Morning, everyone. Thank you for attending Jefferies Global Healthcare Conference. My name is Kelly Xu, one of the equity analysts on the BioTech team. We are very pleased to have Steven Elleman, CEO of Cabaletta Bio, join us today for this fireside chat session. Welcome, Steven.
Thanks. Thanks for having me.
Maybe we can start a question with the great news from Cabaletta. You've aligned with the FDA on the registrational trial design for Resocel. You might cite us. Could you share more details about your meeting with the regulatory agency? Specifically, what kind of efficacy data do you believe could potentially support accelerated approval?
Wow. Yeah, we were thrilled last month to announce that we've met with the FDA, received minutes from that meeting confirming our understandings, which are in that press release that we announced the alignment with the FDA. Myositis, as a target, as an indication, has a validated clinical endpoint called the TISS score. Our primary endpoint in that program is going to be the TISS score in a composite. The TISS score was used for IVIG approval in dermatomyositis. We've chosen to use the exact same TISS score, if you will, plus another component that makes it a composite and makes it even more rigorous than simply achieving the TISS score.
Because of that endpoint, as it was proposed, and because the endpoint in the composite form we proposed almost never occurs in nature or with current therapies, we were able to agree on the statistical design of our clinical program for registration. That design entails treatment of, in an open label, cohort, not a brand new trial, but added to our existing myositis, RESET myositis program, a new cohort, which will have up to 15 patients approximately, and which will use the primary endpoint that I've described, will enroll patients who are refractory to other forms of therapy and who still have exacerbations of disease, will follow them for something less than 26 weeks in order to see if we can achieve the primary endpoint that I've described. In 2022, we said we were going to use one dose, and we wouldn't need to do dose finding.
That promise has now been delivered on. We will be using the same dose we have always used. We said that we would not have to start new clinical studies because our RESET program has individual INDs for each indication with homogeneous sets of data. Indeed, we are not starting a new phase three trial. We simply have to add a cohort to an ongoing study, which is opened at more than a dozen clinical sites for myositis alone. In addition, we proposed two cohorts, not one, for our registrational program. Either one of these two can be filed independent of the other for a BLA. One cohort has the ASyS and the dermatomyositis subtypes of myositis. That represents about 85% of all myositis patients. In both of those cases, we see two things that are similar.
The pathophysiology of disease is the same, very similar, I would say, not the same, but very similar. The response to Resocel is very similar. In other words, a maximum response, as we've previously presented data, achieved at 29 days and persisting over time. For that reason, we put those two together in one cohort. The necrotizing form, the IMNM subtype, about 15% of patients in myositis, they have a mild, a minimal response, it's called, on the TISS scale. Because of that, we put them in their own cohort. You would think, as a CEO, as an investor, as a company, we would say, it's only a mild response, and why do it? Really, does it matter? It turns out that cohort is enrolling as fast as any cohort we have across the 13 cohorts that we're currently enrolling in autoimmune diseases.
The unmet need is profound because the muscles are necrotizing in that subtype. Time is muscle. Patients and physicians know it. We are seeing the results of that being the enrollment. We are really thrilled that we have these two cohorts. Each has a slightly different endpoint on the TISS scale. They both are composite endpoint, which, again, contains this validated TISS. We are thrilled with the opportunity to start up both of these cohorts in the second half of this year.
Fantastic. Do you expect FDA could also allow a similar trial design for the registrational study in SLE lupus, maybe also other autoimmune indications? In another word, what are the key learnings from this FDA communication in terms of thinking about, I mean, grounding accelerated paths? What are the key factors for this decision? Is it disease severity and all the available therapies for that indication, or you're selecting the patient by CAR-T?
Yeah, it's a great question. It's all of the above. In order to do what we're doing in these two cohorts with 15 patients in each cohort, approximately, we had to have a safety database. Although we have 13 cohorts and six INDs, the truth is that the safety data is collected similarly across the entire RESET clinical program. We've agreed with the FDA that while we will have about 35 or more patients with myositis-specific data using the same dosing regimen, the same way to collect the data in the same clinical program, we will have 100 or more patients in our safety filing, along with the 15 in each of the two cohorts.
Number one, you have to set up your clinical program in a way that you can use the data to inform the more specific efficacy outcomes that are easily achieved when you're talking about functionally curative therapies, right? When we formed the program and designed it, we knew that efficacy could be proven with only a few patients, but that safety would require far more, thus the design of the RESET clinical trial program. The implications for the industry, I think it's all going to be data-driven. I think that having listened to the NORD presentation from the CBER director yesterday, I think it's clear.
If you have functionally curative therapy, the FDA wants to figure out how to partner with you to safely develop and deliver that with real clinical data, not surrogate markers, not new fanciful things, but real hard data, and in a very efficient way. I think that's becoming clearer from their public statements. We will learn more tomorrow morning at the gene and cell therapy briefing from the FDA that's scheduled, as well as the listening sessions that are being scheduled.
Very informative. Maybe let's look at a couple to one. Now you have named Resocel's data achieved to date. Maybe at a higher level, firstly, since the pioneer work from Dr. Chang, over 100 patients have been treated with CAR-T cell therapies across different autoimmune indications. Efficacy seems like variable across different programs sponsored by industry, by companies. In your view, what drives this variability? Is this the disease heterogeneity or different patient baseline, or even the CAR-T efficiency, the transduction efficiency? Does this data variability worry you?
No, it doesn't worry me because we have individual cohorts of patients that are homogeneous where we have excellent, outstanding clarity as to the efficacy and the safety by patient type and by patient subtype. Within myositis, the example of that would be ASyS and DM. They respond similarly. We know how to develop each one. IMNM responds differentially. I wouldn't want to mix those two into a single trial, for example. Generating clinical data requires great care, as we all know. I think that there's been a gold rush of sorts into the CD19 targeting landscape. Unfortunately for everybody, honestly, there are 35 cell therapies currently IND cleared for the treatment of lupus. Every autoimmune disease requires its own indication. Payers are not going to pay for anybody's autoimmune therapy for any disease unless there's data.
In fact, the inclusion-exclusion criteria, the actual data will matter. Knowing that, we designed our programs to allow for that kind of clarity. I do think there are major safety and tolerability differences between the programs. I want to highlight that with Resocel, we replicated what Professor Chang did by using a fully human equivalent of his binder, but more importantly, much more importantly, we used a 41BB COSTIM domain, which nearly everybody in the industry has chosen to use for its safety characteristics. Much more important than all of that is something we have not said very loudly until now. We are the only company in the industry that is using weight-adjusted dosing.
If we look at our safety data that I would say are thrilled to present at EULAR in three oral presentations, one for myositis, one for lupus, and one for scleroderma, you will see in that clinical data the results of weight-based dosing, particularly in myositis patients where you do not have complicated organ system failure as you might in lupus nephritis, for example, or as you might with interstitial lung disease and cardiovascular involvement in scleroderma. Every patient, I think, is becoming clearer for us, every patient type is going to have a different risk profile when CD19 CAR-T is administered.
If it's administered in a weight-adjusted or a weight-based dosing regimen, we believe that that is one of the reasons why we have said for a very long time, and we will continue to say until the data persuade us otherwise, that we believe Resocel will be as safe as any therapeutic approach to the treatment of, in the first case, Myositis. Let's let the data speak for itself as we present it at EULAR. The efficacy differential could be a bit about the dose that was given. There was a patient who was given only half of the currently administered dose from a different company. In this, from what I understand, relatively obese patient, they really never had a response to treatment because the dose was too low. It was a dose-finding study, as I understand it. It was understood.
Very, very rarely do you give a CD19 CAR-T and avoid seeing efficacy. It's sort of profound how effective this category of autologous CAR-T is for the treatment of autoimmune patients. The differentiator, I think, Kelly, is going to be in safety and in the quality and the simplicity of administration.
Fantastic. Maybe regarding the treatment goal, especially efficacy, Dr. Chang actually outlined three pillars for evaluating the success for CAR-T in lupus at last year's ACR. The first one is preservation of kidney function. The second is decrease in SLEDAI score or achieving DORIS remission. The third, reduction or elimination of immunosuppressants use. Does this align with your learnings from your trial experience? Also, how do we think about quantitatively on the SLEDAI and the DORIS remission for a CAR-T product to be commercially viable in the future?
Yeah. It is profoundly clear to us. Patients do not want to be patients anymore. For that to happen, they have to stop all their medicines, the immunosuppressants and the steroids, and they have to eliminate all of their symptoms. That is the number one driver for patients. There is no doubt. That is achieved if you achieve DORIS remission, which, using today's standard of care in today's phase three programs that were approved into products to treat lupus, occurs about 15% of the time with full maximum treatment. If you can do that in 85%, 90%, 100% of the patients that you administer a CAR-T product to and do it off of medications, because with all of the therapies out there, you require continued medication. If you can do this and do it off of medicines, patients will have their nirvana. That is the dream. That is the Holy Grail for patients.
For physicians, it's a little bit different. For physicians, they want organ protection. They would prefer, if you gave them these choices, they would say the number one, and we've done the research, they want complete renal response. The patients want to be off medicines and feel good. Both are important. How you design your phase three program and how you deliver on the promise should be, in my opinion, driven by what physicians and patients want and ultimately what payers need. Your question earlier was, will the myositis achievement of agreement and alignment with 15 patients in existing cohorts at the current dose be repeated with the other indications? All of it is going to be data-driven for us. The objective was to be the first out in each of the indications that we are pursuing. Where it is most compelling would be the priority.
You'll remember we filed our first IND in lupus, but that is not and never was. We said two, three years ago, myositis is the path to victory for Cabaletta. That is more true today than ever. Although lupus is the third quarter regulatory alignment, it may or may not be the second product we bring into phase three cohorts. I do believe that we have now agreed with the FDA on use of the entire safety database. We have agreed on the proper dosing of Resocel. We've agreed on the ability to insert new arms into our ongoing trials.
Many of the things have been de-risked for the other programs, but the exact nature of the program is going to be determined by the clinical data we see in phase I and II trials and the nature of the disease, as well as the existing therapeutic options, right? All of that will come into play. I think that scleroderma, where we are also seeing remarkable levels of enrollment, and most recently on May 9th, we said we were enrolling one or more per week, we are continuing to see acceleration, meaningful acceleration as data starts to come back to the physicians who are treating and enrolling patients. We're seeing meaningful acceleration where the data is really compelling and safe, I think. Let's see the data at EULAR, and you'll all be the judge of that, but thrilled with the enrollment in scleroderma.
The unmet need is very profound. The data, I think, are equally profound. That may turn out to be a similarly sized and rapid path to approval, pending our data and pending the FDA's agreement with it.
Talking about data, you have three presentations at EULAR next week. Could you give us some expectation in terms of number of patients, follow-up time, and how much information we can get on efficacy safety front from EULAR?
Yeah. So we are now in the, for those of you who have talked to us over time, for the last year, we've been talking about a hockey stick phase, a flywheel phase. We're in that flywheel right now. There are days when two patients are dosed. There are weeks when three patients are being enrolled. There are also weeks where zero might enroll. It's not like a flat line of constant. So it's variable. But it is no doubt increasing on number of patients enrolled per week, per month. The data at EULAR will include 18 patients who have been dosed and followed for at least one month. That's the primary endpoint in our phase one and two program is the safety data at one month. The longest follow-up that we will present is just over one year. The shortest, I think, just over four weeks.
The expectations that I'd like to offer, or not so much expectations as recommendations, first and foremost, evaluate the safety of the drug by indication. Look at myositis, look at lupus, look at scleroderma. They're all easily understood. Then look at the efficacy and ask yourself if the patient is getting what they need, that is to say, off of all their medicines for the first time since they were diagnosed, and actually with either no symptoms or stabilized disease to set expectations for all of CD19 product administrations, in my opinion, for scleroderma. In scleroderma, we have seen in the academic data the beginning of regression of the disease. We have some really interesting data in scleroderma that will be presented as well as across the board in myositis. And you'll see the data in myositis that allowed us to reach alignment with the FDA.
I want to be really clear on this point. We highlighted in a separate section of our submission, and we discussed at great length the single case of ICANS grade four in a lupus nephritis patient, which occurred a little over a year ago. We have previously shown data showing that this patient has reached a complete response, is on no medicines, is a year out or so, and has, in our corporate presentation, we have included her quote, "She would like to have Resocel again if she needs it." That is our worst side effect. What we presented on that patient and what we shared with the FDA, we presented, I believe it was at ACR, if I am not mistaken, last year.
What we presented was the evidence that through T cell receptor sequencing, the Resocel concentration in the patient, the T cells that expanded, did not expand due to the presence of Resocel. The T cell clone that was seen to expand was driven, we think, by an occult unrecognized infection, which was reacted to by the T cell population that was recognizing that infection. Part of the cells had our CAR in it, and we were just along for the ride. Once our cells expanded, once the cells expanded with Resocel in them, the concentration of our binder was present, and it caused toxicity. We believe that is a really unusual and unique situation. We do not believe it is due to the drug. We do not believe it is due to some unusual characteristic of the product.
Only more and more data is going to show over time that this scientific data and the conclusions that our scientists and others have reached around it is the truth. At the end of the day, though, the FDA agreed with our assessment and allowed us 100 patients total of safety data in the autoimmune space to seek BLA approval for myositis. That's sort of the fullness of the data you'll see at EULAR is an awful lot of safety and efficacy in myositis, some in lupus, and in scleroderma.
Great. Maybe safety, what kind of a safety profile would be viewed ideal for Resocel across different indications? Maybe put it at a higher level, there was a theory that physicians are going to be, patients are going to be very stringent on safety front for autoimmune disease versus oncology, despite the disease severity is also very high in certain populations. As the industry actually accumulated data over the last year, how do you think doctors treating autoimmune disease, like for example, rheumatologists consider the risk-reward for CAR-T? What's the change from last year to this year?
Yeah. I think clinical data wins, period. We are seeing acceleration in the number of sites, right? We now have, last we said publicly, I think it was 62 or 64 sites. It changes literally every week. Our enrollment last we said was 43 or 44, if I recall. Doctors and patients are showing up because they see what they see. They see the clinical data. They have the personal experience now of using the product. I think at the end of the day, it is clinical data followed by the reaction of sites to open with Resocel. After that ICANS event, which is now thoroughly discussed with every site as it was with the FDA, they open up for Resocel, not for the other 35 CD19-directed products that are being developed, but for Resocel.
I think it all comes down to the ability to execute reliably as a trusted partner for the clinicians. I think their brand choice is going to center not on efficacy, because I think everybody's going to have durable efficacy. It seems like you cannot escape that with autologous CAR-T. I think it's going to revolve around safety. We've always thought that. Now we're going to start to show the data at EULAR to support the thesis that Resocel was designed as the only product that is fully designed and developed for an autoimmune population and has been developed in accordance with the need to be the safest product. To seek to achieve that, we're using the weight-adjusted dosing as one of many strategies to make sure we have the ability to deliver on that promise.
I think safety is going to be paramount for the rheumatologist, the neurologist, but there are two audiences here, at least. There are probably three or four. One is the rheum neuroderm who refers the patient. When they refer, you can be sure we are educating them to understand that not all CD19-directed products are created equal, and you should care a lot about what your patient is going to go through. The simplicity of the approach, the safety data behind the product, those matter an awful lot. The person who administers therapy doesn't want one CAR-T for each indication. They and the hospital administrators want one CAR-T for all autoimmune indications. The position that we've put ourselves in by filing a separate IND for every indication, no doubt we were later to the party of initial clinical data as a result.
We knew that was a cost we would have to pay. Now we're in a position to literally accelerate our lead across the portfolio of indications, making us, we hope, the preferred CD19 CAR-T for all of these indications, because the combination of myositis, scleroderma, lupus, myasthenia gravis, and so forth, all in one product makes it an easy decision for the P&T committee.
Fantastic. Maybe lastly, what are the key catalysts and milestones we should look for in the next 12 months? Also, how many patients you target to enroll across all the indications maybe after 12 months?
Wow. We haven't given a forecast, and I can tell you this on enrollment. I looked at it yesterday. We are exceeding our most aggressive forecast right now. That forecast was developed maybe a month ago, two months ago. I don't believe that safety data is going to be the rate-limiting step. Very importantly, when you talk about milestones, it's just like every week or month, there's going to be some other clinical regulatory milestone, right? As we come into the second half of the year, after EULAR, three oral presentations, we then go to the third quarter, regulatory alignment with lupus and lupus nephritis with the FDA. Fourth quarter, regulatory alignment on scleroderma. We haven't yet talked about 2027, but you can imagine what comes next in that line item.
In terms of clinical data, we'll continue to provide updates as warranted at medical and scientific meetings, but we absolutely expect in the second half of this year to have the data in-house and by JPMorgan or early next year to be in a position to potentially present the full cohort of myositis patients as it will read against the actual endpoint that we will by then reveal in great detail. We will be able to say, using the same drug at the same clinical sites with essentially the same protocol, administered by the same doctors in the same way, whether or not the data meets the endpoint. We are, of course, designing the trial with the opportunity to know what we see in our phase I and II program and to design it. In this case, we're using something on the order of a 50% failure rate.
We're making the assumption that half the patients don't respond. The assumption that we need 15 patients assumes that about half do not respond, do not hit the endpoint. I don't think that's going to be the case. If it's not the case, we have alignment with the FDA that when the trial becomes impossible to fail because we have enough patients who have responded, at that moment, we can cut the data and submit for BLA filing. At every turn, our team has tried to consider what needs to be true to make this a reality, this very hyper-fast path to approval, to replicate it across the programs, and then to deliver one after the next on the regulatory pathways, the clinical data, right?
I described the myocytes, but the same thing will happen potentially in lupus, the same thing potentially in all of the indications as we go through the next quarters and as the data matures. That is sort of the key bread and butter. On top, the icing on top of the cake, the cherry on top of the cake is we continue to work diligently and in a terrific partnership with Solaris. While our administration of therapy to myositis patients can potentially eliminate the use of IVIG, a $500,000 a year cost, and there is a lot of value and pricing opportunity, getting the cost of goods to be cut in half potentially, as Solaris describes it, and scaling tenfold greater than we can in a manual process in manufacturing is a real upside.
We will start to hopefully bring that to the clinic at some point in the foreseeable future going into 2027. Finally, we have data on a no preconditioning cohort. We have already started dosing, and we will be in a position later this year to present information on the pemphigus patients dosed with Resocel at various doses, but without preconditioning. That could be a game changer for everybody. That is our story.
We are right on time. This is a truly exciting time for Cabaletta, thanks again, Steven, for great discussion as always.