All right, good afternoon, everyone, and, thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Altman, the biotech analyst here, and it's my pleasure to introduce, Steven Nichtberger, CEO of Cabaletta Bio, and just a reminder for everyone, the format for today is a fireside chat, so if anyone has a question, please feel free to raise your hand, and then we can add it into the discussion here, but before we get started, I just need to read a quick disclaimer. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." With that, Steven, thanks for joining us today. We really appreciate it. Maybe just as a first question, maybe high level, just talk about the strategy for Cabaletta and CAR-T.
Yeah, absolutely. So first, thanks for the invitation. Thanks for having us. Appreciate it. Thank you, guys, for being here at the end of the day. This started at 7:00 A.M. for a lot of you, so really appreciative that you're here. So Cabaletta, most of you probably know, autoimmune CAR-T has been and will continue to be the focus for the company. Developing and launching the first targeted curative cellular therapies for autoimmune patients was the reason we started the company in 2018 , and with that as our focus, we have relentlessly pursued that outcome. We've spent the past 2-2.5 years , focused on CABA-201 primarily.
The CABA-201 construct is a 4-1BB-containing CD19 CAR-T product, which is designed to be essentially the fully human equivalent of the construct that Professor Schett used, which really ignited the field. Back in 2022 , when we in-licensed CABA-201, it was designed, and to this day, I believe is the only construct that has been designed exclusively for use in autoimmune patients. We took the construct into the RESET clinical trial program by filing an IND for lupus first, because there was more data with lupus patients than there were with any other patient type. Once that IND was cleared, we then went forward, and two weeks after it was cleared, we filed an IND separately for myositis.
The reason we did that is through an exclusive translational research partnership with Professor Schett, we knew that myositis data was about to be published, demonstrating some pretty remarkable efficacy and safety. While we were doing that, we were preparing for an IND filing in scleroderma and subsequently in myasthenia gravis. So all of that has been done and cleared within 30 days by FDA using the starting dose, which we predicted would be the same as the dose that Professor Schett used, based on preclinical publications from two different laboratories that replicated each other in vitro and in vivo. The dose that Professor Schett used had the same activity as the dose that we are using, and therefore, we predicted, and FDA agreed, we don't need to do a dose-finding study.
We went into the clinical RESET program with one dose for all patients and every one of our indications in a separate IND. The reason we did that is because FDA, when asked, told us that if you file a bundle, a basket trial, one IND, and you do a basket trial, yes, it's better and easier and faster and cheaper for you and the clinical sites to get started on many indications, but the benefits of investing your time, your effort, and the money to have a separate IND for every one of the indications is that when and if you see side effects, they may well be very different between different patient types.
And similar to the Humira label, the largest drug in the world for a decade, similar to that label, which has many indications, some of them have a black box for patients in certain indications, but not in others. And so we could isolate the side effect to the indications. In a way, they were prescient because in our clinical data presented so far. And actually, let me take a step back. After we had the IND cleared and we pursued this different IND for every indication, and within each IND, each subtype of the disease in a separate cohort, we designed the program so that any six patients filling any one of those nine cohorts, so lupus or lupus nephritis, three forms of myositis, scleroderma with and without organ damage, and myasthenia gravis, acetylcholine-positive or not. That's nine cohorts that are currently enrolling.
Any one of those nine cohorts, after the sixth patient is enrolled using the same starting dose, any one of those cohorts, we can go back to FDA, and this is based on prior discussions with them, and we can propose a registrational pathway. Most, if not all, of our programs have Fast Track designations, so we have real-time access to FDA for advice, for counsel, for design of our programs. We expressly discussed with them in the lupus filing what phase III, what registrational program might look like as part of an extension of the lupus IND filing. We went back and forth one time, and then after the first back and forth, they said, "You know what?
Let's put this in the parking lot until you come back with safety data on your first six patients, and we will know more about what to tell you as, as far as guidance for your registrational study." And we said, "Well, we don't want to wait six months between six patients and phase III, and it could be just an extension of your current study. So can we come back to you in real time?" And they said, "Well, file Fast Track, and we'll have real-time access."
So we feel great about the prospects for both the design of our product, the fact that we're starting with what we believe to be the right dose, and the design of our clinical program, which really has incredible flexibility that I'll go into during our conversation today, allowing us to do things that are strategically really valuable, both for CABA-201 and for potentially future products that can be brought into this clinical trial construct. So that was the construct for the program. We then went about opening sites. So, it's now clear to everybody that it takes anywhere from 7- 12 months to open your first clinical site when an IND is cleared in autoimmune CAR-T. That's not our data, that's everybody's data in the field. That's how long it takes.
When you do that, you have to then get the second, the third, the fourth. We now have two years behind us. It's now, what, August or September of 2024. We in-licensed the molecule in October of 2022. The IND was cleared in March of 2023 or April of 2023. Here we are in September of 2024. Cabaletta has 24 open, actively enrolling clinical sites in, and this is really important, not investigator-initiated trials, not compassionate use investigators using our drug, but company-sponsored, IND-cleared clinical trials. That is how you get drugs approved in this country, and we have 24 sites that do exactly that. That number is up from 20 about four weeks ago, and it's not going to stop anytime soon. We've engaged with, I don't know, 75, 100, or more clinical sites for over a year and a half now.
We are way down the path of getting more and more clinical sites open. Why did we do that? Our Chief Medical Officer required 75 or more clinical sites globally to get approval for Saphnelo for lupus, a pharmaceutical product, and he also developed Benlysta, and it required a similar number of sites. Knowing that, as soon as we had the molecule and we said, "Well, anybody can develop a CD19 CAR-T. They won't have the same thing as Schett. They won't know Schett as well. They won't have the collaboration, but there's going to be a lot of players. Everybody's going to pivot, and the logjam is going to come at the clinical site, so here we are." We have 24 open clinical sites actively enrolling in company-sponsored, IND-cleared clinical studies. The next closest player in the United States, as of yesterday on ClinicalTrials.gov, is Bristol Myers Squibb.
They've been at this for two years now, longer than us. They have 15 U.S. clinical sites open and enrolling in their basket study. The next closest behind that on company-sponsored, IND-cleared clinical programs is Kyverna, with 6 in lupus nephritis and 2 in scleroderma. All of the other indications don't have open clinical sites yet. Collectively, all of the allogeneic companies, all of which are valued far more than we are, collectively, all of them have 10 clinical sites open in the United States. Just pause for a minute. Value creation comes from company-sponsored clinical trial data. I'm not sure how you create value when all of the allogeneic players in the country have a total of 10 clinical sites. So we think this is a completely strategic asset, this head start in clinical trial engagement with the sites.
We've heard from the sites that they are being approached by many companies, and they no longer have capacity for more cell therapies. It doesn't matter that apheresis isn't required. It doesn't matter that you don't use both forms of preconditioning. It doesn't matter the promise of what you're doing. I simply don't have the clinical trial nurse to work with you. So they can't get in the front door. I understand that earlier today, at least one of the companies focused themselves away from rheumatology. I don't know why, but rheumatology is really crowded, and if you're not already in the door, I don't think you're getting in very easily. So we feel really good about the prospects for the future. We said on August 10th, we have nine patients enrolled, and there was a hockey stick sort of movement. We had five patients enrolled after eight months.
We enrolled four more patients after we presented our initial clinical data, making nine as of August 10th. Although we're not going to continue to update real time with the numbers, I will say that it continues to accelerate in the last three weeks, and we feel really good about the prospects for enrollment. That's really important because when you think about, you know, the ability to create value, you've got to treat patients. And we are now in that moment where in any clinical trial, you start, and then eventually you take off, and we're at that moment. That acceleration of clinical trial sites in the last month or two and in enrollment has occurred after the most recent clinical data. So let's talk about the clinical data. Our first two patients were presented at EULAR.
Patient number one was a myositis patient. Patient number two was a lupus patient with a Grade 5, a Class V nephropathy. So the way a lupus trial is designed, typically, if you have Class V nephropathy, you cannot be in the lupus nephritis patient population because you can't possibly improve on your nephritis measurements. But you don't want to not treat all the other symptoms for that patient, so you put them into the lupus category in CD19 CAR-T land. So this is a patient whose kidneys are never going to get better. They couldn't even put them into the lupus nephritis protocol, but they're in the lupus protocol. The first patient, the myositis patient, demonstrated clinical, translational, and serologic markers that were nearly overlaid directly on the most similar patient from Professor Schett's experience. The safety was pristine, no CRS, no ICANS.
Some people even wondered whether the drug was working because there was not a hint of any side effect. In the lupus patient, the second one, we only had one month of follow-up. I'm sorry, I forgot to say in the myositis patient, at month two, we started to see naive B cells repopulate, no mature B cells to be found, flow cytometry demonstrated, we presented all immature B cells being developed. That was really the full promise delivered in that first patient. We need durability. We need to see more data. Of course, we do. Lupus, first patient, patient number two for us. That patient with their severe renal disease started with a SLEDAI of 22, and by the time we were at one month only, their SLEDAI was down to 10. A really dramatic reduction in their clinical profile.
We also had other markers that suggested all of the right T-cell accelerate, B-cell diminish, and so forth, but very early. Very limited data, very early. With that at EULAR, with that presentation at EULAR, we then went on to treat more patients, and the next patient treated was a lupus nephritis patient with either Grade 3 or Grade 4 nephropathy. And, this is a 24-year-old woman on 5-6 medications for lupus, like, all the heavy-hitting medications. They had run out of options and a very, I would say, active patient in activity in sense of disease. So the patient enrolled, they were waiting for their cells to be returned to them. They had another exacerbation requiring hospitalization. That hospitalization was for acute pericarditis. It was within maybe 10 days before they were treated.
The patient was discharged after steroid treatment. They clinically resolved and looked very much at baseline. What we have since seen is that their cytokine profile put them at exceptional risk for CRS, for ICANS, and their cytokine profile is something we will publish in due course as we get the full story of safety and efficacy on this patient. But the biologic patient was not as calm as the clinical patient in that situation. So, we took this patient who had Grade 4 ICANS. They were treated, they went home after four days fine, came back with fever on day nine, I think it was. By the next, they were admitted out of just, you know, precaution. And following the fever, they had a diminished mental status slightly.
They were transferred into a neurologic monitoring unit where the brainwaves are monitored, and they found that the patient, although no evidence of any kind of movement, they found that the patient had seizures. Their brain was not functioning properly. Their mental status declined as the seizures continued. They treated these seizures, which are not uncommon within the context of ICANS. They treated it with a routine ICANS regimen for such a patient, and rapidly, the patient's mental status reversed completely, and they were discharged a matter of days later. They went home, and their issue with the ICANS event was fully resolved, so of course, you know, we saw that, and until we understood what happened over the coming weeks, we needed to figure it out, so we actually just quieted, disappeared from the conversations with investors, with anybody.
We really needed to figure out what was going on because this was a surprise to us. What we learned subsequently is the biologic patient was not as calm as the clinical patient appeared to be. Having a recent acute inflammatory or acute infectious event puts you at risk for being activated and for responding in a hyperinflammatory way to the T cell infusion that you would be giving. So you need to put more space between such an event and the infusion of cells. You also might want to give seizure prophylaxis, and there's been a lot of, you know, mention of this in the investment community and so forth. So, for clarity, based on long-standing conversations, as well as confirmatory conversations last week with Professor Schett, he has confirmed for us on all occasions that every patient he has treated at Erlangen received Keppra prophylactically.
It is part of their institutional guidelines for all CAR-T patients to get such therapy, and it's just part of the regimen. He always questioned, he said last week, "Why we use it? There's not a lot of clinical evidence that it should be used, and we just use it because it doesn't really cost much, and it doesn't really have side effects that are meaningful. So, like, why not use it and prevent seizures?" Having heard about our event, he said, "Now, I'm definitely going to be using it in all of my CAR-T patients. Why not?" It's not that there's something different or unusual about CABA-201, it's that we are learning, as Carl June said to me after we were discussing this case in the light of day, this is how you learn. You do early studies.
You treat a patient who, more than any patient we have treated, needed our therapy. And if she is fully cured, I bet she will be a grateful patient, very grateful, to be off all of her medicines and to have no symptoms. But to get there, we got to do it with less risk. So maybe we treat with IL-6 prophylaxis in the industry for patients who have a hyperinflammatory event, recent, you know, in the recent time prior to infusion. Maybe we also give seizure prophylaxis. Maybe we have them stay inpatient longer. There's a lot of things you can do, but you have to treat patients like this. You can't carve them out of your program, and it's why you do the early studies.
None of the next five patients that we had slated for treatment were, I would say, hyperinflammatory or having active disease in that way across all of our program, and, you know, we're on the lookout for this now, so we feel pretty good about the prospects. Until we publish the data, you know, this is just the company talking. What matters more is, what did those who are in a position to see all the data do, so the DSMB said, "Keep going. No need to change anything at all in your protocol." We said, "Well, wait a minute, can we add some seizure prophylaxis?
Because Schett did it, and seizure was the proximate cause of the mental status change." And they said, "Yeah, if you want to, go ahead." So we proposed that to FDA along with all of the data, and we said, "We're not going to change anything in the not the dose, not the timing, not the number of patients, nothing." And FDA, in a way that is routine, received the information and offered no comment. That was over a month ago. We then went to each and every one of the 20 investigators we had at the time, and we said, "Here's a new event. You need to reconsent any enrolled patient who has not yet been treated, and if they want to pull out of the study, we should. You know, and if you want to pull out of the study, you should pull out of the study."
Not a single one did that. Moreover, enrollment has picked up even from the optimistic view that we offered on August 10th, and the number of sites opening has accelerated, even though we had this event. So the behavior of everybody who knows what the data really show and has had the opportunity to see the data tells you more than I can possibly tell you. So we're really excited about the prospect that after years of getting this into position, the foundation is now set for Cabaletta to deliver, number one, meaningful clinical data that you can assess and risk, evaluate CABA-201 for what it can do for patients across a portfolio of indications later this year.
In enough patients, I think, that and with clarity of presentation of the data as we historically have been known to do, that you'll be able to decide and risk assess the molecule and the company. Number two, to enroll rapidly. I don't know how many patients we'll enroll by the end of the year, but I guarantee you that nobody is going to enroll more U.S. patients in FDA-cleared, company-sponsored trials for CAR-T therapy and autoimmunity than us. It's just a result of having more sites and having a very highly functioning team and machine that's already doing a great job, so enrollment pace matters a lot, and we're going to continue at pace.
Remember that when we get the sixth patient enrolled in any one indication, we're going to talk to FDA, not about designing a trial that we then have to implement, but about in certain parts of our indication portfolio, adding 15 or 20 patients to the already treated six in order to get FDA approval, we would propose, for certain of these indications where the population's only a few thousand, similar to Luxturna, which was developed by Spark, with 16 patients giving them first-ever gene therapy approval. Not unreasonable to think that a couple dozen patients gets you across the finish line with certain forms of myositis where no therapy works. Juvenile myositis, there's nothing, and these kids are pulled out of their social life, their school life, and permanently harmed by the disease in a life-altering way.
The enthusiasm of the investigators and the patients in those indications is not exceeded by any other indication. And so we're really excited and have been for two years now about myositis as an indication. We think we'll compete as well as anybody with lupus patients because of the number of sites we have, and you know, all the others will fill in. So by next year, we hope that we will be in a position where we can present even more robust data, six- and nine-month follow-up on a lot of patients, and allow ourselves the opportunity to then reveal the full manufacturing strategy, the ability to scale potentially based on innovations in-house and with Cellares. And finally, to deliver on what I think is the most important trial in the CD19 targeting cell therapy universe.
That is the pemphigus trial with CABA-201, no preconditioning. The reason we're doing that trial is, number one, Cabaletta demonstrated to ourselves, to our own satisfaction, that CABA-201 is effective with preconditioning. As soon as we saw that, we filed CABA-201 as a sub-study in the 10 clinical sites that are already open for pemphigus with our legacy portfolio program. There's 10 open sites. We know the investigators, the contracts are done, the budgets, everything is done. We just want to add a sub-study to the already existing pemphigus program. FDA said yes four months ago, not 9-12 months, which is the typical time it takes to open your first site. Four months later, the first site for that program is open. The second site is going to open within weeks, and the third is going to open within weeks as well.
That program is going to start treating patients. We'll start with the usual dose of CABA-201. We'll then go to a higher dose, one that FDA has approved for all of our clinical program because they believe in our safety profile based on our filings and our IND, our IND data. If that is positive, if it shows us T-cell expansion and B-cell elimination in the first month, and antibody reductions of the sort that we've all come used to, that's a game changer, because our clinical trial program is designed such that we can instantly put a new arm in every one of our nine programs without preconditioning. I wouldn't launch without preconditioning because I don't know if it's durable.
But if we can go without preconditioning and you're a patient, ask yourself, would you prefer to have somebody else's cells tomorrow, 'cause it's off the shelf, and it might be cheaper for you, with preconditioning, that is chemotherapy, or would you like to wait a month and have your own cells give you your cure with no preconditioning? So it's a complete game changer for the field. We think it might work for a number of reasons. The most important of which is a 2019 paper from one of our scientific founders, demonstrating that if you go after, BCMA-targeted cancer therapy with a normal dose of BCMA CAR-T and preconditioning, the outcomes, the activity of the product is the same when you just increase the dose, but don't use preconditioning.
You don't do that in cancer because you can't increase the dose of cells. It's too risky. But if you have the sort of safety profile that I believe we will demonstrate in the first 5- 10 patients, and I, I acknowledge, I can't tell you for sure that's true until I have more data. The ICANS event is a stain that we have to prove against. But once we do that, we already have the approval to move to higher doses, and we are moving to that and then higher doses. If we have the efficacy and activity in that program, it just changes everything.
So I'll, I'll pause there at eight minutes left in this discussion and give you a chance to answer the second question. Right before we started, he said, "Look, just go and pause for a question if you want, but it's late. I don't want to ask questions.
No, it was great. You covered a lot of stuff. Maybe just to follow up on, and you mentioned this, just presenting some updated data in the second half of this year. Maybe just talk a little bit more about, you know, how you're thinking about a venue, number of patients-
Yeah?
Kind of level of follow-up .
So, we expect to be able to present data, robust data on lupus and myositis patients. Robust being, you know, we said we had nine patients enrolled on August 10th. We were actively manufacturing five patients simultaneously. That gives you a sense of the capacity of the company to manufacture at this moment. And so doing five patients at once, if you manufacture, you have to finish the manufacturing, you have to send the cells to the site, the site has to schedule the infusion, there has to be preconditioning before they infuse. And you can begin to think that one-month data by November, December, that timeframe in five, six, I don't know how many patients, it all depends on scheduling.
We should be able to have six, seven, I don't know, patients worth of data at one month, some at three months, and some at even six months of follow-up from the original patients treated, the first three patients treated. So that cohort of patients, you know, total, will be presented in the third or fourth quarter. The more we wait, the more we can present. We hope also to present data on scleroderma, the first patient, myasthenia gravis, the first patient, and we say by the end of the year, as most companies, for us, that includes at JP Morgan, right?
Because the last couple of weeks of the year, not so much, but in that timeframe, we would expect to present a pretty a very robust data set, hopefully at a medical meeting, but maybe even follow up in the January timeframe, allowing for just more mature data to be presented, as well as an update on the number of sites, the number of patients enrolled, and perhaps expectations for when we will have a cohort of six and discussions with FDA about moving into registrational designs using our existing cohorts, not starting new trials.
Great. Maybe just, manufacturing, you know, some of the innovation-
Yeah?
Y you're doing there and just kind of the current status of your supply and plans.
So on manufacturing, we have a core strategy, which is really driven by the simple concept, never let manufacturing get in the way of clinical path. Having capacity from University of Pennsylvania, WuXi, and Lonza allows us to believe that not only in the U.S., but as well in Europe, we should be in a position to deliver drug to patient, clinically and then commercially. On the innovative side, we've already presented at ASGCT the opportunity to get rid of the apheresis. Just do a blood draw of a normal sort, maybe close to 8- 10 tubes of blood instead of 5 that you normally would take for the blood test that you might get annually.
And in the lab, you take that blood and you send it back, and we've demonstrated that we can create CABA-201 from that blood draw equally as well as from an apheresis product. We are generating more data in more types of patients to see how robust our process is, to confirm that it's as robust as we believe, and then to bring it into at least one of the nine arms of our program initially, not putting at risk the lead program. In addition to eliminating apheresis, which has benefits that you can, I think, think about relative to all other therapies, we've also partnered with Cellares on the manufacturing side. Our technology assessment program started in October, I think, of 2023 . We were just behind Bristol Myers Squibb in their technology assessment agreement.
Bristol has now signed a $380 million deal with Cellares to manufacture clinical and commercial supply. More recently, Gilead has partnered with Cellares to do a technology assessment program, the sort of thing that we initiated a year ago. We're at the tail end of our technology assessment program. We recently expanded to our next phase of partnership with them. The phase after that will be engineering runs and clinical commercial supply agreements. The reason that we're excited, and frankly, I think the industry is excited about the promise of Cellares, is that they promise, with their fully automated closed system, to eliminate the need for a company like us to invest in fixed bricks and mortar.
They eliminate the need for us to hire the hundreds of people required to manufacture and to do quality on the manufactured product. It changes the entire financial profile of any model that any partner or any investor would be doing on Cabaletta. The amount of capital we need to build this business, all of those fixed costs that historically have been an albatross for autologous CAR-T, are suddenly converted into a variable cost that is not incurred until the patient order is in and their cells are ready to manufacture. Because that variable cost goes towards these disposable cassettes that they sell, that replace the need for all the hands and all the bricks and mortar that you might have invested previously in, in autologous manufacturing. So there's a really important strategic benefit to the approach that Cellares offers, especially for a company like ours.
So excited that we jumped on that bandwagon very early and looking forward to seeing if we are able to confirm the full integrated use of their system as an equivalent to what we currently do. And for us, it's got to be an equivalent. There's not a new IND here in our minds. It's got to be comparable to the point where regulators would agree that they are interchangeable, and we can shift our program over to using the Cellares system without starting new trials, without a new IND.
Great. Looks like we're just about out of time. Why don't we end it there? Thanks so much, Steven.
Thank you.
Appreciate your time.
Appreciate you.