Good morning. At this time, I would like to welcome everyone to Cabaletta 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 Cabaletta Bio. Unauthorized recording, reproduction, or transmission of this call without the express written consent of Cabaletta Bio is strictly prohibited. I will now turn the call over to Will Gramig of Precision AQ. Please go ahead.
Thank you, Michelle. Good morning, everyone, and thank you for joining Cabaletta Bio's Conference Call and Webcast to discuss clinical and translational data from the first eight patients in the phase I-II 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 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. 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 Cabaletta'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 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.
Thanks, Will, and thank you, everyone, for joining us today. We're excited that we have the opportunity to share updated clinical and translational data from our RESET clinical program evaluating CABA-201 in myositis, lupus, and systemic sclerosis this weekend at ACR. We're evaluating whether a single dose of CABA-201 can safely deliver compelling clinical responses after discontinuation of all immunosuppressants. By way of background, CABA-201 was specifically designed for patients with autoimmune diseases. It was engineered to be similar to the academic 4-1BB first in domain containing CD19 CAR-T that's been evaluated in multiple academic studies. CABA-201 contains the identical signaling and 4-1BB co-stimulatory domains as the academic construct, with a fully human CD19 targeting domain that binds to the same epitope on the CD19 antigen as the murine FMC63 binder utilized in the academic studies, with the same biologic activity as published earlier this year. Next slide, please.
CABA-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, CABA-201 is being evaluated in 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 SSc trial, which we believe support a favorable risk-benefit profile and the use of the selected dose of CABA-201 at one times 10 to the 6 cells per kilogram. The data we will present supports the potential of CABA-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 RESET 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 12. We recently announced that clinical development is expanding into Europe, with EMA CTA authorization for CABA-201 received for 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 CABA-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 for Cellular Immunotherapies at Penn 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. 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 has established now a foundation for the application of the same CAR-T cell for autoimmune disease. Next slide. So 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 an 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 that's being borne out in the initial data, as you'll see. Next slide. So here are the 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, tocilizumab, which blocks IL-6 receptor signaling, is given first. And for ICANS, steroids and anti-seizure medications are given. And adults usually do not require replacement of gammaglobulins. The anticipated hypogammaglobulinemia is to be short 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 ACR. David.
Great. Thank you, Carl. 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 nephritis studies, and the proteinuria tends to be slow to respond.
However, we have elected to include these patients in the SLE non-renal cohort to evaluate if other manifestations of lupus can respond to CABA-201. Next slide. All the RESET clinical trials share common elements of the same preconditioning, with the exception of RESET PV trial evaluating CABA-201 without preconditioning, same single weight-based dosing, same minimum four-day inpatient stay, 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 5 lupus nephritis. Next. The one lupus nephritis patient treated LN1 is shown here.
Next, the first scleroderma patient with severe skin involvement is shown here. Next. The highlighted areas identify 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 eliminate 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, ICANS neurotoxicity, and other important adverse events through the latest follow-up. The myositis patients had no CRS, no ICANS, no serious infections, no hypogammaglobulinemia, or related serious adverse events. Next. One non-renal lupus patient had a grade 1 CRS of fever. The scleroderma 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 cytopenias, which is a labeled warning and precaution with approved oncology CAR-T products. The patient also had a transient and reversible grade 4 ICANS, which was previously reported, and I will discuss later. None of the other seven patients had ICANS. 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 antiplatelet agents, recent hospitalization for back pain and fatigue with decreased mobility. CABA-201 levels were undetectable since day 22. At day 38, a TE 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-201 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-month follow-up, B cell repopulation with naive cells started as early as eight weeks in patient IM NN1 and SLE1 shown in the upper right panel. CABA-201 exhibited PK/PD profile with peak expansion between day eight and day 15 as expected 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 shown in the right two panels. Next slide.
The first known adult dermatomyositis patient dosed with a CAR-T therapy demonstrated compelling early clinical responses off immunosuppressants, as shown by skin improvement on the CDASI-A, muscle improvement on the MMT-8, and overall improvement on the total improvement score TIS at day 29. Next slide. The first IMNM patient with 24 weeks of follow-up demonstrated continued clinical responses off immunosuppressants without flares. Initial clinical response in the IMNM patients are consistent with published data, and response kinetics may differ among myositis subtypes. 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 SLEDAI-2K were present in any of the three patients through the latest follow-up. This includes SLE1 with isolated class 5 LN with persistent proteinuria as expected. Next slide.
Patient LN1 proteinuria markedly improved by week 8 with alopecia and rash as the remaining clinical manifestations at week 16 after discontinuing all immunosuppressants and continuing prednisone tapering. Next slide. Unlike the other seven dosed 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 ICANS. Two days later, the ICANS 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 of 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 CABA-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 continue to get worse despite all of the strong medications I was on. I had multiple occurrences of fluid around my heart. CABA-201 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 CABA-201 again." In addition, we have dosed our first scleroderma patient with severe skin involvement. At day 42, the patient is demonstrating skin improvement with datas at hand even after discontinuation of disease-specific medication. Now, I will turn it over to Stephen to conclude our presentation.
Thanks, David.
So in summary, CABA-201 appears to have a favorable risk-benefit profile. In patients with recent fever or infections, delaying CAR-T infusion should be considered. CABA-201 provided compelling efficacy in highly active and refractory autoimmune patients through the follow-up period. Initial data support the potential for drug-free clinical responses with all patients discontinuing all immunosuppressants and with SLE patients with longer follow-up completing steroid taper to off or continuing ongoing steroid taper down to prednisone equivalent eight milligrams per day. Finally, the PK/PD data support the current dose of CABA-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 curative steroid therapies for patients with autoimmune diseases. Patients want a drug-free, symptom-free life. CABA-201 has the potential to address their aspirations.
Looking ahead, we anticipate meeting with the FDA on potential registrational trial design for CABA-201 as early in 2025 as data permit. We appreciate that you chose to invest the 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 11. If your question has been answered and you'd like to remove yourself from the queue, please press star 11 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 Yatin Suneja. 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 SLEDAI score that you are seeing in lupus patients. So could you maybe talk about the reason we are seeing some residual SLEDAI activity or SLEDAI 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-dsDNA 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?
Yeah. So I'll take the first question regarding SLEDAI scoring and why we may be seeing some residual SLEDAI 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, etc., have completely resolved. So if you look at the 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 SLEDAI. The DNA and complement, again, six months could be early.
It may take longer, and there are some data suggest that sometimes double-stranded DNA may be refractory to resolution even with B cell depleting therapies, either with CAR-T or reduction methods.
And in addition, David, as a reminder, we have a translational research partnership that is exclusive with Professor Schett, and 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 CABA-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 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 LN1 patient, we saw both before infusion and also at that secondary peak, elevated levels of MIP-1 alpha and beta, 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 cells. And that's detailed by TCR sequencing in the poster.
Thank you. Our next question comes from Yifan Xu with Jefferies. Your line is open.
Hi. This is Yifan from Jefferies on behalf of Yifan Xu. Congratulations on your progress. I actually have a similar question is that when we are evaluating efficacy outcomes in these CAR-T studies, should we focus more about the, like for SLE patients, the SLEDAI-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, it's great questions. So let me try to take a stab and ask David to fill in if I missed something. So 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. 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 typical standard measurements, whether it's SLEDAI 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, that you would mention?
Yeah, that's all. I thought I'd add on to that. And one thing, just going back to that lupus nephritis patient who was on five systemic therapies. So we're thinking about where that patient ended up with a SLEDAI 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 the fourth, 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." 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 CABA-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.
The answer to the question, I think in summary, is both really important, both the drug-free, symptom-free life and the hard objective data that you have impacted the 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 III 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 going to rely on discussions with FDA and the data that we develop. That's our view.
At the end of the day, I'm not going to 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 patient, is highly acceptable for patients with autoimmune disease to be able to live a drug-free, symptom-free life potentially and have their disease halted in its tracks. 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 Semenkow with Citi. Your line is open.
Hi, good morning. And thanks very much for taking the question and congratulations on this nice data update. Q for me. So previously, Steven, 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 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? Just curious on your thoughts there and what's meaningful for both patients and 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 cell therapies for patients with autoimmune diseases. And we're going to do that. So that'll drive our behavior. The second question was?
Of 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 RESET program, but even with preconditioning, physicians are willing to pound the table that patients should take CABA-201 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 Schett'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, the myositis patient, 18 months of drug-free, symptom-free life, and you developed 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, and it 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.
It has now been, with this permission I share with you, 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-Jo-1-positive, antibody-producing plasma cells that just needed to be wiped out after the primary CAR-T was administered. The CD19 CAR-T was administered a year and a half before that. So that's what we know, and that's what we expect of our therapy: real durability and reliability across the patients who are treated based on his data, our data, and frankly, the field at this point, demonstrating that these are durable, excellent therapies. In our case, I would argue a very attractive safety profile for even perhaps outpatient administration.
Thank you. Our next question comes from Douglas Tsao with H.C. Wainwright. Your line is open.
Hi, good morning. Thanks for taking the questions and congratulations on the progress. Steven, I think it would be helpful if you could maybe talk a little bit more about some of the differences in the sort of 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 SLEDAI scores, because I think that seems to be an important point. And then I have a follow-up question.
Yeah, sure. Thanks for asking the question. When do you address the assay that he uses and the assay we use? It may be different.
Yeah. So we previously published a joint publication with Professor Schett looking at double-stranded DNA antibody levels, and 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 luminescence-based assay, showed that we could still detect low levels of antibodies. And so that data, which is jointly published, indicates that you can have ongoing anti-double-stranded DNA antibodies and still have complete clinical responses. So the message there is that autoantibodies are not always pathogenic. In our particular case, the double-stranded antibody levels that go into the SLEDAI calculation are from clinical assay, not our sensitive luminescence assay. So there's those two distinct issues going on, but the underlying message is that you can have continued detection of these antibodies without having a clinical disease.
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. The Schett patient who had anti-Jo-1 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 the CAR-T that wiped up the residual disease demonstrated that those antibodies probably were meaningful in that patient. The fact that Professor Schett 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 in his patients.
His patients with lupus did not demonstrate any failure of treatment or breakthrough clinically with years of follow-up at this point. You had another question, Doug.
Yeah. So for the SLE1 patient who had Class V lupus nephritis as well, I mean, would you expect I think you're showing that their SLEDAI score was still eight 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 5 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're 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 SLEDAI, 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 the four points remaining on proteinuria. So really the question is, can we get anti-dsDNA complements 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 along with plasma 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, Steven, you recently presented data from your legacy CAART platform in myositis 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 CABA-201 program. Thank you.
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 expansion of the cells to the level of activity that one would anticipate needing for a clinical benefit. We saw clinical activity out to a year in a number of patients from that program. To us, that demonstrates that using CABA-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 CABA-201 could go forward and achieve the necessary biologic expansion in the absence of preconditioning.
And so we're going to go forward with the RESET program with seven sites currently open, using CABA-201 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 to get the data on all of the different diseases in a lymphodepletion-free regimen. And so that was the importance of the legacy platform with no lymphodepletion demonstrating biologic and clinical activity out to a year. The ability to replicate that now in the CABA-201 program is what we're pursuing in our RESET program.
Do you think you'd be able to include a lymphodepletion-free regimen in registrational studies, or would that be where you not necessarily have time to collect that?
So it'll be a question of 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 lymphodepletion in their regimens 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 going to 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. Acute responses are not years of durable disease-free, symptom-free life.
And so we wouldn't launch, I think, the lymphodepletion-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 Sami 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 immune suppressants but still on that corticosteroid taper? Thank you.
The disease exacerbations that one would see if you stopped all steroids before you administer the product would not be acceptable clinically, right? 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 seven milligrams. Five milligrams is physiologic steroid dose. So around seven milligrams, eight milligrams is where some of the patients are who have long-term follow-up.
Full expectation is that we're going to see that continue to go down to a discontinuation.
Thank you. Our next question comes from Derek Archilla with Wells Fargo. Your line is open.
Hey, good morning, and congrats on the updates here. Just two quick questions from us. I guess first, it looks like there's only four patients that received prophylactic anti-seizure meds in the RESET study. So just wanted a reminder, was 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 have a major response? And I guess, is there 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 first one?
Prophylactic.
Prophylactic. Yeah. So the first one, you're correct. It's the second choice B, which is that first three patients were treated before, right? LN was the third patient when the seizure episode was noted, 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, IMNM, because these are different patients where 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 that I've shown this with this first patient who also had very slow kinetics and taking at least six months to show some preliminary responses. So I think that we have to look about these diseases, subtypes as 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. And 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 Marc Frahm with TD Cowen. Your line is open.
Hi, yes. 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 being 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 pre-existing damage to organs taking time to resolve or maybe never able to resolve versus kind of low levels of ongoing disease actually still happening?
Specifically in the kidney, is your question?
Kidney, but there may be ways to get at it in other diseases as well that aren't kidney-based.
Yeah. So in our protocol, we have the opportunity to take kidney biopsies. Much easier to do in European than in U.S. studies, but it is part of our protocol. And so that's data that, 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 a longitudinal data set to speak to it. But I can a bit foreshadow to say that we believe we have the right dose of CABA-201 for many reasons, not the least of which is the early insights into that data.
Okay. That's helpful, and then.
Thank you. Our next question comes from Michael Ulz 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 4 ICANS 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 CABA-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 Keppra 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 into the trial, very low cost, the possibility of better safety. And so we've already implemented that.
The reason only four 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 antiseizure 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 antiseizure, whatever the reasons, but we highly recommend it should be given. But we don't specifically say Keppra, although most sites will probably select Keppra just because of its safety profile and prior history of use in the treatment of ICANS.
Yeah. Thanks for that clarification. Next question.
Thank you. Our next question comes from Trung Huynh with UBS. Your line is open.
Hi, good morning. This is Cheng from Trung's team, and thanks for taking our question. 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 mandating it 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 the 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 infusion.
Thank you. And yeah, that's really helpful. Maybe a follow-up question on myositis and different kinetics expected 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 merely hitting the moderate response rate after six months of treatment. So we want to know how does it compare to standard of care and how valuable then do you think a CAR-T infusion is to this subtype of patients? Thank you.
Yeah. I will only say one thing. IMNM is notoriously challenging to treat. There are no approved therapies, and stories go as far as patients who are bedbound 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 MMT-8, so in the 120s at baseline, even while on methotrexate, which is supposedly the therapy that was helping the patient. And I believe was probably on steroids as well at the time. And previously, I 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 continued 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 are off of other therapies.
Thank you. That will conclude the Q&A portion of today's call. You may now disconnect. Everyone, have a great day.