Cabaletta Bio, Inc.

Good morning. At this time, I would like to welcome everyone to Caballero Bio's conference call and webcast. Currently, all participants are in a listen-only mode. After the speaker's remarks, there will be a question and answer session. Please note that this call is being recorded and is the property of Caballero Bio. Unauthorized recording, reproduction, or transmission of this call without the express written consent of Caballero Bio is strictly prohibited. I would now like to turn the call over to Will Gramick,

of precision aq please go ahead thank you michelle good morning everyone and thank you for joining cabaletta bios conference call and webcast to discuss clinical and translational data from the first eight patients in the phase one two reset program in myositis lupus and systemic sclerosis that were presented at acr convergence 2024 in oral and poster presentations over the weekend Before we begin, I encourage everyone to go to the Investors section of our website at cabalettabaya.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 your 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 Stephen Knicksberger, our CEO, Carl June, the director of the Center for Cellular Immunotherapies at Penn Medicine, pioneer of the first CAR-T cell therapy approved in oncology, and member of CAB11's Scientific Advisory Board, will provide an overview of the lessons from CAR-T cell therapy in oncology. as it relates to the expansion into autoimmunity. Then David Chang, our CMO, will review the results of the updated clinical data presented at ACR in more detail. In addition to the previously mentioned speakers, Gwen Bender, our President of Science and Technology, and Denise Marta, our CFO, will join for the question and answer portion of the call. With that, I'll now turn the call over to Dr. Nick Wilkerson.

Thanks, Will, and thank you everyone for joining us today. We're excited that we had the opportunity to share updated clinical and translational data from our Reset Clinical Program, evaluating Kappa-201 in myositis, lupus, and systemic sclerosis this weekend at ACR. We're evaluating whether a single dose of Kappa-201 can safely deliver through telling clinical responses after discontinuation of all immunosuppressants. By way of background, Kappa-201 was specifically designed for patients with autoimmune diseases. It was engineered to be similar to the academic 4-1-BB co-stim domain containing BB-19 CAR-T that's been evaluated in multiple academic studies. Kappa-201 contains the identical signaling and 4-1-BB 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 urine FMC53 binder utilized in the academic studies with the same biologic activity as published earlier this year. Next slide, please. Kappa-201 is being studied across a broad range of autoimmune diseases within four specific company-sponsored INDs in lupus, myositis, systemic sclerosis, and myasthenia gravis, each with distinct disease-specific cohorts. In addition, Kappa-201 is being evaluated a fifth indication without any preconditioning regimen in the RESET-PV trial with seven clinical sites already actively enrolling. Today's presentation focuses on clinical and translational data from the RESET myositis and the RESET SLE trials, as well as initial clinical data from the RESET SSE trial, which we believe support a favorable risk-benefit profile and the use of the selected dose of Kava-201 at one times 10 to the sixth cells per kilogram. The data we will present supports the potential of Kava-201 to deliver compelling immunosuppressant-free clinical responses for patients with active refractory disease while tapering steroid doses to complete elimination. Next slide, please. The recent clinical trial program currently has 40 clinical sites open for enrollment, with 16 patients enrolled and 10 patients already dosed across the program as of November 12th. We recently announced that clinical development expanding into Europe with EMA CTA authorization for Capital One receives for a reset SLE and the appointment of Gavin Winter as our new head of international. With an expanding clinical site footprint and efficient clinical development strategy, data permitting, we anticipate meeting with the FDA as early in 2025 as data will allow regarding potential registrational design for CAHPS 201. Next slide, please. With that, I'll turn the call over to Carl June, pioneer of the first CAR T-cell therapy approved in oncology and director of the Center of Cellular Immunotherapies and Medicine, to provide his perspective on the lessons from CAR T-cell therapy in oncology as it relates to the expansion into autoimmunity. Carl.

Thanks, Steven. So, slide eight. You know, there now is a very large clinical experience with CAR T-cell therapy in cancer patients. Our first patient treated in 2010 in an academic setting, and then 2017, first FDA approvals, and now actually estimates of over 50,000 patients have been treated with multiple indications globally. And so this is established now a foundation for the application of the same CAR T cell for autoimmune disease. Next slide. So, you know, here there is a consideration of what are the expectations of potential adverse events after treatment with autoimmune disease. instead of cancer. And in cancer, we now know with very good precision the side effects and they are on target side effects. And they're related to the volume of tumor that patients have, which is often several pounds of tumor, which is related to the basketball here in volume. In contrast, Autoimmune patients and healthy patients without cancer have about a equivalent of 60 grams of tumor, rather than kilograms, and that's related to the size of the basketball. So those effects, the side effects then, are anticipated to be much less in autoimmunity due to a lot lower target burden in patients. And I think it's being borne out in the initial data, as you'll see. So here are, you know, lists of the side effects that we know from the FDA labels for CAR T cells in cancer. The one set is the effects that are off target and related to the chemotherapy, if that is given. So for lymphodepletion, that can lead to cytopenias. neutropenias and an increased risk then of infection. The other side effects are on target and are related to the CAR T cells killing B cells. And that can lead then to hypogammaglobulinemia. It can lead to cytokine release syndrome or CRS. And finally, it can lead to ICANS, which are CNS side effects. So the management of these are all well worked out now. For CRS, you know, tocilizumab, which blocks IL-6 receptor signaling, is given first. And for ICAMS, steroids and anti-seizure medications are given. And adults usually do not require replacement of gamma globulins. anticipated hypogammaglobulinemia is to be stored in duration, and it's not clinically an issue with cancer patients. And with that, I'll turn it back over to David Chang from the Cabaletta team, who will give a more detailed review of the clinical data with CABA 201 that was presented this weekend at AACR. David?

Great. Thank you, Carol. Let's go to the next slide. So autoimmune disease patients face substantial unmet medical needs despite the use of therapies with chronic broad immunosuppression. This includes current therapeutic options that result in incomplete B-cell depletion in tissues and lymphoid organs. Patients tell us they want to live their lives drug-free and symptom-free. Physicians also tell us they want to prevent end organ damage in their patients. Next slide. The objective of the Phase I-II RESET studies is to evaluate the safety and tolerability of CABA-201 patients with active refractory disease. The key inclusion and exclusion criteria for each of the three studies are listed below. Of note, lupus patients with Class V membranous LN are not typically included in lupus metritis studies, and the proteinuria tends to be slow to respond. However, we have elected to include these patients in the SOE non-renal cohort to evaluate if other manifestations of lupus can respond to KeVA-201. Next slide. All of these clinical trials share common elements of the same preconditioning, with the exception of Reset TB Trial Evaluated Cabinet 2.1 without preconditioning, same single weight-based dosing, same minimum four-day inpatients per day, same primary endpoint of incidence and severity of adverse events over 29 days, and similar endpoints such as achieving drug-free responses. Next slide. So all patients, in the RESET studies had active refractory disease, and most had failed B-cell targeting therapies. The baseline characteristics of the three myositis patients are shown here. Next slide. The three non-renal lupus patients are shown here, and they include the patient SLE1 in the non-renal cohort who had isolated class V lupus mephritis. Next. The one lupus nephritis patient treated LN1 is shown here. And next, the first scleroderma patient with severe skin involvement is shown here. Next. So the highlighted areas identified all the active therapies the patients were taking at screening. All of these therapies except for steroids were discontinued prior to the single CABA 201 infusion. This is the aspiration for CABA 201 for autoimmune patients to achieve long-lasting and compelling clinical responses that eliminates the need for drugs for a lifetime. Next slide. The safety profile to date in the treated patients is encouraging. This table shows events of cytokine release syndrome, CRS, ICANN's neurotoxicity, and other important adverse events through the latest follow-up. The myositis patients had no CRS, no ICANN, no serious infections, no hypogammaglobulinemia, or related serious adverse events. Next, one non-renal Lucas patient had a grade 1 CRS of fever. The square derma patient had a grade 2 CRS, based on fever and the transient use of IV fluids. The lupus nephritis patient was the outlier, who developed a late onset pancytopenia that was consistent with prolonged cytopenia, which is a labeled warning and precaution with approved oncology CAR-T products. The patient also had a transient and reversible grade four ICANNs, which was previously reported and I will discuss later. None of the other seven patients had ICANNs. Three of the eight patients developed low-grade CRS and none received tocilizumab. Unrelated serious adverse events are shown in the bottom row and include the myositis patients with factor V Leiden heterozygosity, a risk factor for thrombosis, recent IVIG treatment, history of MI on anti-platelet agents, recent hospitalization for back pain and fatigue with decreased mobility. KAB2-1 levels were undetectable since day 22. At day 38, a PE leading to cardiac arrest occurred, followed by successful pulmonary artery thrombectomy. the Independent Data Monitoring Committee evaluated the event not to be related and recommended study continuation without change. Next slide. So, CABA-2-1 provided consistent and complete B-cell depletion by day 22 in all patients, shown in the upper left panel. In patients with more than three months follow-up, B-cell repopulation with naive cells started as early as eight weeks in patient IMNN1 and SLE1 shown in the upper right panel. CAVA201 exhibited PKPD profile with peak expansion between day eight and day 15 as accepted, shown in the lower left panel. LN1 was the outlier. with a second later peak expansion and B-cell depletion continuing out to four months, showing the right tooth panels. Next slide. The first known adult dermatomyositis patient dose with a CAR-T therapy demonstrated compelling early clinical responses off immunosuppressants, as shown by skin improvement on the CDAP-DA, muscle improvement on the MMT-8, overall improvement on the total improvement score, TIS, at day 29. Next slide. The first IMNN patient with 24 weeks to follow up demonstrated continued clinical responses off immunosuppressants without flares. Initial clinical response in the IMNN patients are consistent with published data. And response kinetics may differ among myositis supplements. Next slide. All three lupus patients in the non-renal cohort demonstrated early clinical responses off immunosuppressants. Patient SLE1 completed steroid tapering. No clinical symptoms on the flea dye 2K who are present in any of the three patients through the latest follow-up. This includes SLE1 with isolated class V LN with persistent proteinuria as expected. Next slide. Patient LN1 proteinuria markedly improved by week eight with alopecia and rash as the remaining clinical manifestations at week 16. after discontinuing all immunosuppressants and continuing prednisone takers. Next slide. Unlike the other seven dose patients, LN1 appears to be an outlier. In addition to having active severe refractory disease, despite five systemic therapies, The patient had an episode of fever and relapsing pericarditis 18 days before treatment and fever and worsening anemia four days before treatment, both requiring hospitalization. Next slide. Post-infusion, the patient developed transient grade 1 CRS, followed the next day by transient and reversible grade 4 ICANN. Two days later, the ICANN fully resolved after standard therapy without sequelae. Prior to infusion, the patient not only had acute febrile inflammatory events before CABA 201 treatment, additional investigations revealed that the patient also had highly elevated pro-inflammatory cytokines that continued after treatment, suggesting a possible occult infection with supportive data coming from PCR clonal sequencing. The QR code below links to our poster presented on Saturday, which contains details of translational assessments on this patient. At four months post-treatment, the LN patient achieved compelling clinical responses since discontinuation of all immunosuppressants while continuing steroid taper. This patient had the most side effects all the treated patients so we would like to share what the patient communicated to the investigator she said overall I feel much better than I felt before have a 201 therapy I have much more energy I have significantly less joint pain and inflammation. My proteinuria has improved. I no longer have any mouth sores, and I am getting back to my normal self. At 25 years old, my kidneys were not functioning properly and continued to get worse despite all of the strong medications I was on. I had multiple occurrences of fluid around my heart, Kava 2-1, has put a stop to that and has allowed my body to heal. Although I faced complications afterwards, I believe the improvement that I've seen in both my numbers and how I feel was far worth it. If I had the choice, I would choose to receive Cava 201 again. In addition, we have dosed our first scleroderma patient with severe skin involvement. At day 42, the patient is demonstrating skin improvement in the face and hands, even after discontinuation of disease-specific medication. Now, I will turn it over to Steven to conclude our presentation.

Thanks, David. So in summary, Cavitrol 1 appears to have a favorable risk-benefit profile. In patients with recent fever or infections, delaying CAR-T infusions should be considered. Kappa-201 provided compelling efficacy in highly active and refractory autoimmune patients through the follow-up period. Initial data supports the potential for growth and with SLE patients with longer follow-up, completing steroid taper to off, or continuing ongoing steroid taper down to prednisone equaling eight milligrams per day. Finally, the PKPD data support the current dose of Kappa-201. So today we took an important step to working towards achieving the vision of the company since it was launched in 2018, which is to develop and launch the first targeted study with therapies for patients with autoimmune diseases. Patients want a drug-free, symptom-free life. CAPIT-201 has the potential to address their aspirations. Looking ahead, we anticipate meeting with the FDA on potential registrational trial design for CAPIT-201 as early in 2025 as data permit. We appreciate that you chose to invest time with us today and want to express our gratitude to the patients enrolled in our clinical trial program, along with the sites and investigators that we've partnered with in our trials. Now I'll turn the call over to the operator to begin the Q&A portion of the call. Operator?

Thank you. If you'd like to ask a question, please press star 1-1. If your question has been answered and you'd like to remove yourself from the queue, please press star 1-1 again. In the interest of time, please limit yourself to one question. If you have an additional question, feel free to return to the queue. Please stand by while I compile the queue. And our first question comes from . With Guggenheim, your line is open.

Good morning, everyone. Thank you for the presentation and all the details. So two questions for me. First one is on the SLEDI score that you are seeing in lupus patients. Could you maybe talk about the reason we are seeing some residual SLEDI activity or SLEDI score at six months? Obviously, it's very promising to see that it is not associated to any clinical activity, but how should we interpret the lack of normalization of complement and anti-DSTNA and autoantibodies? And then the second question is on the LN patient. Does the immune cytokine profile of this particular patient help explain the secondary peak? Just curious to understand how often do we see the secondary peak and any safety sort of consideration for that? Thank you.

David, why don't you take the first part of that? I'll take the first question regarding the sleet eye scoring and why we may be seeing some residual sleet eye activity. So as you pointed out, these are all laboratory abnormalities. The clinical features for all three of the non-renal lupus patients have completely resolved. So the arthritis or vasculitis, et cetera, have completely resolved. So if you look at two of the patients, they are only one month follow-up, so it may be too early to look for resolution of the double-stranded DNA and or the complement. For the SLE1, note that that was a patient with a class V lupus nephritis who tends to have proteinuria that is somewhat refractory or takes longer to see resolution. So that proteinuria remains as expected, and that's contributing four points to the sleet eye. The DNA and complement, again, six months could be early. It may take longer. And there are some data that suggests that sometimes double-stranded DNA may be refractory to resolution, even with B-cell depleting therapy, either with CAR-Chi or reduction.

And in addition, David, as a reminder, We have a translational research partnership that is exclusive with Professor Shen. We believe and our agreement suggests that we are the only company that receives his patient samples to analyze in our translational research facilities. And in our hands, his patients with a more specific dsDNA assay that we use versus the academic one that he has used, we are seeing dsDNA persist in some of his patients as well. So we're not surprised by this, and it is consistent with his data in our hands. And then for the second question, maybe Gwen, can you address the second peak?

Yeah, sure. Thank you, Yatin, for the question. So in this LN1 patient, we saw an unusual second peak both in the Kappa-201 persistence and also a second peak in cytokines. And that is something we haven't observed previously. And this was detailed nicely in the poster, so I would certainly recommend you have a deeper look there if you would like any more information than what I'm about to say. But this patient was very unusual, both in terms of the level of cytokines prior to infusion and also in the second peak of cytokines. Now, the profile of those cytokines were distinct from the peak cytokines that this patient and all of our other patients had at the initial stage. CABA-201 peak. So during that initial peak expansion, most patients have elevated interferon gamma, some have elevated IL-6, but not all of them. But in the LM1 patients, we saw both before infusion and also at that secondary peak, elevated levels of MIP1-ELSA data, elevated levels of IL-27. So these were distinct from the cytokines that were associated with the initial CAR-T expansion. And the secondary expansion, we believe, is related to a monoclonal outgrowth that's related to an infectious disease response where the CAR-T is simply a marker or a carrier in those zones. And that's detailed by TCR sequencing in the poster.

Thank you. Our next question comes from Yifan Xu. With Jeffries, your line is open.

Hi, this is Yifan from Jeffries on behalf of Kelly Shih. Congratulations on your progress. I actually have a similar question is that when we are evaluating efficiency outcomes in this county studies, so we focus more about the, like for SLE patients, the SLE diet 2K score. or we should focus more on whether the patients are drug-free, in your opinion. The second question is that, can you talk about your patient enrollment? Because currently, you have more than 11 cohorts in your studies, and each cohort may enroll six patients. So with the current patient enrollment and the potential future patient enrollment speed, can you guide us the developmental timeline of these five trials? Thank you.

Yeah, great questions. So let me try and take a stab and ask David to fill in if I missed something. The top priority of patients is to live a drug-free, symptom-free life. They want to wake up in the morning and not remember that they have a disease, not have to take a pill, inject themselves, go to the doctor's appointments regularly, and worry about the side effects of the drugs they're taking. But that is their top priority. And so I think that is very important in a patient-centric universe. In addition, it is, you know, that's necessary, but it's not necessary and sufficient. I think, in addition, you need to show that you have fundamentally impacted the disease. And, of course, that includes all of the, you know, typical standard measurements, whether it's VDI or other more technical measurements. of B cells being completely eliminated and a continuous evaluation of B cell receptor sequencing over a period of three, six, nine months comparing the B cells at a distance from the infusion to those that existed prior to the infusion in order to truly define that you have eliminated all of the B cells that could cause recurrent disease. And that to us is sort of the scientific standard of care, if you will, that we think is necessary to demonstrate a true reset. The lymph node biopsies and the peripheral B-cell measurements and the flow, those are all very nice and useful. But if you really want to understand whether you have impacted the biology in a way that should be expected to be durable, I think you want to end up looking at longitudinal B-cell receptor sequencing. So anything else on that, David?

I thought I'd add on to that. One thing, just going back to that lupus nephritis patient who was on five systemic therapies. So we're thinking about where did that patient end up with a sleep diet that started at 22 and now down to proteinuria and some alopecia and rash. So that patient has pretty much resolved all the major clinical symptoms. and off of those five medications, or at least tapering down on the steroids, so off of four, tapering off the fifth, with a one-time therapy that the patient received months ago. So if you think about that, it is drug-free, or approaching drug-free, which is really important for the patient. The second thing to point here is that we're thinking about this not as typical drugs that have been used to treat many of the autoimmune diseases, those patients are taking medications. You're saying, they're not doing well, so I'm going to add on another medication. I'm going to add you a sixth medication or your fifth medication, see if I can get control of that. The difference is not an add-on therapy, it's a replacement therapy. So you stop everything short of steroids, replace this with a single dose of Kappa-201, and the aspiration is for many years, if not a lifetime, that the patient has no symptoms on no medications, and that is the aspiration.

So the answer to the question, I think, in summary is both are really important, both the drug-free, symptom-free life and the hard, objective data that you have impacted with disease. Regarding milestones for 2025, what we have said is that as early in 2025 as data will permit, we fully expect to be discussing our registrational program with FDA. We do not expect, and I underline, we do not expect to initiate brand new phase three trials. We do expect to be able to extend our existing trials with additional arms or with extension of those arms, but all of that is gonna rely on discussions with FDA and the data that we develop. So that's our view. At the end of the day, I'm not gonna, jump in front of what will be the 2025 plan, but I do think that the safety profile that has been shown in the myositis and in the lupus patients, as well as even in the scleroderma patients, is highly acceptable for patients with autoimmune disease to be able to live a drug-free, symptom-free life. So we feel really, really good about the data and what it will allow us to do as it relates to going forward with the registrational program.

Thank you.

Thank you. Our next question comes from Samantha Semenko with Citi. Your line is open.

Hi, good morning, and thanks very much for taking the question, and congratulations on this nice data update. Two for me. So previously, Stephen, you said that you may be able to go to FDA once you have six patients' worth of data from any of your cohorts. Is that still the expectation, and how much follow-up do you think you need before you can go to FDA? And then just as you look forward to commercial opportunity for a 201, What do you think the bar for durability of drug-free remission is? Is it a minimum of one year, or do we need to see two or more to really make this a commercial opportunity? I'm just curious on your thoughts on what's meaningful for both patients and for physicians. Thank you.

Yeah. Thanks for the questions. So the side effect profile that we have seen, the majority of patients having no CRS and no ICANS at all. has caused us to revisit the assumption that we need a full cohort of six patients in any one of our subsets. And so internally, we're actively discussing exactly what programs we would want to advance. As you can imagine, with 16 patients enrolled as of November 12th, that number may have changed already, I don't know. We're going to start seeing those cohorts fill up pretty quickly. And we have a singular focus as a company for five years, six years now, more, seven years, which is to develop and launch the first targeted curative self-therapies for patients with autoimmune diseases. And we're going to do that. So that will drive our behavior. The second question was?

Durability.

Oh, durability. So this is interesting. When we do market research with physicians, They pretty uniformly tell us, and we know that others have done research and corroborated this belief, that if I can take, even with preconditioning, and of course we'll see whether or not we need preconditioning from our configures program, but even with preconditioning, physicians are willing to pound the table that patients should take CABITUO-1 as long as they can reliably achieve minimally 12, preferably at least 18 months of symptom-free, drug-free life. For the patient, that is completely relieving. And the doctors, I think, recognize that. Our expectation, just to be very clear, is that similar to what Professor Shett's cohort in its long-term follow-up is demonstrating, there should not be treatment failures as it relates to CD19 CAR-T administered patients in autoimmune disease. There may be patients who have non-CD19 targeted cells, such as plasma cells, where maybe you get a reactivation of some disease, as Professor Schett saw in the patient who had reactivation, it's a myositis patient, 18 months of drug-free, symptom-free life, and you develop a little muscle weakness and a CPK elevation when they ultimately decided to go forward with The CD19 CAR T readministration, it was a murine CAR that had antibodies, so it didn't achieve the expansion that it needed to. And so they shifted over to a BCMA CAR T on a compassionate use basis. And it has now been, with this permission I share with you, it has now been six months of drug-free, symptom-free life for that patient whose clinical recurrence was due to Most likely because of the treatment response the plasma cells that were anti Joe positive antibody producing plasma cells That just needed to be wiped up after the primary care. It was administered the cd19 part He was administered a year and a half before that so that that's that's what we know and that's what we expected of our therapies real durability and reliability across the patients who are treated based on his data our data and frankly the field at this point and demonstrating that these are durable, excellent therapies, and in our case, I would argue, you know, a very attractive safety profile for even perhaps outpatient administration.

Thank you. Our next question comes from Douglas Sal with HC Wainwright. Your line is open.

Hi, good morning. Thanks for taking the questions and congratulations on the progress. Stephen, I think it would be helpful if you could maybe talk a little bit more about some of the differences in the assays being used by you versus Professor Schett. I think you touched on how that might explain some of the differences we're seeing with the SLEDI scores, because I think that's an important point. And then I have a follow-up question.

Yeah, sure. Thanks for asking the question. When do you want to address the assay to be used and the assay to be used?

Yeah, so we previously published a joint publication with Professor Shett looking at double-stranded DNA antibody levels and where he reported that the patients had gone down to below the limit of detection with his assay and our assay, which is a very sensitive luminance-based assay, Shows that we could still detect low levels of antibodies and so that data which is jointly published, you know, indicates that you can have ongoing Anti double strand DNA antibodies and still have complete clinical responses. So it's, you know, message there is that, you know, auto antibodies are not always pathogenic. In our particular case, the double-tran antibody levels that go into the SLEDI calculation are from clinical assay, not our sensitive luminex assay. So there's two distinct issues going on, but the underlying message is that you can have continued detection of these antibodies without having a clinical disease. And in fact, that's well established in autoimmune disease populations where you oftentimes get these autoantibodies in the population with no evidence of clinical disease prior to the development of disease years later.

And look, until all of us in the field have more data, we don't know the answer. You know, the Shett patient who had anti-CO1 antibodies persisting turned out to be the patient who had a clinical relapse. And again, the track record on that patient with BCMA treatment with a CAR-T that wiped up the residual disease, you know, demonstrated that those antibodies probably were meaningful in that patient. The fact that Professor Shett has three years plus now of follow-up without any breakthroughs clinically, in his lupus population, and included among those are patients who have DSDNA-positive findings with follow-up in our Luminex assay, I think gives us some pretty good confidence that in our patients, two of them are at one month, so let's give time for things to resolve. But the six-month patient with DSDNA, not surprising, consistent with what we have seen with years of follow-up at this point. You had another question, Doug?

Yeah, so for the SOE1 patient who had class V lupus pruritus as well, I mean, would you expect, you know, I think you're showing that their sweet-eye score was still 8 at week 24. Would you expect that to continue to go down?

Yeah, so, Doug, thanks for your question. The proteinuria is hard to say, right, because as we discussed earlier, a class V isolated proteinuria in lupus nephritis tends to be refractory or very slow to respond, even to other therapies that have been approved. And typically, they are not even studied in lupus nephritis studies. But what we were looking for is could we actually improve the other symptoms of lupus? And as you can see, 26 down to 8 on the sleet eye. That well exceeds the SRI-4. Four-point improvement, that's a minimum required to get a drug approved, that was the criteria to get Benlysta approved was the SRI-4. So here you're getting an 18-point improvement, even with four points remaining on proteinuria. So really the question is, can we get double-stranded DNA complement to also improve? And that, again, we just discussed that regarding what is the double-stranded DNA, where is that a relevant marker of continuing disease activity, and where is the double-stranded DNA antibodies coming from? Could it be lung lymphocytes in the cells? in some patients. So we can't say whether that will or will not. We can just follow over time to see if those parameters would improve. But also more important is to see if she can maintain the clinical improvement that has been maintained and whether that patient continues to feel well.

Okay, great. And then just, Stephen, you recently presented data from your legacy CAART platform in musk patients that had some interesting findings. I'm just curious if it might be helpful to share some of your perspectives on what that might mean for the CAPA 201 program. Thank you.

So our legacy portfolio includes a musk CAR-T product, which is used to treat the musk form of myasthenia gravis. In that program, we used the cells alone, no preconditioning, and we were able to demonstrate biologic, well, pharmacodynamic, pharmacokinetic and pharmacodynamic expansion of the cells to the level of activity that one would anticipate needing for a clinical benefit. And we saw clinical activity out to a year in a number of patients from that program. To us, that demonstrates that using Cava-201 could potentially replicate the lymphodepletion-free regimen that we used in that different product, that legacy product. It gave us reason to believe that KABITUL1 could go forward and achieve the necessary biologic expansion in the absence of preconditioning. And so we're going to go forward with the PEMFIGUS program with seven sites currently open, using KABITUL1 with no preconditioning, and bringing it across to the early part of next year when we see some clinical data at one month whether the drug expands, whether the B cells are eliminated, and whether there is a clinical effect. If there is, the next step will be to move CABA 201 with lymphodepletion-free regimens into all of our disease categories in order to move as quickly as possible lymphodepletion-free regimen. And so that was the importance of the legacy platform with no lymphodepletion demonstrating biological and clinical activity out to a year. The ability to replicate that now in the KABAT-201 program is what we're pursuing in our PENTICUS program.

And do you think you'd be able to include a lymphodepletion-free regimen in registrational studies, or would you not necessarily have time to collect that?

So it'll be a question of, you know, any therapy that doesn't have durability hasn't delivered on the promise for patients. So we would probably prefer to stay with what we know works for patients at launch and simultaneously enroll patients who have no lymphoid depletion in their regimen and then launch that product subsequently, with the rationale being, similar to the TNFs and the JAK inhibitors, until they demonstrated years of durable activity, they didn't have a meaningful place in the market. And here, autologous CAR T with preconditioning, we know, provides years of durable outcomes, and autologous CAR T without lymphodepletion, we don't know if that's gonna last for years. We may get some acute effect, I think the same thing would be true for any other modality, whether it's allogeneic or T-cell engagers. You know, acute responses are not years of durable, disease-free, symptom-free life. And so we wouldn't launch, I think, the mental depletion-free regimen until we knew that we had the ability to deliver on the promise that patients are seeking.

Thank you. Our next question comes from Sammy Corwin with William Blair. Your line is open.

Good morning. Congrats on the data, and thank you for taking my questions. I was curious if you could remind us the rationale for not tapering steroids before treatment, and how does the value proposition for these patients kind of change if they can get off all drugs versus if they're off immunosuppressants but still on that corticosteroid taper? Thank you.

So the disease exacerbations that one would see if you stopped all steroids before you administered the product would not be acceptable clinically. You need to control the disease. These patients, as you see in our baseline, are on as much as 20 milligrams a day of steroids. And so you really don't have the option, when you administer any of these one-time therapies, of stopping the steroids before you administer your therapy. We have reason to believe, based on all the data that's out there, that these patients are going to achieve a steroid-free and immunosuppressant-free life, a total drug-free life that is symptom-free. And we just have to let the steroid tapers occur. Our patients are down in the range of 7 milligrams. 5 milligrams is physiologic steroid dose. So around 7 milligrams, 8 milligrams is where some of the patients are. We have long-term follow-up. And, you know, full expectations that we're going to see that continue to go down to a discontinuation.

Thank you. Our next question comes from Derek Arcilla with Wells Fargo. Your line is open.

Hey, good morning, and congrats on the update here. Just two quick questions from us. I guess first, It looks like there's only four patients that received prophylaxis anti-seizure meds in the reset study. So just wanted a reminder, were there something specific about these patients, or was this a function of the timing when you added it to the protocol? And then the second question is on myositis. I was wondering if you could just provide some more color on the kinetics in IMNM relative to dermatomyositis. I guess, when would you expect a patient with necrotizing disease to to have a major response, and I guess if there are any specific factors driving the differing kinetics, thanks.

Yeah, so do you want to take the questions? Yeah, so which one do you want to hear first, the IMNM or the, what's the first one? The prophylactic. Yeah, so the first one, you're correct, it's the second choice, B, which is that The first three patients were treated before. Ellen was the third patient when the seizure episode was noted, a subclinical seizure. And so the subsequent patients did get prophylaxis. One of them just did not have the timing in terms of IRB approval to get that in place. So it's just a timing issue. And the second question is IMNN because these are different patients. That's why it's called necrotizing myopathy. So there can be more significant muscle damage than you might see with the other two subtypes where it's maybe more inflammatory with less necrosis. So there may be a slower response in terms of kinetics clinically for these patients to show improvement. And this is consistent with what we've seen with other CAR-T therapies. Shet has shown this with this first patient. who also had very slow kinetics, taking at least six months to show some preliminary responses. So I think that we have to look about these diseases, some types of being different in terms of those kinetics, and probably IMNM patients are going to be slower to respond, and maybe not completely as much, we just don't know. That's why we're studying these patients, and as we get additional longitudinal data, we'll have a better indication.

Thank you. Our next question comes from Mark Fram with C.D. Cowan. Your line is open.

Hey, thanks for taking my questions and congrats on the data. Maybe first to just follow up on a couple of the earlier questions, kind of thinking on the pace of improvement of certain aspects of the disease and the remaining double-stranded DNA antibodies in some patients and other autoantibodies elsewhere. Do you have any plans to pursue kind of biopsies and things to try to get at this question of, is that truly just the preexisting damage to organs, you know, taking time to resolve or maybe never able to resolve versus kind of low levels of ongoing disease actually still happening.

And specifically in the kidney is your question.

Well, kidney, but there may be ways to get at it in other diseases as well that aren't kidney based.

Yeah. So there's, um, In our protocol, we have the opportunity to take kidney biopsies. Much easier to do in European than in US studies, but it is part of our protocol. And so that's data that, you know, to the extent that patients agree to have the biopsies, we look forward to collecting the information. And at the end of the day, as I said before, the tissue and the lymph node biopsies are interesting and useful information. But the sine qua non of a true B-cell elimination is going to be sequential B-cell receptor sequencing, looking for clones that were pre-existing prior to therapy to see if any of them survived the one-time infusion. And that really defines whether or not you have successfully achieved the goal of therapy. So it's sort of the fast path to the right answer. comes through doing that work. And that's work that we are doing currently. We just need to let the patients bake a little bit longer in terms of a little more progress to get to the point where we have the longitudinal data set to speak to it. But I can a bit foreshadow to say that we believe we have the right dose of Cava 201 for many reasons, not the least of which is the early insights into that data.

OK, that's helpful.

Thank you. Our next question comes from Mike Ols with Morgan Stanley. Your line is open.

Good morning. Thanks for taking the question. Maybe just based on that lupus nephritis patient with the grade four ICANS and your decision to delay dosing in those patients with fever, just curious if you've implemented that already, and have you seen any other patients have fever prior to dosing? Thanks.

Yeah, so as a result of the grade four ICANN's patient that we clearly described biologically and clinically as an outlier, we made two changes to the protocol. And frankly, we think these should be universally applied in the industry. And one, because we don't think they're specific to anything about CAPIT-201, but they do enhance the prospect possibly of patient safety. The first, as you suggest, is to have a two-week delay before infusion of the product. That should, we hope, give the patient more time to resolve not only their clinical exacerbation of fever, inflammation, whatever they had, but the biologic resolution as well, so that we won't be in a position where we are as likely to treat a patient who is at risk of more severe side effects. The second thing that we did, and that has been implemented across all of our trials already, again, completely on a voluntary basis, Nobody recommended that we do that other than internally at the company we decided this is all about patient safety and we want to be sure that we achieve that goal. And then the second thing we did is we added a daily dose of Kefra for 30 days starting at the point of infusion. A tablet, a pill, and not much in the way of cost or side effects. but the possibility that you can diminish the risk of seizure activity, which would lead to an ICANS event, we thought that was prudent, again, to integrate it to the trial, very little cost, the possibility of better safety, and so we've already implemented that. The reason only for patients is because of the timing of adoption of those protocol amendments by the individual sites that were enrolling patients at that point in time. Those who were able to integrate that protocol amendment fast enough were able to administer in the trial for their patients. Yeah, David.

Yeah, so if I could just clarify that we actually don't mandate Keppra. We say that anti-seizure prophylaxis is recommended and should be administered unless if there's a reason why they shouldn't. There may be institutional standards. They may be adverse to giving anti-seizure, whatever the reasons, but we highly recommend should be given, but we don't specifically say CAPRA, although most sites will probably select CAPRA just because of its safety profile and prior history of use in the treatment of high gas.

Yeah, thanks for that clarification. Next question.

Thank you. Our next question comes from Truong Haiyan with UBS. Your line is open.

Hi, good morning. This is Ting from TransTing, and thanks for taking our questions. For what happened with the lupus nephritis patient, could you confirm screening of the pre-existing pro-inflammatory cytokines is not in current protocol? And if not, would you consider for future patient screening? And I have a quick follow-up, if I may. Thanks.

Yeah, sure. So, no, we don't. It turns out the inflammatory cytokine data that we presented takes weeks to generate. These are not CLIA-approved, routine, standard tests that you can send to lab and have the test done. And so, no, we don't anticipate, we don't currently, and we don't expect in the future to do any cytokine screening, if you will, of patients. We do think that clinical signs and symptoms of this patient were profoundly different than any other patient we've seen. And as a result, we think it should be pretty straightforward to look at the clinical signs and symptoms of patients who are enrolled. And if they have evidence of inflammatory or infectious or febrile events within two weeks of the planned infusion, we would, in our protocol, recommend delaying the infusions.

Thank you. And yeah, that's really helpful. Maybe a follow-up question on myositis and different kinetics expect for different subtypes, which David talked about. For the IMNM subtype, you have one patient with longer follow-up. It seems like the TIS score was nearly hitting the moderate response rate. after six months of treatment. So we want to know, how does it compare to stand-up care, and how valuable, then, do you think a CAR T infusion is to this type of patient? Thank you.

Yeah, I will only say one thing. IMNN is notoriously challenging to treat. There are no approved therapies, and stories go as far as patients who are bed-bound and, frankly, unable to get to the bathroom themselves because they can't walk without pain and oxygen supplementation. But David, do you want to really expand?

And maybe just go back to the drug-free concept again. This patient had pretty severe muscle weakness on the MMT8, so in the 120s at baseline even, while on methotrexate, which is supposedly the therapy that was helping the patient. And I believe it was probably on steroids as well at the time. And previously had tried other medications, yet we stopped the methotrexate. replaced it with CABA 201 and showing a moderate response on the total improvement score at week 24. So if you think about it that way, multiple prior therapies, refractory, stopped the current medication that was supposedly helping the patient, yet continue to get better while stopping all those medications and giving one-time therapy with CABA 201. So I think we have to rethink that, it isn't just about these drugs getting some responses. It's getting tremendous responses because patients also love the therapies.

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