Cabaletta Bio, Inc. ($CABA)

Nice. So kind of going down that vein before we jump into the ULAR data. So for Resicel, it's an autologous 4-1BB CCART. And given the breadth of approach is being investigated in autoimmunity, how is resell differentiated from not just competitor autologous CAR-Ts, but also allogeneic and bispecific approaches? And sort of where does resist in the competitive landscape there?

Yes. Thanks for the question. So among autologous CAR-T, let's start there. Nature Biotechnology had a review of all of the data that's previously been presented. It's about 2 months ago. And in this paper, Restel looked to have a side effect profile, CRS risk, both the frequency and the magnitude, ICANs risk and overall safety profile, tolerability profile of resite looks like it will be second to none, in the autologous space, a very excellent tolerability and safety profile with the vast majority, 97% of patients now ICAMs of any sort. 94% of patients either no iCAMs, which is about 2/3 of them or if they have ICANS, it tends to be a fever and not much else. So really excellent safety and tolerability profile, to start with. So among autologous products, we feel really good because they're all pretty much effective in comparable ways. And the difference in autoimmune disease is going to be safety. So that brings me to in vivo. And I think I'm going to very quickly comment on bispecifics. Far better than rituximab. They will replace many of the chemotherapeutic or other agents that are currently used in these diseases. There'll be better therapy for many, many patients, chronic therapy when added on to existing therapy, they'll be great for all those patients, terrific. For patients who no longer want to be patients, you want to reset and that's what we believe we can do reliably and well. In vivo, really interesting data presented recently, right? Legend had some CD19 20 data that looks very promising for those patients that they treated and in the Colonia data, BCMA targeting in vivo car. Their data also looked very interesting. What neither of them has done yet is demonstrate safety over the long term, right? So any integrating product I think is -- I don't know if it's a nonstarter in autoimmune disease, but it's got a very high hurdle to prove safety, both in the short term and in the long term. And remember how safe resi cell is compared to whatever else you're looking at in the future, that's the bar for safety. The other thing that needs to be proven is durability, right? And durability of treatment effect, not the persistence of the cells. So in the Legend data, they rightly highlighted, that the durability of the car persistence was 116 days. They still had CAR T cells. By 116 days, our patients are regaining their normal B-cell population. So it's just a fundamentally different approach. And over the next few years, we expect to launch Resac for myositis, for scleroderma for PC free containing regimens in other indications, and that will be the standard against which they will be judged in safety and in durability by the time these drugs first develop the right product for autoimmune then actually become developed for those diseases. We will have 4, 5, 6 years of durability data similar to the JAKs against the TNFs, you need to have durability data to compete, you need to have safety to compete. So I think there's a very long road ahead for the in vivo autoimmune products, but it's thrilling what's happening in cancer. Yes. No, I totally agree. I think it's a very interesting innovation, but it does take a long time to kind of get these things optimized so for NVOCAR-T. Now jumping to the ULAR data. So last week, you shared several important updates that you are. So let's start with the data and myosin as this is your lead indication. So you showed that 5 out of 6 dermatomyositis patients in 3 out of 4 patients with anti-synthetase syndrome. Achieved immunomodulator for your remission at week 16. So could you frame this result in the context of read through to your ongoing pivotal reset inside of study? Yes, I'm happy to do that, Mark. Thank you for the question. I think a nice place to start is patients when they're coming on this study are discontinuing all of their immunomodulatory medicines prior to infusion of a single weight-based dose resell. That's where we started. That's where we started in the Phase I/II study, and that's where the registrational study starts. Now the way we designed the study, the reworking and extension Phase I/II study, there is really quite a lot of overlap between the inclusion exclusion criteria and the patient population in the Phase I/II versus the registrational study. So with the data that you just quoted that we reported last week that you are 80% of those patients and 5 out of 6 dermatomyositis patients adults and the first tubenematomyositis patients, all were able to, at week 16, achieve either a moderate or a major TI response while discontinuing and remaining off all immunomodulators for the duration of the follow-up. Now not only that, but in those patients who achieved the primary endpoint, they all maintain their response the latest follow-up, which we now are seeing in dermatomyositis as as long as 1.5 years. Now that's an opportunity to not only in our minds, achieve a positive registrational study where if you assume very conservative assumptions on the control group, we need 50% of patients to achieve the primary endpoint. But more importantly, maybe I can turn it over to Steve for this point, as we start to see the emerging durability of Resac, in dermatomyositis in particular, really shaping ourselves up to be favorable from a commercial and value perspective to generate the type of data that we need to have patients and the healthcare overall benefit. But Steve, maybe I'll turn it over to you from that. Yes. Yes, it's an important piece, right? So Stephen talked about the Nature Biotech article. We're kind of clearing their first toxicity question around the program, best-in-class. It appears to now. The second thing is we just have to wait this out to see how long these patients continue to response. So now you're starting to see that, right, 1.5 years. Teresa while 1.5 years milestone is very important is in the private insurance side of the house, which is the overwhelming majority of payment for Resacel. This is obviously a very different patient population than the ones I've been involved with in cancer, which is extremely important, and we could talk about that on the side. But the fact that the commercial insurers have been very clear in terms of the milestone that they would like to be seen a minimal of 1 year, 1.5 years. and 2 years plus. Obviously, they'd like to see multi multiyears, we all would. But in terms of that initial milestone, and this is the important part of this point that we've done the research around this because we knew going into ULAR what the data was -- we're going to be presenting. We did some research with payers as well as U.S. providers, hospitals. And what we did not present to them, which we will, because we're building it right now, economic impact models that drug-free represent for them in this patient population, it's significant. So it's very exciting now from a payment perspective, we're starting now clear that hurdle, that requirement under ability, and as we get closer to them and closer to our launch of the program, we'll be able to demonstrate the economic impact, which is obviously going to have a lot of interest for them anyway.

Got you, that makes a lot of sense. So on the line of durability, you guys mentioned that duality in dermatomyositis patients is 1.5 years. But in ACIS patients, durability was more variable. And I was wondering if there's any sort of mechanistic differences or disease ideology that could explain the result? And how you're thinking about treatment and responses for the asset?

Yes. Absolutely, Mark. Just a little bit of context of the way our registrational study is designed it's a 17-patient study, where the vast majority of the patients, 14 of them will be adult dermatomyositis, the remaining 3 antisynthetase syndrome patients. That's a reflection of the prevalence the U.S. where probably 80% to 85% of patients represent the adult dermatomyositis portion. So let's say, 60,000 patients in the U.S. roughly from a prevalence perspective, the remaining small piece of things represent the ASIS patients. I would say, in those 2 different subtypes, what we are seeing, to your point, is divergence in what the durability appears to be in the anti-synthetase syndrome patients. These patients have rapid responses deep responses. And at least in the Phase I/II data, most of them are achieving the primary endpoint. However, somewhere between month 6 and onwards. And this is the case in our data and in the academic data also presented by cheat ULAR actually this past week. It seems at some point in that journey, there is an emergence of disease activity that requires immunomodulatory medicine help continue to control disease. Now a lot of times, these patients are significantly better off than when they originally started refractory to 3, 4, 5, 6 medication sometimes with severe active disease. However, what we are seeing is that the persistence of autoantibodies in many of these cases in this particular population may point to a CD19 negative subset of cells that may be responsible for continuing to drive some emergence of disease versus in dermatomyositis where it seems like when Rescal is able to do its job completely or transiently deplete the B-cell population, that is sufficient for maintaining those responses, at least in the patients we followed so far through latest follow-up and as long as 1.5 years as Steve referenced. So in ASUS, it seems like there is, from a physiologic perspective, a difference in the mechanism of disease, which may allow for rapid and deep responses early and some emergence or breakthrough of disease as we continue to follow. So it's still more to be learned, but that's -- those are some of the early findings.

Got you. And sort of kind of understanding that finding, are there particular indications where you think Resita could be best applicable given like you're saying, there are CD19 cells that are negative cells that are active in this particular subset.

It's -- so it's a really good question. It's exactly why we the studies across the portfolio the way we did. So each of our studies evaluate a single wave-based dose in cohort to patients in Phase I/II as we gather that data in that population. The ability to see how that data is and make decisions as a company based on that data to determine -- does this make sense to extend a registrational study, does it make sense evaluating -- does it make sense that this should not be an indication where CD19 CAR-T should be developed. We came up with that design kind of as a cross-functional team that is years go, so that we could efficiently develop resacell broadly across the portfolio. And by using that same weight-based dose, extend the learnings in 1 indication across more but still able to make independent decisions across each based on the data that we get. And so a great example here is in our myositis registrational program, we are now prioritizing juvenile dermatomyositis in addition to adult termatomyositis because not only does the data seem to show that there's the opportunity durable responses to emerge. It also allows us to become potentially eligible for a priority review voucher. So those are learnings that we've been able to sort of obtain and apply into that study. directly that's been, I think, really beneficial for us.

Got you. Sort of along for the pivotal study design, you recently initiated the registrational study in most -- and if you can walk us through sort of the recent myocyte study design with any time lines for data, but also given the recent changes in commentary from the FDA, could you provide any color on your FDA interactions regarding study alignment and point selection and your overall confidence in the single-arm study design?

Yes. So a few highlights, and then I want to turn over to see for an important feature here in terms of why the design is important for commercial uptake. Motista which we'll plan to submit when we submit the myositis BLX. Importantly, in this study, is the opportunity to evaluate outpatient dosing. And with the safety profile that Steve and Steven talked about in terms of emerging for redose where in my sites, we've had no its observed whatsoever in the patients that have been treated to date setters either have no CRS or Phase 1 transient across the portfolio so far based on data reported at ULAR. All of this has helped us enable the ability to enable outpatient dosing in the registration study and in the Phase I/II expansion cohorts actually, and maybe I can turn it over to Steve to talk about why outpatient dosing, there's no question from a patient and provider experience perspective can be really positive. But maybe, Steve, you can talk about what that means for the commercial opportunity and the reduction of burden on the health care system. Yes. I mean normally side of care, you don't really -- there's not a lot of conversation around that with a lot of product launches. However, with cell therapies, in particular, it's been 1 of the biggest rate limiters for auto CAR-T therapies for cancer. And if you look at just the treated eligible patient population in cancer therapies, you see anywhere from be 20% to 25% of all eligible patients actually being treated One of the challenges -- the reason for that was that there was only so much inpatient capacity to treat these patients. So here you are basically look -- you're launching in the large patient populations, -- and the ecosystem cannot actually take those patients and treat them all as an inpatient administered product. So 1 of the key strategies behind Rescal and the toxicity profile is what enables this to happen. -- is to safely treat these patients in the hospital outpatient setting first and eventually to transition into the full outpatient setting. And it's all predicated on this toxicity profile that was originally discussed by Steve and upfront is that you have now what appears to be the safest product in the class that's going to enable that to happen. So obviously, patients love being able to take it as an outpatient, right, of course, -- the hospitals love it because payment is much better for them. That's been also a rate limber for them, and the payers love this because now you're able to treat these patients and totally reduce total cost of inpatient admissions. And you're looking at taking from $1 million-plus patient administered in the inpatient setting and significantly reducing that cost point for a payer. So it's an exciting part of the launch, and it's a key focus for us as we move forward.

For sure. Yes, keeping hospital that's open, it is great for every Absolutely. Sort of what safety parameters are you monitoring? Or like what specific criteria are you tracking in the study to support an outpatient label? And what proportion of patients do you expect will be treated in the community outpatient setting upon RISA launch.

Yes. You take a piece, and I'll take doctors Sure. So from a safety profile or sort of parameters perspective, what are we looking at? It's really in the perifusion period, how being managed? And is this something that is suitable for the outpatient setting. Now 1 of the things that we've been able to leverage, and this is a thing for the guy on my right here, Steve, who led the effort at Legend with CARVICTY is there's all already a significant outpatient infrastructure developed in the oncology setting for CAR-T. And that's with the safety profile across the products that is substantially more significant, more severe CRS and ICANs where cell therapists are now accustomed to understanding what the protocol is to manage CRS, what the protocol is to manage iCAN. And already in the Karvy setting, nearly half of new outpatients were half of new patient starts were happening in the outpatient setting, resacell we're seeing with a significantly more favorable safety profile in terms of lower CRS frequency lower CRS severity. The lower ICAN frequency in particular, a real opportunity to move much earlier in sort of the line of the -- not the line of therapy, but in terms of how rentacellcan sort of move early to launch in the outpatient. I think it's why we incorporated the option in our outpatient study to begin with. And maybe, Steve, you can walk through kind of how we see the transition to outpatient happening how quickly what that looks like. Yes. That's a key point. We've talked about -- Room was talking about my old program with CAR VICT, -- it took about 3 years to get to that point of about 50% or so new starts in the clinic for these hospitals. -- the rate limiter again, that you start to run into is these patients are still extremely ill, these end stage and even mid-stage cancer patients that many of these programs are treating historically. The beauty that I keep coming back to is the beauty of this program. These folks are very -- they're ambulatory, they're younger and now and they're working class, right? So they want to continue to continue on with their lives. The adoption sequence in outpatient here that we're starting to see in the research that we're performing, based upon the profile that we have been demonstrating at ULAR, that data is way faster been the 3-year point that I referenced in terms of my old programs. So you're going to -- like I said earlier, you're going to see a very rapid adoption on the back of the infrastructure that's been created with CarVICTY. Many of the sites are the same. And again, all the data that we're seeing that we are fielding right now is suggesting a rapid uptake there so fast that we are looking at how do we safely now move this to your point about really community practice. Community practice, there's -- it's limited right now. You see it a little bit. It's spotty with KarviCTI. So the proof of concept has been established in really sick patients, okay? Like I said, it's our intention to follow the model that we created before, but really start to open it up. You have to do it. In order to reclassify these CAR T therapies, to really treat the patient populations to the fulfill -- like the potential of them. You have to do that. It's the first time ever that a product like this has had a profile to enable you to actually get there.

So you touched on the inclusion of juvenile matomiositis patients and given you have rare pediatric disease designation for reticle in JM. How many get patients will the pivotal study enroll? And also, could you talk about the significance here for both review time lines and capital amusement.

So we were fortunate enough to actually have -- and I know 1 of your questions, Mark was talk about the FDA kind of discussion and how those are going. So I don't think we forgot it, but we can fold in this question. I think the nature of the RMAT designation that we received long ago in myositis leverage or provided has afforded us the opportunity to have frequent interactions with the agency really over the last several years now. And 1 of those interactions was actually a type B meeting back in April of 2025. And there was the point where in those discussions with the agency, what was determined was that at the time of submission of the myositis BLA they encouraged us to submit the available pediatric data in the population on the basis that if the PK/PD looks similar in the pediatric population and the adult population then that may provide the grounds for potential inclusion of the pediatric data, pediatric indication into the adult into the overall myositis BLA. Now this is really only possible because unlike every other CAR-T player in the field, we are advancing a weight-based dosing, and that weight-based dosing regimen allows us to transition seamlessly into the pediatric population. That's why we opened up the study to tuberomyositis to begin with years ago. And so as we stand today, what our plans are, are to submit the available juvenile dermatomyositis data at the time of submission of the adult -- or myositis BLA overall. And it's 1 of the reasons why we narrowed in our guidance into 227 for the BLA submission for myositis because we want to ensure that we have robust 16-week and 52-week outcome in that patient population to enable the maximum chance of inclusion of the pediatric indication into the initial BLA approval because that's what affords us the to have the priority review voucher. And what we can say from our early canvassing of the site in juvenile dermatomyositis is that the physician urgency to treat and the patient and advocacy strength with which they advocate for something like Rescal to provide immunomodulator free outcomes for their patients for kids who can go back to school, kids who can resume normal daily activities of life, is so strong that it was really a clear opportunity for us to be able to deliver for these patients in this population as a whole, an opportunity to get as a cell in the context of initial registrational study and an initial hopefully, initial approval. And on the capital envision point. Let's say that -- on the capital confusion point pediatric color the those priority review vouchers, if you look in the last probably 3 months have 3 to 6 months have sold anywhere from, let's say, $180 million to $200 million on -- now this is multiple sales. I think for us as an emerging biotech company, why that's important is -- if we are able to obtain the priority review voucher at the time of approval, that's now immediate nondilutive capital that comes in and allows us to fund the business, to fund the launch in a way that's really differentiated because most companies don't have that -- and so when we think about doing all the things that can help Steve enable an excellent launch and when we can think about funding the business within myositis and within the broader portfolio, that type of capital infusion really can come in.

Yes, for sure that's really meaningful. So in the last few minutes, I know we have several 1 programs to touch on. So we're going to pivot to reset SSC -- so you additionally announced plans to initiate the single-arm registrational study in systemic sclerosis in the fourth quarter, and you showed strong data at EULAR demonstrating durable responses through week 36 for that indication. Could you walk us through the key findings at EULAR and the decision to pursue SSE as the second resell registrational study?

Absolutely. So FSC is 1 of the highest burden in terms of mortality and morbidity for autoimmune diseases that exist in the landscape. I think you summarized it even nicely actually in terms of what the key findings were. The 1 point I would add on is that in systemic sclerosis, what we saw pretty consistently is that the responses actually seem to increase in magnitude over time as patients remain off all their disease-specific medications. So the data we saw at week 12 versus the data we saw at week 24 versus the data we saw at week 36. And then even if you extend it out a little further to week 52, those responses seem to be increasing in magnitude over time. And for us, that was an interesting finding consistent with the academic standard of care is with 52 week end points for the 2 approved drugs in the is, let's say, at week 36 on average or a median 7.5% improvement in FCC. And that can be hard to contextualize it just looks like numbers on a paper. But the 2 approved medications at week 52 in their registrational studies actually had FCC worsening in 1 at 52 weeks, and the other had FPC stabilization, which means from time 0 to week 52, there was either no change in FCC or the worsening was simply less than the worsening that you would have if you were not on that medication. Again, in contrast with reside, what we're seeing is an improvement of 7.5% at week 36 across the patients that were identified and that type of really unprecedented data across the field in terms of CAR-T enabling these sorts of outcomes is really what guided us 1 of the main things that guided us to enable the registrational design that you just mentioned briefly. For us, it's a 25-patient single-arm study with a 52-week FPC based endpoint in patients with ILD. And we think based on the Phase I/II data that's emerged that really sets us up really favorably for what the registrational study could be, which we expect to initiate -- just to repeat, all of that is after you discontinue all of your immunomodulators. There's not, I think, enough light shed on the outcomes that we are discussing about resi cell in those 50-some-odd patients. They're all in patients who frankly are no longer patients. That has not taken any medicines anymore. The vast majority of patients are no longer on any medication. And when we talk about other modalities or other categories of drug Remember, those are all on top of existing therapy with chronic administration of the new and probably very expensive therapy, right? So when you put it all together, the proposition for resi cell in autoimmune disease, I think, compares quite favorably on the safety and tolerability to frankly, any alternative modality any alternative therapeutic opportunity that you may have for these patients if they want to go off their medicines and they want to no longer be a patient. This is the 1 way you can get there -- and if I tell you that the primary side effect of resi cell is safety related to a fever that occurs day 7 to day 12 in that range. And about 1/3 of the patients -- last time we saw in ICANS was about 14 or 15 months ago. Now we may have 1 tomorrow, and we'll have them from time to time. But the risk of ICANS is we've dosed 50 or 60 patients in that period of time. This is not autologous CAR T of the past when it comes to the safety profile or when it comes to the value proposition. And then the flip side that we're not talking about today, but is our ability to industrialize and automate manufacturing and lower the cost of goods to among the lowest in the industry at launch, it's just something nobody has ever seen before. So I think it takes diving in to really explore each of these in order to understand the value proposition that is risk so.

Yes. Another, I think, key value proposition and data you showed at EULAR was around the no preconditioning program. And so for those unfamiliar, maybe could you explain why eliminating preconditioning could be such a key value proposition for patients.

Yes, absolutely. So what we've established with radical with preconditioning to start with, and this is in the 50-plus patients that Stephen just referenced that we presented is an ability to reliably see an immune system reset. And we actually, in the transitional Posttrong Saturday, to find what the immune system reset was both from a B-cell depletion perspective and a B-cell repopulation. I know we don't have enough time to go into it, but it really is the poster we're looking into because those parameters are going to be key as we look forward to evaluate how other modalities do or don't achieve in set and for us guiding our own efforts in the PC free regimen. So what did we share in PC free in the first 2 patients with lupus who were treated with the lowest dose of resicell without preconditioning we saw in 1 of those patients, they achieved essentially the hallmark of immune system reset from a depletion perspective. And we saw another -- the second patient achieved a decrease in peripheral B-cell depletion. And so overall, to us, what that demonstrated was similar to the patients that we reported in Pemphigus at that same lowest dose, we appear to be at a threshold dose where some patients respond -- some patients may respond, but not completely. And for us, with the safety profile offered up throughout this discussion, we believe really strongly that the opportunity to dose explore and find the optimal dose to achieve immune system reset and the subsequent clinical outcome for a sufficient number of patients to receive a PC free regimen is there in front of us, and we're already enrolling at the higher -- at the next higher dose cohort in both Tensigus and in lupus. So really encouraged by that data, really encouraged or the opportunity it can provide patients. And here, I do think it depends based on the indication of the disease. In lupus, I think what we can say is that the urgency to remove preconditioning is at an order higher than it may be in some of the other indications because of the demographics of patients that are affected. So by that, I mean most patients with lupus that are enrolled in our studies and across the field are women of child-bearing potential. And when you can eliminate preconditioning from the regimen and ideally achieve similar sorts of outcomes, especially from a translational perspective, that then can lead to clinical outcomes that are similar. We now have the opportunity to differentiate ourselves from really every other player that's in the field of lupus and again, really excited for that.

Yes. Now likewise, I agree. I think the potential to get preconditioning is huge for the field sort of in the last couple of minutes, could you just remind us of your cash runway and sort of how you're thinking about cash burn in the context of pivotal study expansion, expanding their programs and also commercial build-out as you potentially get ready for the first resell launch?

Yes, sure. So after the -- for those who aren't familiar, we recently completed a $150 million financing, which included many of our current investors, a number of new large mutual sovereign wealth funds and Eli Lilly among the investors from a corporate perspective. with that cash in addition to the cash on hand, brought us to about $0.25 billion of cash. That will take us well into 2027, and we expect that we'll be able to have in 2020 the delivery of our pivotal data on myositis. We'll begin to see enrollment in scleroderma we are not committing to specific time lines for presenting the preconditioning free data, the PC free data in lupus or in any other indication, partly because we recognize that this is incredibly important information and we are clearly leading the field. And frankly, from a competitive standpoint, we don't want to educate the world on what's going to work well in terms of dosing. The opportunity to break away from the field with regard to PC free is paramount. So the time line and nature of disclosure there is going to be more thoughtfully in created over time. That makes sense. I think that's a good place to end it.

Thank you so much to the team. Really appreciate your time. Thank you. Thank you Thanks, Mark. Appreciate it. Thanks, Great. Good.