioning regimen of cyclophosphamide and fludarabine, fludarabine that was identical to that used in the academic study by the Schett and medicine group. Next slide, please. CABA-201 was administered on the first day of a 4-day hospital stay as currently required by the study protocol and was generally well tolerated with no serious adverse no infections reported for either patients through the follow-up period. There was no cytokine release syndrome and no Immune effector cell-associated neurotoxicity syndrome or ICANS of any grade observed for either patients during their post-infusion 28-day dose-limiting toxicity observation windows. Tocilizumab was not administered to either patient. All chronic maintenance therapy or concomitant medications were discontinued for both patients prior to infusion of CABA-201 and through the follow-up period other than a planned prednisone taper for the lupus patient. Next slide. In both patients dosed with CABA-201, the kinetics of CAR T extension in B cell depletion was consistent with the initial patients reported in the academic studies. Peak expansion on the left-hand side, occurred at day 15 post infusion, which is also when complete B cell depletion was observed in both patients, which you can see on the right side. The rapid contraction of the CAR T cells following peak expansion is suggestive of elimination of the target B cells in the body. Next slide, please. B cell depletion was sustained in both patients dosed with CABA-201 through the first month of follow-up despite the recovery of leukocytes as anticipated on the right side after approximately 2 to 3 weeks. This transient leukopenia is an expected effect of the preconditioning regimen. Next slide. As shown in the graph on this slide, the serologic and clinical markers in the first myositis patient with predominantly muscle symptoms related to the immune-mediated necrotizing myopathy was dosed with CABA-201 demonstrated improvement while discontinuing all disease-specific therapies that is consistent with the clinical data reported by Dr. Schett and his colleagues using the academic construct. Autoantibodies, on the bottom left declined expected with SRP declining as well as the SS-A/Ro-52. The CK levels approach normal levels by 3 months and the MMT-8 was starting to improve consistent with academic data of another IMNM patient. On the far right-hand side, you can see that TIS or the total improvement score graph demonstrating the clinical effects of CABA-201 during the first 3 months and to [indiscernible] and put this into context, we've also included in the background data that has been previously reported on the clinical response from the myositis patients treated with the epidemic CD19-CAR T product in gray. While the 3 anti-synthetase syndrome myositis cell type patients who had significant lung disease, demonstrated variable responses at 3 months. And by 6 months, they were all major responders. More recently, as reported by Professor Schett earlier today, the first IMNM patients treated with the academic construct in the ongoing castle academic study demonstrated a minor improvement in the total improvement score at 3 months, which continue to improve to a major response by 6 months despite no additional therapies. We believe that taken together, these translational and clinical data demonstrate that the dose of CABA-201 we are using is replicating the data from the academics, the design of our RESET clinical trial program with individual cohorts for each subtype of each disease should allow us to develop early insights regarding any differences and clinical responses for each of the myositis subtypes. Next slide. The first lupus patient treated with CABA-201. We are very encouraged by the early trends that we are seeing here. And the early trends are showing improvement -- towards improvement across multiple components of the SLEDAI-2K from a baseline of 26 to 10 at week 4, including resolution of the patient's vasculitis, arthritis and hematuria for patients who had previously received disease-specific therapies, including voclosporin, belimumab, cyclophosphamide, tacrolimus and mycophenolate. We believe it is important that these results to date were achieved with no administration of B cell depleting therapies within 6 months of enrollment as well as discontinuation of all therapies at infusion of event ongoing taper for prednisone 10 milligrams per day. Next slide, please. We are excited to share translational data from the first myositis patient dosed with CABA-201, who illustrates both the tissue level effects of CABA-201 in addition to the repopulation of B cells at 2 months post infusion. On the left side of the slide, you can see that interferon gamma peak prior to the peripheral CABA-201 expansion peak suggests that the CAR T cells may be migrating to tissues where they demonstrate cytotoxicity against relevant CD19-positive target cells. The result in B cell depletion that occurs observed on the right side of the slide is then followed by a spike and B cell activation factor or BAFF, triggering the reemergence of B cells for that patient. Next slide, please. So based on the B cell phenotyping assays conducted so far to characterize the B cell repopulation in the first myositis patient, the data demonstrated a complete elimination of the B cells following a B cell population followed by repopulation with a market shift towards emergence of early naive transitional B cell population consistent with the potential reset of the patient's immune system. Confirmatory analyses, including single cell B cell receptor sequencing is ongoing. By week 12, the patient's B cell repertoire is beginning to gradually shift from the early naive traditional phenotype to a naive B cell phenotype. We are encouraged by this initial data indicating the potential for CABA-201 to deeply but transiently deplete the immune system in patients with autoimmune diseases. Now I will turn it over to Steven to conclude our presentation.

Thanks, David. CABA-201 has been specifically designed for patients with autoimmune diseases, and was engineered to be similar to the academic CD19-CAR T construct, which ignited interest in the field based on academic data from over 20 patients with autoimmune disease, including long-term follow-up for up to 3 years. We aim to answer 2 primary questions with our initial clinical data at EULAR. One is the initial safety profile of CABA-201 consistent with the academic construct, which inspired our design. Specifically, what is the incidence and severity of CRS and ICANS. And two, is the initial CAR T cell expansion and B cell elimination profile for CABA-201 as well as the serologic translational and clinical data consistent with the academic data, supporting the continued use of the selected dose of CABA-201, which is identical to the weight-based dose used in the academic studies. Based on the initial clinical data presented today, we are encouraged by the observation of no CRS, ICANS or infections of any grade reported through the follow-up period for each of our first 2 patients. On the dose selection front, we believe the pharmacokinetic, pharmacodynamic serologic translational and clinical data that we've presented are supportive of the dose we're developing. Starting with the engineering of CABA-201, we have been focused on replicating the academic clinical experience at least as well as any other company in the industry. Today, we took an important next step to working towards achieving the vision of the company since it was launched in 2018 to develop and launch the first targeted curative cellular therapies for patients with autoimmune diseases. The RESET clinical trial program currently has 18 clinical sites open for enrollment across 4 clinical trials, lupus, myositis, systemic sclerosis and myasthenia gravis. Following a relatively modest start to the year, we are seeing enrollment ramp up with 5 patients now enrolled across the program, including 3 patients enrolled over the last 8 weeks. As we move into the second half of 2024, we believe the initial clinical data presented today on CABA-201, combined with our expanding network of engaged investigators, with an industry-leading number of sites open across the country provides the foundation for accelerated enrollment in our clinical trial program. Next slide. In the second half of 2024, we plan to present additional follow-up data from these and other patients dosed in the RESET-Myositis and RESET lupus trials. We also plan to report the initial clinical data from the RESET SSc and RESET myasthenia gravis trials, each of which are now actively recruiting patients. We really appreciate that you chose to invest the time with us today and want to close by expressing our gratitude to the patients enrolled in our clinical studies. Now I'll turn the call over to the operator to begin the Q&A portion of the call. Operator?

[Operator Instructions] Our first question comes from Josh Schimmer with Cantor Fitzgerald.

I guess I just got one last for the Cabaletta team. When do you expect the other 3 patients who are enrolled to be treated? And what would -- if you have 18 sites currently enrolling, how do you expect that to evolve over the course of the year.

So historically, you can see from clinicaltrials.gov when each of the first 2 patients were enrolled in the clinical study and dosing and the follow-up are subsequently reported today. So you can calculate. It typically takes us as well as other companies who have similar requirements to post their information on clinicaltrials.gov for their first patients, about 2 to 3 months to go from enrolling to dosing, and that's a fairly standard time line. A lot goes into that, ranging from the need to make an appointment for apheresis, thus our interest in apheresis free solutions, to the delay associated with scheduling around vacations or of the patient or the physician or holidays for the hospital. And so there's a lot that goes into those time lines, but that's the nature of the approach right now. As to the way we expect it to roll out, I think the answer is we don't know. And because nobody has ever done this. It is incredibly difficult, challenging to get the rheumatology, the neurology, the nephrology any medical specialists who manage these patients with neurologic or rheumatologic disease or dermatologic disease to, first of all, meet second of all, trust and third of all, desire to work with the hematologist, the infusion specialists, the oncologist who is going to do the infusion of the therapy and managing the handoff of the patient from the medical specialists to the infusion specialist and back again is a very complicated logistically challenging task. And that may explain why despite major pharmaceutical companies competing with us for these sites. We lead the industry with 18 sites open in the United States. The talent of the team, home for the 4 years before we ever in-licensed CABA-201 on our legacy portfolio were exactly the same tasks were required to open clinical sites gave us a window into how to do this really well. And that explains why we have the number of sites open we do. We expect those site numbers to continue to relentlessly increase not only for lupus and myositis trials, but for the newly opened scleroderma and myasthenia gravis trials. So we're going to see more and more sites opening we're going to apply the learnings and share the learnings from our clinical data with all of our investigators as soon as we can, through personal visits and engagement very deeply allow them to share these data with their communities of referring rheumatologists and others. And all of this is going to result in what we would argue is a setup for Cabaletta to be among the leaders in enrollment for autoimmune CAR-T products in the industry. I don't know what that number is, and I don't have expectations that I want to set. And frankly, I think if we did that, we would be gauging how well we guess as opposed to how well we did.

Our next question comes from Yatin Suneja with Guggenheim.

Congrats to the team on the presentation and the data. Two questions for me. Could you talk about the response kinetic difference between the antisynthetase patient and the IMNM patient? I also noticed that the IMNM patients can achieve a max score of 70 on a 100-point scale, but the antisynthetase patients can go up to 100. Could you maybe also help us understand the nuance there?

Maybe our Chief Medical Officer, David Chang, can answer this.

So let me answer the second one first and if you could just clarify the first question after that. But the second question related to the maximum. So on our slide, we showed the maximum total improvement score for our IMNM patient was approximately 70. And the reason behind that is it all depends on where patients start. So if they start at a mild disease level, there's less room for improvement. So it's an improvement score. It's not a final state score such as achieving remission or low disease state. And it isn't a difference between a antisynthetase versus anti-SRP, immune-mediated necrotizing myopathy. It's more dependent on where patients start at their baseline and how much room there is to improve. So when we did the calculation for that particular patient, knowing what the design was, we said, if everything got better. Everything got better, then that maximum score could only be 70 because the patient already started as a less severe state. But you can see that even with the Schett data with his IMNM patient, that patient doesn't get up to 95, 99, 100 that the other 3 patients -- the other 2 patients with antisynthetase syndrome patients are achieving. And maybe I'll just give you one example just to help you think about this is a -- let's use one of the components of the test is physician global, and your maximum point is 20 one needs to get a 4-point improvement to get that maximum score. So somebody starting with a physician global 3, they're never going to get the maximum score of 20. So you can go down the line with all the 5 to 6 components to calculate that out, what's the maximum score you can get. So I think here, it isn't a difference in disease synthetase, more of the baseline disease activity. And it's in some way just take longer. So it's very possible in IMNM patients there's a longer time to see that muscle improvement because they have such a predominant muscle disease, whereas an antisynthetase part of it is driven also by the lung disease. Iain, do you want to add something?

Yes, just to add to that. It's a more generic phenomenon, but there is a common misunderstanding that the symptoms and signs that a patient presents with are directly correlated to immunologic activity. By corollary, you switch the immune system off the symptoms improve immediately, but that, of course, is not what happens. There are target tissues that are damaged. And if you would like to reflect on history, we've been very familiar with tissue damage in the immune disease field for years. Think bone erosion and rheumatoid I think unrecoverable renal function in lupus over the years. And if you think about muscle for a moment, we all know that it takes time to rebuild muscle strength and muscle conditioning. Anyone who's been off their feet for a while or suffered a fractured be well aware of that. So in fact, the logical prediction of the biology here and remember, this is a really high-quality biology-driven intervention. So we should use the biology to help us understand the impact. The prediction is that there will be delay between immunologic restitution and actual functional recovery of a tissue organ. It's really important that we bear that in mind as we reflect now and reflect in future on what the CAR T revolution is going to deliver.

Our next question comes from Kelly Shi with Jefferies.

This is Yun on for Kelly. Congratulations on the positive data. One question on the B cell phenotyping I noticed that the markets that you used slightly different from what Dr. Schett looked at. So I assume you're going to look at the same and including class switching, for example, please?

Gwen, maybe you can take this question as our President of Science and Technology, Gwendolyn Binder.

That's a great observation. Yes. In our slides, we're looking at the transitional B cells, naive B cells whereas Professor Schett looked at IgD as a marker of naive B cells and then look for that class switch. So he's looking at B cells expressing IgD containing BCRs or IgG containing BCRs, there's a simple way of saying it, which represents whether there is antigen experience in the B cells. This patient that we're presenting today is unique. As David mentioned, the patients had experienced rituximab about 8 months prior to enrollment on the study. And so the frequency of those memory IgG expressing B cells was so low, the sensitivity of the assay could not capture those cells, but our assays could capture a little bit of those memory B cells by using the markers we use, CD38, CD24. So if you look at the graph on Slide 21, you can see that there's a small proportion, about 4% as a red line shown in baseline, which represents those memory B cells. And then in the light blue are the transitional B cells, which as illustrated in the picture on the left-hand side, you can see that these are cells that are recent immigrating from the bone marrow and now antigen experienced. And in dark the naive B cells, which are a little bit more mature, but still [indiscernible] experience. And so what we see as the B cells come back at week 8, is we see a complete loss of those memory B cells. You see no red line, and you see that the predominant population of B cells are those transitional B cells coming out of the bone marrow as the patient is regenerating the B cell compartment. And that is also the corresponds of data took us through with the increased levels of BAFF to support that B cell reconstitution. And then you can see at week 12, you start to get further progression into that naive B cell compartment as you would expect. And so we would anticipate over time, we would start to get some memory B cells come back as we continue to survey this patient. But this data is wholly consistent with a deep depletion of B cells and then a regeneration of new naive transitional B cells. But as we move forward, we will continue to look at both these markers and also the markers, and we will continue to use markers that Schett utilized in his studies as well.

Our next question comes from Samantha Semenkow with Citi.

Just looking at the expansion data, if we compare the magnitude of CABA-201 expansion with the data that Schett has reported, it seems CABA-201 has a lower magnitude of expansion and a later peak expansion date but the efficacy data [indiscernible], it does seem to be tracking in line with Schett data. So I -- obviously, we're working more small numbers here in both data sets, but I'm curious if you have any hypothesis for why this might be the case given both of the CABA-201, they do look similar in their magnitude? And how are you thinking about the amount of expansion you need for CABA-201 in the context of efficacy and [indiscernible] data that you've seen thus far?

Maybe we can answer this in 2 parts, starting with Gwen and then passing off to David for the clinical.

That's a great observation. So maybe just looking at Slide 16. So first, the magnitude of expansion for the IMNM patient falls squarely within the median of peak expansion observed in the case series published by the Schett group. The SLE patient is a little bit lower peak expansion. And I believe that, that is due to an overall lower level of leukocyte counts in this patient. If you look at Slide 17, this patient had a pretty consistent and low level of leukocytes at baseline. And so we think that this lower peak expansion may be reflective of that. But just flipping back to Slide 16, you'll see that even though it's a lower level of peak expansion overall, the percentages of CAR T cells is similar between the 2 patients. And this also falls within the range of previously reported. Interestingly, and as you noted, despite the peak being around day 15, which, as you noted, is a little bit later than the peak published in the case series with Schett, which is day 9. We do see this immediate drop in B cells in the periphery, so on the right panel there. And as David took us through on Slide 20, we are seeing this peak of interferon gamma early on, which indicates that interferon gamma is produced when T cells are engaging with their target antigen. And so that indicates that the T cells, the CAR T cells are actually active. They're engaging with the target B cells earlier than we actually see that peak expansion. And so this is why we believe that this reflects that the cells are actually going into the tissues and mediating that B cell cytotoxicity ahead of when we actually see that peak of the CAR T cells in the peripheral circulation. So the majority of the B cells that are being targeted in the body are actually in tissue. So I will pause -- the one last thing I will add here is that the one difference between our product and the Schett product is the Schett process was able to use fresh cells because they manufacture on site, they treat on-site, our cells are frozen. And so with fresh cells, they will be more able to immediately expand rapidly upon infusion to greater levels than with frozen cells and that may contribute to a different dynamic on the actual timing of the peak, but it's very well established in the literature. And of course, all of the approved CAR-T products are frozen, and our peak expansion is similar to peak expansion time frames that you will see in, for example, multiple myeloma with the anti-BCMA CAR T in the myeloma setting is much more similar to the frequency of target you would expect to see in healthy patients versus the peak expansion that you would see in leukemia and lymphoma, where the tumor burden is much higher and would drive a much faster expansion and peak. So our data is consistent with what we expect. And then again, the correlatives in terms of the cytokines and the cadence of B cell depletion is consistent with a therapeutic that is behaving in a similar fashion to the Schett construct. And I'll turn it over to you, David, to talk about the clinical aspects.

And one thing I want to add to what Gwen had just indicated is that regarding the peak expansion timing that we're reporting at day 15, we actually didn't have a time point in between day 7 and day 8 and day 15. So it could have been earlier. But the discussion that we've had with Carl June, who's one of the developers of CAR-T therapeutic oncology 15 years ago. We spoke with them and he said, yes, this makes sense in terms of kinetics of a frozen product. So one thing we've done everything we've done, we've done almost identical to what we've done by the German Group in terms of the dose, the preconditioning regimen, the one thing we didn't do was using fresh cells, but there was a reason behind that. And the reason was because it makes the convenience, the flexibility much more palatable for patients in sight. So that if you have a frozen product, in essence, you're allowed to let the patient and decide choose their time to do the dosing. So this is the most likely explanation that has been confirmed by Carl June, that the onset of peak expansion occurring a few days later is not unexpected. I think there's a question that I just want to go back to regarding the expansion. If you look at the numbers, you see numbers of 3.7% and a little bit higher, but we went back and looked at the Schett's data. And in its first 2 myositis patients, the first patient, the peak expansion is 3.5%. The second patient who relapsed was 50-some percent. So that doesn't really explain the peak expansion is not necessarily the driver for patients actually achieving full immune reset. What it tells you is that there was cells that multiplied because it engages with the target B cell and that's what you want. You want the target engagement, you want the expansion, reflecting that target engagement, then you want the immune reset you want naive cells come back. And the data that we see today confirm that, that's what we're seeing. So it isn't necessarily the peak expansion. I think we have to look at all the parameters, in particular, the complete depletion and the repopulation of naive B cells.

Our next question comes from Douglas Tsao with H.C. Wainwright.

Maybe what I'm curious is when interpreting this data or thinking about this data, how do you -- obviously, you've started to see very nice sort of similar results to the academic experience. I guess at what point do you feel confident to sort of use that data since they're sort of further ahead of you, both the number of patients as well as just the time course of treatment in terms of response rates and durability to inform your own development plans. And I'm curious, you've had some success using the data from academics in terms of sort of help getting the FDA to approve your initial dosing. Do you expect or how do you expect the agency to consider the data from the academic experience in terms of design and potential registration studies?

Listen, in 2022, actually '21, when we first saw Professor Schett's publication of the first patient. We thought it was too good to be true, but we decided that we need to get into the CD19 directed space at risk in a sense knowing that if this worked, the original premise of our company was going to be aged. And so we invested ourselves in thinking about what the perfect product would look like. And we came up with the notion that there are very few things that have ever been developed with this level of clinical data in the first study. Think about how many other targeted therapies you've ever seen where 15 out of 15 patients have not just a response but a complete response where that response is completely transformative versus everything else out there. And where the #1 safety issue was fever that can be managed usually with an antipyretic Tylenol or the equivalent. And in some patients, if they have a second day of fever, they would prophylactically use a dose of Tocilizumab that's the side effect profile for this complete response cohort. And so we ask ourselves, how could we improve on this? And the answer was not to manufacture it differently or to a fast manufacturing time line to get the product back to the patient more quickly. That added more risk than benefit. The answer was not to change elements of the targeting domain. If we could, we wanted to target the same epitopes. And so we did with a fully human equivalent of the FMC63 binder. It was not to try to change the co-stimulatory because this was delivering data that was just really terrific. It was generational. And so we started there, Doug, with the idea that we need to imitate everything that this bold academic physician and his team achieved through replicating their product as closely as we could. We then approached the FDA with data in hand showing that not only our structure and our epitope binding domains, but also our function was comparable sufficiently that we did not need to do a dose finding study. And in fact, if you dose find and try to go to a lower dose, you don't know if you'll get durability, so you're going to wait 2 or 3 years to see if you have comparable outcomes, if you're trying to improve safety, what are you trying to improve, fever? You're going to get rid of the fever is part of the mechanism of action. So I'm not sure either of those was viable. And we made that argument to FDA, and we came away with no dose finding required, which is a distinguishing feature of our company's program versus every other that we know of when starting an autoimmune-focused program, with a novel chemical or construct. And so now your question is directed to, okay, so you've leveraged the Schett data, very clever perhaps, and you've had great advantage from doing that. But the proof is in the [ quoting ] as to whether we exceeded. Today, we took the first step on a long road to demonstrating through data, not to our beliefs, but through data that, in fact, we are replicating the Schett data. we'll continue to hold ourselves to that standard. Not that we are going to have data that is as fabulous as his initial cohort because I don't think anybody will. We will have side effects. We will have failure to treat effectively in some patients. And that's fine as long as what we have is at least as good, if not better, than any other company in the industry. And there's room for all of us, but I'd like us to be the best and I'd like us to be the first. And to do that, we rely not on what we need to do data wise going forward, which, of course, is necessary, but the design of our clinical program. Unlike other companies, we chose not to do a basket study, and I want to -- maybe investors appreciate maybe not, so I'll just review quickly. To set up a basket study means you get a group of the rheumatology, neurologists, et cetera, to partner with the oncologists around a single protocol, and then you go to the hospital and the administration of each of those departments. And you say, I have one protocol. It's going to be really easy. We get a lot of patients that all you need to do is use our drug, and it's really easy to enroll in one clinical trial. It's easy to open up a site because after all, we just have one clinical -- one legal set of documents, one budget. It all hangs together and it is fast and easy. If you are objective as a company is to generate the fastest and first clinical data in the industry, that's what you would do. But if your objective is, on the other hand, to launch the first product that is targeted and curative for autoimmune diseases, you would do what we did. What we did was informed by discussions with FDA, both at the operating team level and formal discussions, but also informed by more informal discussions at more senior levels with the agency. And what we came away with was the following. By having a separate IND for each indication and within each indication, having separate cohorts for each subtype. We will have the most scientifically rigorous homogeneous set of data barring none. Using that as a foundation, we can then go back to the agency, we believe, based on early discussions we can go back to the agency in order to discuss our early data in the first 6 patients of any 1 of our 10 cohorts and ask whether, number one, a comparator is necessary. And number two, whether or not it is necessary, whether we can take what is a homogeneous clinical study set of data, set of patients and simply expand the cohort that is already enrolling. If there's a comparator required, add in a comparator arm to that existing clinical study. That will save us the time it takes to open a new study. The reason nobody else did this is because it takes a very long time and an awful lot of effort to go through the same budgeting and contracting and IRB and cell therapy reviews for 4 or 5 or 6 INDs. It takes 4, 5 or 6x the effort for the hospital systems as well as for the company. And so it's very hard work to set the foundation that we've set. But going forward, we believe that if all else is equal on enrollment. We have the foundation built from which we can move directly into Phase III studies without starting new clinical trials but rather by modifying the existing clinical study. In many of these indications and subtypes, there are no active therapies approved by FDA. And in that context, we think adding more patients is the way to go. Where there is usual care that is seem to be effective or where approved therapy exists, we would add on and propose adding on additional cohorts in our existing trials, all of this is going to be driven by our data, not by the academic data. We're no longer in a regulatory sense at all relying on the academic period. That was a stepping stone for our company. We now today move into our clinical data, and we're really looking forward to the next 6 months, 12 months and a couple of years. to talk about what the Phase III programs look like to deliver that data and to launch the first targeted curative cellular therapy in the industry. Does that answer your question?

Yes, it does. And just really quickly, Steven, I mean, as you say you're going to go back to the agency after you have dosed that 6 patients in any given cohort. I'm just curious how long after that patient does adjust, I mean, is it just completion of dosing? Or are you going to wait for 3-month data, 6-month data? I'm just curious or is that still a little to be determined?

Yes, and it's a great question. So we are not going to publicly say what our trigger is internally. We've obviously discussed at length. It will be driven by the quality and quantity of our data, not only the data with the single cohort, but the broader cohort because I failed to say the activity, if you are providing a complete response in the vast majority of patients, proving that you are better than any comparator or better than no comparator, proving that you are effective, it's fairly easy. It's dozens of patients. And statistics would be on our side with those sorts of numbers with any of these cohorts. But if you want to talk about safety in 100,000 potential patients or 1 million potential patients, you want to have far more than that. And the way we're addressing the safety question, part of which will inform when we go back to FDA to discuss our regulatory pathway to approval is informed by how much safety data we have and the nature of that data. So because we have a single dose in every patient with a single preconditioning regimen in every patient, confirmed by these first 2 patients, and I'll be the one to say it's only 2 patients. that sometimes you have an engineering problem and you recognize and cell therapy that's often the case. And we feel pretty good about this on the backdrop of the 15 patients from the academic experience with a similar product. But at the end of the day, we need to see our own efficacy, our own safety and our own data overall to be able to inform the question, how soon we go back to FDA, and it's driven by the combination of how much follow-up do we think we need in that 6 patient? And how many patients do we have overall in the program, applying safety data from all of these cohorts to each of the indications. And we believe that given the similarities in autoimmune disease across all of these diseases, the abnormality of the immune system being addressed in an identical way with an identical dose that the combination of disease-specific safety data plus compounded by enhanced by the data from all of our patients allow us to move forward with these regulatory discussions with FDA, pending again, the quality and the quantity of the clinical data on all aspects, efficacy and safety.

And our last question comes from Ben Burnett with Stifel.

Congrats on the data. I just want to ask just about kind of the enrollment trends you're seeing or expecting in the clinical program. Just based on the epidemiology and the clinical trial footprint that you have, is there a certain type of myositis that we should expect to sort of dominate enrollment in that study?

So those who don't learn from history are doomed to repeat it. We were arguably overly optimistic in 2023 about what we felt we could achieve in early '24. So rather than guess and be judged on how well we guess, we will keep all 18 sites as the basis for going forward. We'll expand on all 18 with each of our 4 trials, adding dozens together, dozens and dozens and dozens of additional sites across our program. And as we expand the number of sites as we generate more clinical data and as we begin to see how patients show up will be better informed to start to address some of these important questions that you're asking. But at this point, it's too early for us or, frankly, any other company to know who's going to show up and how quickly in a discussion with Professor Schett yesterday, he has been very impressed by 2 things that really stuck with me. One is the number of patients with scleroderma who showed up, we reported on 6 treated patients with scleroderma at this meeting. He was hardly trying and the patients were reaching out through any way they could to get into the trial. I think that's generally similar to what we perceive that like myositis, the unmet need in lupus -- in scleroderma is extremely high. These patients have terrible prognosis. In the case of lupus, if you're a 35-year -- in the case of -- I'm sorry, scleroderma, if you are diagnosed with scleroderma and you're 35 years old and your kids are in tow in the doctor's office and you're just diagnosed with scleroderma, you have a 50% chance that you're dead in 10 years despite best therapy today. Think about that for a moment. Do you want to try CAR-T therapy if the safety profile looks like the academic experience and the efficacy is even remotely close. And the same in myositis, terrible situation for the patients to have almost no options. And in both of those, I have to say there is almost no competition for sites or for patients right now. There aren't many pharmaceutical products and many cell therapies already IND cleared and ready to ramp up trials. So we are thinking pretty expansively honestly, about our ability to continue to engage clinical study sites for those indications as well as myasthenia gravis and lupus, where over 35 cellular therapies are actively being developed in the United States. And I have to say, of those 35 sites -- 35 cellular therapies in our last review, possibly about a week ago, all but 2 or 3 are talking about data from a single site or maybe from 2 sites, but no more than that. And that's not a path to drug development and approval. That's a path to exploratory data. So our job is to launch the first product in the field. Having the site is the first step in rolling whoever shows up, and that is the objective, to enroll whoever shows up who meets our criteria and provide them the opportunity of the promise of a drug-free long-term durable complete response. That's the objective in the program. So thank you for your questions, and I believe I'll turn it over to the operator.

That will conclude the Q&A portion of today's call. You may now disconnect. Everyone, have a great day.