Good morning, and welcome, everybody. I'm Doug Tsao, senior analyst at H.C. Wainwright. We are thrilled to have with us Cabaletta Bio, represented by the company's CEO, Steven Nichtberger, to present or have our conduct fireside chat. So, you know, Steven, maybe as just a start, just provide a quick overview and introduction to the company for those in the audience who may not be familiar with you.
Sure, and thanks for the opportunity. Appreciate it, and thanks for joining us this morning. Cabaletta was formed in 2018 in order to discover and launch the first targeted curative cellular therapies for patients with autoimmune diseases. In 2022, we in-licensed CABA-201, and with that in-licensing of a fully human binder, which replicated the binder that was a murine binder used by Professor Schett in his studies that really ignited the CD19 targeting field, we built CABA-201. Within months, we filed our first IND. We subsequently filed multiple INDs, one for each of many different indications at this point. We are now in the midst of a clinical program which addresses myositis patients, lupus patients, myasthenia gravis, scleroderma, and pemphigus.
And in that portfolio of different INDs for each indication, we have dissected down to the level of this type of patient. So in lupus, you have lupus and lupus nephritis. In myositis, three subtypes. And we did that because FDA guided us when asked, that you know, you may find different side effect profiles in different patient subtypes with your product, and you want to be able to isolate those side effects to the types of patients that you're treating. And that was, of course, as usual, sage advice from FDA. Today, we'll talk about data, but today we have what we think is in the United States, the largest clinical network of company-sponsored, IND-cleared, open clinical sites that are actively enrolling.
There's a big difference, often lost on investors, I think, very big difference between the company-sponsored INDs that have forever been the basis of data generation that will support approval of products versus compassionate use or individual investigator-initiated trials. Within company-sponsored, IND-cleared trials, we have an industry-leading 28 clinical sites open as of today, which is, I think, three or four more than it was last week. So we're excited about the opportunity now to present data later this year.
Steven, you did present some initial clinical experience data in June from patients treated with CABA-201. Maybe just provide an overview of what some of the key sort of initial takeaways were.
Yeah. You know, the initial takeaway on only the first patient from the lupus product program and the myositis program, those first two patients were presented at EULAR. The takeaway was we believe that biologically and clinically, the evidence is clear that we have chosen the right dose based on that slim data set of only two patients. Choosing the right dose matters a lot because most others in the industry are tasked with proving that they are choosing the right dose. We believed we had chosen the right dose because of the comparisons to the Schett product and program and published data showing the dose effect relative to that product, and we were thrilled with that.
And then the second thing we presented at EULAR was a safety profile where both patients had a perfectly clean profile as it relates to CRS and ICANS. There was no CRS and no ICANS in either patient. Subsequent to June fourteenth, we treated a third patient. This patient was a lupus nephritis patient with highly active lupus, very severe lupus, with a SLEDAI of 26, but a 24-year-old woman with a very active lupus history. And that activity, we believe, formed the basis for what became a significant side effect in that patient, which we reported a grade four ICANS event, which with routine treatment, rapidly resolved, and without any sequelae, the patient was discharged.
But that was a surprise to us, and we subsequently have learned an awful lot about the promise of CD19 CAR T therapy in autoimmunity and which patients might actually be at higher risk. Think cancer, you have higher risk if you have tumor burden. In autoimmunity, you may have higher risk if you have a recent exacerbation of your disease. We'll talk more about that.
So Steven, I, I did want to touch on that one safety issue, or safety event that occurred, and you obviously provided some color in terms of that individual patient. And so I'm just curious, you know, what changes did you make in terms of execution of the studies subsequent to that? And has that event had any impact on enrollment and diminished enthusiasm in any way?
Yeah, so it depends which audience you're talking about. For investors, it clearly diminished enthusiasm, but for investigators, we have opened. We had 20 sites on the day of that event. We now have 28 sites open within the next four or six weeks since then. As to patient enrollment, on June fourteenth, we had five patients enrolled. On August tenth, we had announced publicly that we have nine patients enrolled. We no longer have nine patients, and frankly, we don't have near nine patients enrolled at this point. We continue to see high, high enthusiasm, and the conversations around the leadership team table are more about meeting the demand for the clinical program. We had five patients simultaneously being manufactured in August for infusion, and we're thrilled with the progress.
We always said there's gonna be a moment where the hockey stick happens. It took us eight months to get five patients. It took us less than eight weeks to get the next four, and we're continuing to see the patient flow increase. So that event, in our view, had no impact on, you know. The DSMB said, "Keep going and don't change anything." The FDA agreed with our advice: "Don't change anything, and keep going," and we came back to the DSMB and to FDA, and we said, "You know what?
Out of an abundance of caution, we think the key learning here is when a patient has, at that, as that one did, a hospitalization near to the time of infusion for an exacerbation of her lupus. She was on five medications, twenty-four years old, and she goes into the hospital yet again for shortness of breath, on five medicines for lupus, and the reason she went in was she had pericarditis, or swelling and fluid around the heart. They gave her high-dose steroids. That resolved. She went home, and clinically, she looked great. The investigators in the company said, "She's looked great for a number of days now, and seems like it's resolved." But biologically, you'll come to see when we publish the data, the full case report, safety and efficacy, you'll see that this was still a tinderbox of a patient.
This was a patient who took the activated T cells, the CAR T cells that were infused, and you saw a dramatic rise in the cytokines, which explains the ICANS, and it explains why we talk about this patient as a real learning for the industry. If you have an activated patient who has active recent disease, you need to put more space between your infusion and that, in that active disease, and for us, that meant a two-week change in the protocol, at least minimum of two weeks from the most recent active disease expression, if it's a hospitalization, a high fever, whatever it is, and we added the use of prophylactic seizure medicines.
Her reduction in mental status, that was the ICANS grade four, was clearly correlated tightly with seizure activity, not moving of muscles, but just seizure activity detected by EEG, and with routine care, that reversed, and her mental status reversed. So we added the seizure prophylaxis, a medicine that is not expensive, and it doesn't have major side effects, which was used. We reconfirmed yet again with Professor Schett a week ago, verbally on the phone with him, or on a Zoom with him. The Erlangen University uses seizure prophylaxis in all of their CAR T patients, cancer and autoimmune, and there was some debate in the investment community whether that was true or not. We believe, based on last week's discussion, absolutely true.
We feel like seizure prophylaxis is no cost, may be useful, and everybody, frankly, should probably be doing it in light of the learning, and we'll publish, and the industry will evolve.
And, you know, one of the things that you referenced earlier in your earlier comments was the advantages of getting individual INDs for each indication. And I think, and versus, you know, sort of executing basket trials, which is something-
Yeah
... you know, approach that others in the industry have taken. You know, what does that, how does that set you up in terms of accelerating your program from a development stage and moving to the next, you know, sort of getting to registration ultimately?
You know, for those who have ever built a house, it takes longer to build a really good house, and the foundation of a really good clinical program with a separate IND for each of the indications takes a really long time to file all those INDs and then to open each clinical site for each indication, versus a basket trial, one IND, and then you go to every site, and it's like: "Yeah, here's my basket trial. Let's enroll patients." It's one-fifth of the work that we've done. Why did we choose that hard path, well, in conversations with FDA, before we filed our second IND, before our first IND, I'm sorry, we asked them, "Would you at FDA prefer a basket trial with all, or would you prefer to manage this as separate INDs?
What is your advice to us as to how we should manage a single product that may have utility as broad as Humira or other major drugs in the industry? Their advice to us was, "If you file a separate IND for every indication, you will be able to more accurately reflect in your label where you are seeing different side effects." There's a black box on certain medications, autoimmune medications, large ones, that is applicable to certain populations, but not to others. There are side effects that occur in certain populations, but not others.
FDA knew that, and when they advised us to file separate INDs, it was with an eye towards allocating your safety events to the different patient types who appear in your trial and, or your trials, and in whom CABA-201 is associated with either a better or a less attractive safety profile. So we're seeing exactly, you know, frankly, the benefits of FDA's advice and of the hard work we've done to build a really excellent foundation. That's number one. We can allocate side effects by indication within our label. That's our belief. Number two is, when we come upon a new opportunity, we can, or when we want to go to phase III. So you heard we're really, very bullish on our pace of enrollment, and, in that regard, remember, we have six patient cohorts.
We have nine of them, that with each of them, six patients allows us to go back to FDA and discuss registrational pathway. When we go to registrational pathway, for example, in IMNM myositis or in lupus, we're going to be going back with not, "Let's start a brand-new study and take nine months to open sites for a brand-new study," but rather, we've got dozens and dozens and dozens of sites open by then. Right now, we're at 28 clinical sites across the country. The next closest company, by the way, for reference, not for lack of trying, is Bristol Myers Squibb. They're at 15 in the U.S. Now, they have a boatload in Europe as well, and we're not yet in Europe. But it's not that they didn't try, and it's not that every other company's not trying.
All of the allogeneic companies across the country are trying to open new sites. What they're bumping into is we can only have so much CAR T capacity at the hospital, and no matter how attractive your product might be, we are. I'm sorry, we don't have capacity in our hospital system. So we knew two years ago getting into the sites was critical, and it turns out that is going to be the rate-limiting step. Anybody can make a CD19 CAR T. Not anybody can develop it and launch it and develop it through all of the clinical trial network that is necessary here. So we're really, frankly, thrilled with the opportunity to have this separate IND for every indication, which gives us flexibility to go right into phase III off of the existing clinical program, potentially, pending data and pending FDA's agreement.
But that is the expectation that we have discussed with FDA in the early days. And, number two, this clinical trial network, which don't take it for granted, right? Ask every company in the industry that you're interested in, "How many clinical sites do you have today, and when do you think you're going to have twenty?" The last two drugs for lupus, I just want you to realize, the last two pharmaceutical products for lupus that were approved were both programs that were run by our chief medical officer at Cabaletta. He was at Glaxo and at AstraZeneca for Saphnelo and for Benlysta. Each of those two programs required seventy to over a hundred clinical sites to get a pharmaceutical product approved across the finish line. We knew that in 2022, when everybody else was trying to figure out how to pivot into autoimmunity.
So we are way ahead of the pack in terms of what will be necessary to get your drug approved for the indications that we're pursuing, and we're frankly excited. In the company, the level of enthusiasm is now really palpable because we see the enrollment, and we believe the drug is going to deliver on the data that we think, the profile that we think and we've said publicly, repeatedly, should be the profile. We need data. Investors are not interested right now in Cabaletta because we have a safety issue that we have to have data to counteract, and so we're thrilled. The pace of enrollment, which is the second major issue, our pace of enrollment was not fast enough. It is now exceeding our own expectations.
We're thrilled with that opportunity to generate the data quickly, to have the pace of enrollment pick up, and to be able to do it with a foundation where you may be able to plug in phase III and start to see the filling of a six-cohort patient. Talk about registrational design, and as we move into 2025, maybe even move towards that part of the development program.
And Steven, I think, you know, to your point, investors really focused on the one ICANS event and when you sort of provided your 2Q update. But I think one of the more overlooked nuggets, if you will, and maybe nuggets sort of understates it, because I think it is important, was your announcement of the sub-study in pemphigus that you were doing-
Yes
... without preconditioning. And I think it'd be worth highlighting what that ultimately could do for you.
Yeah. Well, for patients, really. So as soon as we saw that CABA-201 was safe and effective in the one-month, one-and-a-half-month time period with preconditioning, we had a long-standing plan to use CABA-201 with no preconditioning. And the reason we believe that that might be effective, excuse me, is not that we want it to be, right? There's actually scientific rationale for doing this, and that rationale is that in our scientific co-founder's history, he generated data and published data on BCMA CAR T with preconditioning in usual doses, compared with BCMA CAR T with no preconditioning at very high doses. And you don't do this in cancer, because you can't afford to give more cells and have more side effects than you already have.
But he was curious to ask the question: "If I go with higher cells administered to a patient, can I get similar biologic activity and outcomes?" And in about 25 patients, he published this data, and it showed that you have similar activity with and without preconditioning, as long as you have a safety profile for your drug that will allow you to go two, three, four times higher in your dose. Cabaletta, when we filed our IND with FDA on all of our - I think it's six INDs, cleared all within 30 days. In every one of those, we have the permission of FDA to double and triple our dose, because the safety data in the cancer population, where our binder was used previously by our partners at Iaso, was at two to three times the dose that we're actually using.
So it was a pretty straight shot for FDA to say, "Look, there's clinical data on two to three times your dose. You can go up two to three times higher in dose, and you don't need to come back to FDA. You don't need to do anything. Just if you and your investigators believe you should do that, go ahead." So that opened the door to go right into our 10 open clinical pemphigus sites, which I do not include when I tell you we have 28 sites open, 'cause including pemphigus, there are 38, but those are not yet all open for CABA-201. The first one of those reviewed the protocol, and what we did, just for clarity, is we inserted the CABA-201 program product as a sub-study in the DSG3, the legacy portfolio program in pemphigus.
We went to FDA, we said, "Look, different product, pretty much the same protocol." And they said, "Fine, go ahead." That meant we don't have to take what is industry standard, nine months to open our first clinical site. It was four months to open our first clinical site since that IND or since that sub-study was cleared. So we're now looking at opening an additional two sites in the next weeks, and there'll be three clinical sites open and recruiting pemphigus patients for treatment with CABA-201 without any preconditioning. The impact of that, if it is positive, is more important than I think any other study in this industry right now of cell therapy for autoimmunity, because the treatment paradigm could well become CABA-201 with no preconditioning for all of our indications.
Having a separate IND for each indication means we just start a new arm in the existing IND, pathway that we have for every indication, with no preconditioning. Now, you don't launch with that, because you don't know yet if it's durable. But if you are in the space of cell therapy, and you're using preconditioning, if that study proves positive in the first couple of patients, and you know it early on, the T cells expand to a level of efficacy that you need, and the B cells disappear, the antibodies go... You know what that story's gonna look like in that patient. So we're gonna know really pretty quickly whether that is positive, and if it is, it changes the game and moves, it moves the cheese for the whole industry.
Anup and Steven, how quickly, if it does succeed, right, and, and given the importance and the benefit to patients without needing preconditioning, how quickly would you think about transitioning the rest of your program to a-
Yeah, we wouldn't. It's a really good question. We would not transition. We would add a new arm to the existing program. We would go ahead and launch with preconditioning, 'cause we know it's durable by the time we do that. The no preconditioning arms would be started and probably, you know, this is a question internally at the company we haven't debated and discussed yet. Announcing any positive data from the pemphigus program with no preconditioning would be completely transformative to Cabaletta, no doubt. But it also is a competitive advantage to know what dose it works at and to know that it works, and to get the INDs supplemented and have all of those trials enrolling before we say anything publicly.
So that debate, we haven't even had the debate internally at the company, but that is probably, honestly, as I sit here and say it, probably on Tuesday, when we meet as a team next week, we'll be talking about that. This is what, you know, I have said in this discussion. We're really excited about where we are right now as a company, and thrilled with the opportunity to really advance the field and hopefully safely and effectively treat and maybe even provide complete responses that are durable for the majority of patients with autoimmune disease that we would treat.
Okay, well, I think we're out of time, so-
Yes
... we've got to wrap up.
Appreciate it.
Thank you.