Good morning everyone. Welcome to day two of the Wells Fargo Healthcare Conference. My name is Derek Archila. I'm one of the senior biotech analysts here at Wells. For the first fireside chat this morning, we have Cabaletta, and from the company, we have the President, CEO, and Co-founder, Steven Nichtberger. Steven, thanks for joining us.
Yeah, thanks for inviting. Appreciate it.
Yeah, of course. So maybe just to start us off, you know, kind of just give us the high level of the company and what you're working on, and the n we can go through some of the program updates for CABA-201 afterwards.
Great. So, thanks everybody for joining nice and early in the morning. So Cabaletta was formed in 2018 with a sole focus on autoimmune cell therapy. Our belief was that cell therapy can be curative for patients with autoimmune diseases, and we launched on an initial platform that was a more specific and focused form of CAR- T therapy for patients with autoimmune diseases. That platform is known as the CAART platform, C-A-A-R-T platform. And around 2021 , the initial clinical evidence appeared, was published by Georg Schett, demonstrating that CD19 CAR- T was actually safe in patients with autoimmune disease or in a patient with autoimmune disease. And that prompted us to act on our long-standing curiosity about CD19 CAR- T as an option.
We then proceeded to identify the fully human equivalent of what he was using. He was using a murine targeting domain, CD19 CAR- T, and we in-licensed. In October of 2022 we in-licensed the CABA-201 binding domain. And that domain had been used as part of a cancer CAR, in a tandem CAR, CD19, CD22, and in the 20-some odd patients treated, it had an exceptional safety profile with, in those 20 patients, majority of the patients had either no or grade one CRS. There was no grade three or four CRS, and there was no ICANS at all in those 20 patients.
Based on that safety profile and the fact that it had comparable binding characteristics as the Schett targeting domain in vivo and in vitro, we decided to in-license and build CABA-201, which is a 4-1BB containing CD19 CAR- T product, which I think to this day is the only CD19 CAR- T product that was exclusively designed, built, and directed only towards autoimmune patients.
Got it. All right. So, yeah, maybe you can provide an update. You had, you know, some initial data from CABA-201, and then also, you know, recent update in terms of some ICANS seen, you know, from your program. So maybe can you just kinda put into context what we've seen and you know, where we're going from here?
Yeah. So, CABA-201 program, maybe I'll start just by, for those who aren't familiar, sketching out the program and then get into the recent data updates. So, when we built CABA-201 and filed it with FDA, initially, we asked them, "Should we file the many different indications under one IND or under many different INDs?" And, their guidance was really prescient and clear. They said, "Because you could do it either way, and it'll be faster and easier for the sites, the clinical sites, if you file it as a single IND and just run a basket study.
But it will be more pure from a clinical data perspective to have a different IND for each one of your cohorts of patients." And one of the important rationale that they provided was, that you're gonna have different safety profiles in different types of patients. And they almost literally presciently said, "In a lupus nephritis patient, you may have substantially more side effects than in a scleroderma patient or a myositis patient, and you want to be able to isolate those side effects to those patients." And, the comparable would be the HUMIRA label. Many different indications. Some of them warrant black box warnings, some of them don't.
Some of them have different side effect profiles from others, and in the ability to speak to physicians and patients about your product, you wanna be able to tell them about your product when used in their patient types". So we followed their guidance, and we were the first in the industry, others have since followed, to file a different IND for every indication. That meant, probably six times more work for our team, for clinical startup in clinical sites and time and money. So we were the last to provide any clinical data, but we have built a remarkable foundation of a clinical program that now gives us this remarkable flexibility going forward, and I'll talk to that in a few minutes.
So we have nine different cohorts within four clinical studies, and those four clinical studies are directed at myositis, lupus, scleroderma, and myasthenia gravis. Within those four studies, as I said, nine different cohorts. So lupus and lupus nephritis, three forms of myositis, antibody-defined, scleroderma with and without organ involvement, and myasthenia gravis, acetylcholine or not. So very broad program in these four trials that are all actively enrolling across the US. The other choice we made in building the program out, as I come to tell you about the recent data, is that we decided that we are not going to take our eye off the ball. For us, the first slide in our corporate slide deck has always been to develop and launch the first targeted curative cellular therapies for patients with autoimmune diseases.
So when we asked ourselves, should we go into investigator-initiated trials and get clinical data into our hands and investors' hands as quickly as possible, because after all, that's what really matters, the answer for us was no. We should focus on getting to launch first. And launching requires that you file INDs, that you spend. All companies experience the same timelines, 7 to 12 months to open your first site, and then another two years, it appears, to open a critical mass of sites. We focused on opening company-sponsored, IND-cleared clinical sites. As I sit here today, we have., y esterday, we were in New York at another conference, and I was saying we have 24 sites open. I got a note last night on the train on the way up here, we now have 26 clinical sites open.
That's crucial, strategically important information because everybody knows that anybody, any company that has a CD19-directed therapeutic, particularly in cell therapy, is trying to go forward with lupus. We have 26 sites open. It took us two years, a year and a half to get there, and we're not going to stop, right? A hundred is not out of sight, and this is only in the US. In the US, the second most successful company to open clinical sites behind us is Bristol Myers Squibb. They have 15, and I'm sure that it's not for lack of resourcing or attempting to open sites. This is hard. Getting the rheumatologist to partner with the oncologist to figure out how to share the budget, the contract, the patient, how to hand it off, how to get everybody to put their resources towards a common cause is not easy work.
But we've been doing this since, as I said, 2018. So with 26 sites open, as I said, Bristol with 15, and behind them, collectively, right? One of the investment theses that I hear from investors is Allo is going to eat the lunch of all of the autologous companies. You know, first, there's no data whatsoever, but that is it is what it is, and it'll, you know, reveal itself in the course of time. But collectively, all of the leading allogeneic companies in this country have 10 clinical sites open, and it's not for lack of trying. Are they satisfied to have only one site each or two sites each at most? And how will they get to 20? The argument is, well, they don't need apheresis. It's a lot easier. Everybody's going to jump.
The truth is, when you talk to the clinicians, and I urge you to do it, the sites are full. There are so many people who ran through the door before the latecomers. They simply don't have the resources to staff to be able to allow others to do trials in cell therapy. So while anybody can point their CD19 CAR- T product or other fanciful approach to CD19 in a therapeutic way, there aren't IP barriers to a competitive product. If you don't own the land, you can't dig for the gold. The land is the clinical sites. We knew this two years ago. It's now coming to fruition. Our enrollment pace was initially criticized, right? Internally, it was criticized by us, about us. It took us eight months to enroll the first five patients. This is hard work.
It took us seven weeks to enroll the next four. We announced that we had nine patients enrolled as of 10 August . Around 10 August , we announced the third patient data set. We had the first patient presented, the second patient, both at EULAR in June, and then the third patient on 10 August . The third patient had a significant adverse event. I'm going to come to talk in detail about that, which was your question. I wanted to give you the context.
Since 10 August , with this significant adverse event, which was a grade four ICANS that we believe was driven by a uniquely, very important, learning about a patient who recently had, a hyperinflammatory state so close in proximity to the time of infusion, that although they clinically looked stable, biologically, in due course, we will publish they were not, and that led to a grade four ICANS. I'll talk more about that in a second. Since that event, and because we're not at liberty, other than in a medical setting, to talk about all of these details about that patient, the important thing to recognize is what happened to the program, the product, the enrollment, the [audio distortion]. Since then? We reported that event to, the DSMB, of course. The DSMB said, "Keep going. Don't change the dose.
Don't change anything."...The company said, "Well, Professor Schett uses seizure prophylaxis, and seizure activity without any kind of movement was one of the key issues that drove the decline in mental status in this patient." So we said, "Why not use something that has really no downside, seizure prophylaxis, prior to all treatments?" This is something that about a third of U.S. hospitals routinely do in cancer. It is not in the U.S. guidelines, and, Professor Schett, we confirmed last week on a call, every single patient that he has treated has had seizure prophylaxis. It was in the original five-patient publication. It was not listed in the methods section of the New England Journal article, which included those five and another 10. But it is certain, based on our communication with him last week, that all of his patients got... Why?
Because it's just routine for them to do at his institution, as it is around the world, commonly used therapy, and it's about patient safety, right? So we said to the DSMB: Let's use seizure prophylaxis. Let's propose it to the sites. The site said, "You can recommend it, and we can do it. Don't force it on us because some of us don't like to do it." We said, "Okay, you'll come, and you'll tell us if you don't want to do it." We also did something that I think all companies should listen to, which is if a patient has an acute febrile or inflammatory event within two weeks of infusion, don't infuse them. Because clinically, your medications, your steroids, your antibiotics, make them clinically look stable, but biologically, their cytokines are not yet diminished.
And as a result, they are a tinderbox waiting for activated T cells to be hyperactivated, and we think that's what happened in that patient. So what happened? The DSMB said, "Just keep going. Yes, you can do seizure prophylaxis. Otherwise, you know, two weeks from any recent event, absolutely." So we put that across all of our programs because patient safety comes first. The second thing you have to do is you tell FDA. So we told FDA, "Here's the serious side effect that occurred in this patient. We're using the single dose across all of our studies, which is the same dose that Schett used," and the FDA received our recommendation, which is to change nothing, other than what I've mentioned, and they received that information, and a month later, maybe more than a month, they have had no comment.
We then told every investigator and every patient that was enrolled, "Look, you can pull out. There was a serious side effect." All of the investigators moved forward, and since then, enrollment has only picked up. So since August tenth, I would reiterate that we are thrilled with the trajectory of enrollment. Back then, we had nine patients. We had 20 sites open. When I say back then, that was August. We now have 26 sites open, and enrollment continues to grow at a really nice clip. Our team is more worried about manufacturing capacity to meet the demand than it is about enrollment at this point. So the hard work of building the foundation of a clinical program in autoimmune CAR- T cell therapy is now, you know, upon us. We've set a foundation that is unique in this industry.
The number of sites we have open and the breadth of our program. I didn't mention the pemphigus program that's going forward with CABA-201, but no preconditioning, and we have reason to believe, if you'd like to talk about, we can, and that is first sites there are now open and enrolling, so we'll see that data, and there, there's more to come on all of the clinical program. The first two patients, to directly answer your original question with all that context, is, the first two patients, a myositis patient, subtype, and a lupus patient who had grade or Class V nephropathy. So they, they had really bad kidney disease, but you don't put such a patient in a lupus nephritis trial because their kidneys cannot get better, and the purpose of lupus nephritis trials is to evaluate kidney function.
With grade V or Class V nephropathy, they go into the lupus cohort because, after all, they have much more than just kidney disease. Patient number one, IMNM patient at EULAR we presented in both patients, no CRS, no ICANS. Some investors were asking: Is your drug actually working? We showed all of the translational findings, the T cells, the B cells, the antibodies, the cytokines, in great depth, and it all lined up astonishingly closely to what Professor Schett had shown with his IMNM patient. So really promising early data. Only three months of data in that patient. The lupus patient, who has proteinuria that, to set expectations, will never go away. That's why they couldn't get into the lupus nephritis trial. So there's SLEDAI , which started at 22, at one month, was 10, off of all of their medicines.
That includes the four points for proteinuria that we know is going to remain no matter what. It was subsequent to that, that we dosed, and we experienced a Grade four ICANS event in a 24-year-old woman who had five or six lupus medications that she was chronically taking when she enrolled in the trial. If anybody needs our therapy and our form of therapy, it's this young lady. Two weeks, or a little less than two weeks before she was dosed, she was admitted to the hospital for a recurrent episode of fluid around her heart, acute pericarditis. That was treated with steroids. She was discharged. She was no longer short of breath, despite her five lupus medications, and this is all a side effect of lupus, or a result of lupus, not a side effect. She was sent home, she felt great.
She said, "I want to get my cells." The investigator said, "Let's go." The company said, "can we wait an extra day?" And everybody said, "Yeah, that's smart. Let's wait an extra day." And so we all agreed 100% behind each other, this is a right moment to dose the patient. The patient looks perfectly stable. Patient was dosed, four days later, discharged from the hospital. Unique to our product, we believe, a four-day hospitalization, not a 10- or 14-day hospitalization required in all of our program. Patient was discharged. Day 9, comes in with a fever, admitted, because that's what you do. At day 9, you have a fever, you come in after a CAR- T therapy. While she's in the hospital that afternoon, she ends up with a slight decline in mental status.
They transfer her to a neuro observation unit because you worry about ICANS at that point, and they start monitoring her brainwaves for seizure activity because that's common if you have ICANS. They see seizure activity, and the next morning, she wakes up, and she's extremely groggy, barely responsive, not able to take the ICANS test. By definition, that's grade four ICANS. So they immediately institute a completely routine approach to management of ICANS, and they notice the seizure activity, so they treat her with anti-seizure medications for the same medicine that is going to be used prophylactically by us and has been used by Professor Schett in addition to benzodiazepines and steroids. Within a week, she's discharged with no sequelae from this event whatsoever. We will follow up with a publication once all of the data is gathered.
We want to really understand the safety and the efficacy outcomes in this patient in great detail because we think this is an important learning for the field, and based on my discussions with Carl June, during and after the event, you know, this is 100% to be expected, right? You're gonna see outliers. Not everybody's gonna be a Professor Schett patient. And having this information in the public domain as soon as possible is gonna help keep patients safer across the industry, so we want to get it published as soon as possible, including the translational and the clinical data, and we will. And so, as I said, since then, site expansion has only accelerated. Patient enrollment has accelerated even further than we had before, and we really love our prospects.
Got it. Perfect, and thank you for all the context. Super helpful. I guess maybe can you just, in terms of, you noted one thing that I thought was interesting in that intro in terms of, so you only need to have patients in the hospital four days after infusion versus some of the others. Is that what you kind of-
Yeah, we don't, you know, I don't have-
What's the protocol?
I don't have the protocol for others.
Yeah.
I know our protocol.
Yeah.
Is, has been, and continues to be a four-day hospitalization, as agreed with FDA.
Okay, interesting. Okay, so do you guys-
And we believe that everybody else is currently 10 days, 14 days.
Interesting.
Much longer hospitalizations required.
So a point of differentiation, potentially?
I don't think so.
No?
I think that-
You think it all-
I do think that nobody is going to have... When all is said and done, everybody's gonna have an outlier. We're gonna have, we already have an outlier.
Sure. Okay.
But when all is said and done, I think safety will speak for itself.
Mm-hmm.
The management of patients on an outpatient basis requires that you do not have shortness of breath, hypotension, and other serious adverse events commonly.
Right.
If you have fever, grade one CRS, as your number one side effect, you have a pretty good chance of being outpatient therapy.
Yeah.
And that's really important. So we'll see how it all plays out. I think all of those that are now at 10 days are gonna get down to four days, because-
Okay
... that mid-period, if your drug is reasonably safe, like others-
Yeah
... you shouldn't need to be in the hospital. You should have protocols to observe patients, make sure they stay close to the hospital, within an hour of the hospital. If they take their fever once a day and they see a febrile, you know, moment-
Yeah
... they should call in and talk to the doctor. Like, it's just close observation. It's just wisdom of experience.
Got it. And then just in terms of differentiation, so you definitely, you know, highlighted in terms of, like, your development, you know, plans and what you're executing on and how you're differentiated there. But I guess as you think about a lot of these other CAR- Ts, like, ultimately, how do you think not only how are you differentiated, but how do you think the differentiation will play out? Like, will it be, you know, on safety, or will there be something on efficacy? You know, what ultimately, how will that all kind of evolve on-
Yeah
When that data?
It's really interesting. The data that is out there is really, you know, two major bodies of clinical data right now, right? One is Professor Schett, which is pristine, academic, and is never going to be repeated perfectly. We think we will be closer than anybody else in replicating his dataset based on the design of our construct and our design of our trials. But, that, that's one dataset. The other is much more real-world, where drug was given in investigator-initiated or compassionate use trials, not within company-sponsored INDs in a tightly controlled environment, but sort of just give the drug and let the doctors do what the doctors will do. And in that dataset, you don't have nearly the efficacy, you don't have nearly the safety, and it's really messy. And so where is it all gonna land?
I think it comes down to, you know, why is that dataset so different? And why was his so good? I think, you know, if you look at the lupus nephritis population that Professor Schett treated, it was all mostly grade three, right? It was all the more modest form of lupus, of kidney disease in those patients. The other thing he did was he did weight-adjusted dosing. We're the only ones who are replicating his weight-adjusted dosing paradigm.... 85% of the time, it won't matter that we weight adjust because the standard one time, one dose fits all is going to be fine. But for the outliers, is there going to be a difference in the profile of the drugs if you weight adjust for a morbidly obese man, right?
So there is, I think, a widely misunderstood belief that somehow autologous CD19 CAR- T is not durable. I think if you understand and look at the data in detail and talk to the investigators, you'll recognize that the lupus nephritis patient from the commercially treated cohort of patients, the first patient they treated was a morbidly obese man, and he was treated with a subtherapeutic dose purposely. FDA said, "You need to do a dose-finding study." "We're not doing a dose-finding study. We're doing a standard one dose, and we're done." But they needed to do a dose-finding study. They just treated with 50 million cells in a morbidly obese man. It wasn't enough dose. So dose actually matters. We know that. And in such a patient, will the routine dose be enough, or is weight-adjusted dosing a meaningful differentiator?
I think there are going to be things that we learn through the process of doing this work. For Bristol and Novartis, they have these fast-manufactured products. The difference, it's not just a matter of how fast you manufacture, right? It's the quality checks on both sides. Both Bristol and Gilead have recently partnered with Cellares for its efficiency of manufacturing, for its lower cost of goods, for its scalability. And so this idea that there's fast manufacturing, it's only two days versus Cabaletta's like a month, is nonsensical. What you need to worry about is the vein-to-vein time for patients. And in cancer, that is crucially important. In autoimmune disease, the safety and efficacy and breadth of indications of your product are going to make a big difference. So who gets there first, and how useful is your drug?
You're not going to be able to use a CAR- T product for all autoimmune patients just because you have one indication. So the breadth of our portfolio of indications and the head start that we have in company-sponsored, IND-cleared progress towards approval, all nine of those cohorts I talked about are designed with one dose and one dose only. Why? Because the safety data set from all nine cohorts is going to be relevant to each of the nine cohorts as we file it for approval. So the way we get to approval in any of our cohorts, let's take IMNM myositis as an example. 3,000 patients in the U.S., there is no approved standard of care or therapy. Nothing works. Steroids are notoriously useless. It doesn't have a therapeutic option. The first patient we presented was an IMNM patient.
I believe that when patients show up for your clinical studies in greater numbers for a particular indication, it's telling you something, right? The demand is there. The patients are there. Six patients treated in that cohort will allow us, or any of our cohorts, to go to FDA and talk about the registrational trial design. Once we agree on it, we don't have to go back and open up clinical sites to start enrolling patients. We believe that we've designed our trials in a way that we simply can expand the ongoing study to include more patients in this unique IND that's directed to myositis. We save the five months of starting up or nine months of starting up a new program, a new trial, and it further accelerates our time to launch.
So everything we've done has been really a chess game, and we've been penalized, you know, by perception that we were slower and we were this. The foundation is now set, and I think 2024 going into 2025 is our moment. And so clinical data is where it's going to start. That data is going to allow us to talk to FDA about registrational pathways, maybe juvenile myositis, another indication where there is no standard of care and the outcomes are horrific for the patients. The level of enthusiasm in that investigative group is really high. So the pathways to approval are many for us and very efficient, very efficient. The design of our clinical program allows for the extension or addition of new cohorts.
An example of that, I just want to come back for a second to our pemphigus program. Pemphigus is interesting because it's a pure B cell-mediated autoimmune disease. If CAR- T therapy doesn't work there, nobody will argue that somehow the target wasn't perfect because it is the most perfect B cell-mediated, prototypical autoimmune disease. We chose to go into pemphigus with CABA-201 with no preconditioning. I think, and we argue, this is the single most important clinical study ongoing in cell therapy for autoimmune disease. Because if we can use CABA-201, and if the experience is a patient comes to the doctor, the doctor says, "You have scleroderma." They go downstairs to the lab, they're going to take ten purple top tubes. We're going to send that off to Cabaletta.
They're going to make CABA-201, and we're going to infuse CABA-201 a month from now with no preconditioning, and these are your cells that are going to be able to cure your scleroderma. Your risk of death ten years after you're diagnosed with scleroderma is 50%. Typically, you're a thirty-five-year-old woman. All you need to do is give your cells downstairs in a routine lab, come back a month from now, we'll infuse your cells into your body, and you'll have a reasonable chance of a complete response with no preconditioning. Or, you know, we could do something else. We could give you treatment tomorrow with an off-the-shelf, somebody else's cells, off-the-shelf with preconditioning. There's no question, and you have to ask yourself what all of the allogeneic companies will focus on.
because use by patients with autoimmune diseases is certainly going to prefer absence of these, these preconditioning regimens. So it's important that we advance CABA-201 in pemphigus to explore whether it can work without preconditioning. We believe it can work without preconditioning because in 2019, there was a publication of a BCMA CAR at high dose with no preconditioning, and it gave similar action, similar activity as a BCMA CAR with preconditioning. So for those reasons, we're excited to be able to put CABA-201 into the DSG3, into our existing clinical program, with the legacy platform, where 10 sites are already open, and we can rapidly get into the clinic.
So we just now, four months after the clearance of the trial, we're now in the clinic with CABA-201 without preconditioning, and we have one, and we may have more than one site open in the next couple of weeks. We may have a few. That really becomes, in our view, the most important clinical study in the industry of cell therapy for autoimmune because it changes the game for everybody. If it works, we start a new arm in all of our clinical programs. It's easy enough to put another arm into each of these different INDs.
When do you think we'll see that data?
As soon as we can possibly get it to you. There are very few things that are higher priority, like launching the first product is always going to be our top priority.
This data is probably the second priority in the company.
Based on that paper, like, I guess, when would you expect... Like, is it kind of similar timelines that we see these patients respond, like three months is kind of, you know-
We think we'll have our first insight within the first two weeks of therapy.
Okay.
Right? Because the T cells either expand.
We have six years of experience of looking at
Translational data in autoimmune patients with cell therapy. We know what doesn't work, looks like.
Yeah.
Right? We have that experience with our legacy platform. If it works, it's going to be self-evident.
Got it. So you're just looking at the expansion relative to, you know, the-
We'll look at T cell expansion. Does it hit the levels of efficacy that we know are necessary?
Yeah.
Do the B cells disappear?
Yep.
By one month, do we see antibody decline? Do we see symptom improvement? We have a pretty large database of pemphigus patients treated with cell therapy and translational data on them, right?
Yeah.
And the other thing that's really, I think, important to note is we talked about the obese patient that was under-dosed, and that's really not a recurrence or a failure of CD19 CAR- T. That's just an under-dosed patient. The other patient who was a "breakthrough," quote, unquote, was a Schett patient with myositis. This patient had anti-Jo-1 antibodies that persisted, and nobody understood why. It was unusual. A year and a half of drug-free, disease-free existence, which was celebrated by the patient and the physician, is wonderful. But at a year and a half, no lung disease reappeared, but mild muscle weakness reappeared with CPK. The patient was retreated with a CD19 CAR- T by Professor Schett, and it failed completely. There was no change in the symptoms.
Presumably, he'll publish this at some point, but his verbal communication with us and to scientific audiences confirmed that the Flu-Cy- preconditioning in that case didn't affect the myositis. So there's nothing about Flu-Cy that is giving therapeutic benefit other than it enhances the cells. That's a really important piece of data because going without Flu-Cy could be risky if Flu-Cy itself is giving you benefit, but it's not, right? In that case, it went on to be even more valuable when he treated with daratumumab, a BCMA antibody, and he saw symptom resolve. But when he stopped the BCMA antibody, the symptoms restored, the symptoms recurred.
Once again, as in his publication of the lymph node data recently, the original publication of an antibody therapeutic for rheumatoid arthritis and his public statements, antibodies are just not well suited to cure autoimmune disease. They're well suited to treat it. So his next step is a cell therapy with BCMA to get rid of the long-lived plasma cells that caused this patient's problem, his recurrence. Long-lived plasma cells are CD19 negative. They should not have, and they never will respond to a CD19 CAR- T. So it's not a CD19 failure, it's a BCMA breakthrough.
Got it. And then maybe just, real quick, you got some data, you know, you're going to provide some updates, you know, later this year. Can you just tee that up for us and just ensure that, you know, you're still on track for those updates?
Yeah. We're thrilled with the amount of data we're going to be able to reveal later this year. You know, by the end of the year, we expect to have a significant number, and we've talked about enrollment data, a significant number of lupus patients and myositis patients to talk about, and as in the past, the first patient in each of the scleroderma and myasthenia gravis trials, as well as perhaps updates on the treatment of the first patients in the pemphigus trial with no preconditioning.
Excellent. Well, Steven, we'll leave it there. Thank you so much.
Thank you.
Bye. Good to see you.