So welcome, everyone. Thank you for joining. I'm Gavin Clark-Gartner, one of the senior biotech analysts here at Evercore ISI, and really happy to be joined with Cabaletta Bio's CEO, Steven Nichtberger. Steven, thank you for joining us.
Yeah, thanks for having me.
Of course. I'll just turn it over to you for an overview of the company, where things stand today, and I'll throw one specific question out there, which is, what do you think is the disconnect between the current market price, where you see the value, where investors see the value? What's the disconnect today?
Good morning. Thanks for having me. To answer the first question, Cabaletta, for those who are not familiar or less familiar, was started in 2017 and 2018 to develop and launch the first targeted curative cell therapies for patients with autoimmune disease. That experience turns out to be profoundly important because for three or four years prior to the publication of Professor Schett and his team in the New England Journal that ignited this industry of CD19 targeting autoimmune, we had been working with clinical sites across the country to implement cell therapy in autoimmune disease. When we in-licensed and started to develop CABA-201, we were advantaged in that we knew how to open clinical sites, how to get rheumatologists to work with oncologists, how to get neurologists to work with oncologists, how to implement, enroll, and execute cell therapy trials in autoimmune disease.
The answer to your second question is the result of the early experience has now put us in a position that is, to us, remarkably advantaged in many ways versus literally every other company that we know of. First, I would say we have 40 clinical sites across the U.S. currently actively enrolling CABA-201 trials. That leads the industry in the U.S., including big pharma. The history of lupus drug development is something that is very poorly appreciated or understood, we think, because if it were appreciated and understood, one would realize that without 100 clinical sites, you cannot develop a meaningful lupus cohort.
The reason I say that is, historically, lupus drugs, Saphnelo and Benlysta, were both developed using 100 clinical sites across the globe because the number of patients they enroll per site per year, this is how many patients do you enroll per site per year in a pharmaceutical lupus trial? The answer is one. One patient per clinical site per year. If you don't have dozens and dozens and dozens of clinical sites, I don't care how small your trial is, you're not going to be able to get your drug across the finish line first. We knew that in 2022, which is why in 2024 and coming into 2025, we are accelerating our site engagement. We're enrolling at an accelerated pace, and we're about to break away from, I think, the whole field in terms of enrollment and the pace of what we're doing.
You put that together with the clinical strategy that we have, which is a separate IND for every indication, and it gives you another advantage because as we see clinical data in each of our nine cohorts of different diseases: lupus, myositis, scleroderma, myasthenia gravis, pemphigus, each one of them is designed so that when we get to six patients, and perhaps even fewer if the data are as good as they may appear, we can go back to FDA and ask for the registrational pathway, which is not going to be an evolution of a basket trial, which may or may not ever occur for any company, but it will be the evolution, we believe, of our current homogeneous cohort of patients in a subtype of myositis, for example.
So if we see a differential side effect profile in lupus versus myositis, or even within subtypes of those diseases, we are incredibly well poised and suited to allocate those side effects to those patients in that trial and to allocate a different side effect profile to the label that we will have for the drug. Just like with Humira and AbbVie, every different indication has its side effect profile and its efficacy profile, and the design of our clinical strategy will allow us to extend our current cohorts and allocate appropriate success, efficacy, and risk safety within that cohort in a way that we think provides great advantage versus what we see everybody else doing. So we're feeling really great about the opportunity to now excel into 2025 simply by execution. This is a game of execution because there is very little barrier to entry for CD19 autologous.
I think you asked a question around what are investors missing. I don't know what investors are missing, but our impression of the allogeneic data, which has been presented so far, is that B-cell cytopenia is not the same as B-cell aplasia. Reviewing press releases gives you one impression. Reviewing the actual data in the poster gives you a different impression. I think when you read the articles on bispecifics, better molecules may one day do better things than has been published, but there has yet to be an experience, and having had breakfast with Professor Schett last week and talked about his experience in 20 patients who got a high-dose bispecific, and the patients did not reset. So we know that there's no data that supports the thesis that one day this will be true, and one day it may be true, but that day is nowhere soon.
And in the meantime, we're just going to go right into registrational trials and launching drugs.
Great opening, and maybe we could stick on the point of number of sites and put some more numbers behind it. How many sites do you guys have open at the moment? How does that compare to others in the field? How many sites do you want to have open a year from now?
So we currently have 40. We've publicly stated we have 40 clinical sites open in the U.S. We just launched our European organization headed up by the founding leader of BeiGene's European organization, who just left BeiGene to join us, along with a team that has also formed under him with remarkable experience from Celgene and other notable companies. So we'll extend into Europe in 2025. The comparisons would be Bristol has 30 clinical sites in the U.S. compared to the 40 that we have. Ours are disease-specific. So if we opened in your site, it's because you have myositis patients and our myositis trial is open for use in your hospital. If you have lupus patients or if you have scleroderma, and this is not like cancer where everybody goes to MD Anderson for their cancer treatment.
You go to scleroderma sites and centers where there are experts who manage that, and they may not have a myositis cohort at that site. They may not have lupus patients in an enriched way. The benefit of a different IND and a different trial for every indication is you actually are where you need to be. The entire allogeneic industry, all of the leading companies taken together, have 15 clinical sites opened in the U.S. The whole industry has 15 clinical sites. The vast majority are focused on lupus. So imagine, first of all, I don't think there's any evidence that we've seen a true B-cell receptor clone elimination and reset in a rigorous way with any of these drugs yet. If you do, it's going to be with heavy-duty preconditioning. Our pemphigus program, without preconditioning, we'll see how that compares.
But even if they have a single patient that they can report, and everybody's delaying their timelines because it's hard to enroll, but even if there's a single patient or two reported, we expect to start registrational discussions with FDA as early in 2025 as possible based on our data, and I stress as early as possible, and we will be moving ahead towards registration while others are figuring out what their dose optimization should look like in a world where opening 20 or 40 clinical sites takes years and where if you don't have 50-100, I don't care how small your trial is, you're not going to get to a registrational outcome, so I think there's really not a deep appreciation of how hard this is and how well we've been executing.
Yeah, that's well said. And we have a tracker of this somewhere, but the sheer number, like take systemic lupus, for example, the sheer number of patients being enrolled in those trials cumulatively across the industry is staggering. I think it was north of 7,000, which I don't have the number in front of me, so don't quote me on that, but it's a very large number. So it does give you a large moat.
Yeah. And look, a lot of these companies are going to be presenting in 2025, one patient, two patients. They'll come up with a few patients from a site or two. We, for the past number of months, we've enrolled about one patient every week and a half, every two weeks. Going into 2025, we think that's going to accelerate. And we're actually developing a drug now. And to us, I think really the fundamental one-liner, if I can say it, difference between what our management team, our board, and our most supportive investors believe is that we have a drug. We have a product that is apparently safe enough and apparently very, very effective. And now it's an executional game. And I don't think investors believe that yet. I have no problem believing they will believe it after we have registrational clarity and a little more data presented.
Yeah, that makes sense. I guess to bring back one of the points you mentioned earlier, in those historical lupus studies, again, just using lupus as an example, you're obviously working on many more indications, but just using lupus as an example, if they were enrolling one patient a site a year and you're already well above that, what gives you confidence that it'll accelerate further within the existing sites today? And it's maybe worth contextualizing too as you think ahead to the regulatory discussions. Do you have any base case on how large a lupus trial would have to be and how that compares to other modalities?
So listen, Bristol- Myers is neck and neck with us in advancing autologous CAR-T. Like us, they believe that there is a profound benefit to autologous approaches for autoimmune patients. And I think like us, the public statements I've heard them make on panels where we've sat side by side are similar to what we would say. We think FDA has an appetite for single-arm open-label studies if you have a safe product that can reliably 80%-100% of patients deliver drug-free, symptom-free outcomes for patients. If you can get to drug-free, symptom-free, and the cost is a fever here and there or a drop in blood pressure that requires a bag of IV fluid in a couple of patients, there's not going to be a large barrier to getting that drug approved. That's our view.
I think FDA increasingly is very interested in facilitating early access to these types of breakthroughs in gene and cell therapy, perhaps less so in the drug realm, more so in the gene and cell therapy realm. So we don't think this necessarily has to be a very large trial. The more favorable our safety profile looks, the better we think the odds are that we have a trial that's very attractive. To review very quickly the ACR data that we just presented, I would summarize by saying in the eight patients, and it's only eight patients, but in the eight patients that we treated, one was an ICANS grade 4, which we have scientifically, I would say, proven was the result of a T-cell that was carrying our CAR.
The T-cell was expanded dramatically in this patient with our CAR in it as a result of probably an occult infection that was not recognized. T-cell receptor sequencing shown in a poster at ACR makes this scientifically really beyond the shadow of a doubt. We went along for the ride on the body's response in that patient to some infection that it detected. We think that's an outlier. If we look at every other patient, our safety profile, the majority, five out of seven, five out of eight patients that we presented, no CRS, no ICANS. People say nobody's replicated Schett's data. Are you going to regress to the mean? Is it unsafe? We presented our IL-6 data. I would offer the opportunity for all companies to present their IL-6 data. IL-6 is what's triggering CRS. We are the only company that is weight-based dosing.
Everybody else is, look, it works in cancer. Just give a dose. Schett used weight-based dosing. The details matter. And it turns out that the frequency of CRS and ICANS are looking for us like we have a very low occurrence. And the IL-6 data we presented helps you understand why. The one fever that we had, the IL-6 levels were higher in that patient after treatment. The grade 2 CRS that we had, which is neither of these was treated with tocilizumab. One was treated with Tylenol, and the other one was treated with a bag of IV fluid to reverse the blood pressure drop, which came back up quickly enough. They did not even administer tocilizumab. And in that patient, that was the highest IL-6 level. But it seems like in the majority of patients we are treating, the IL-6 levels are not going up very high.
I think we've chosen not just the right dose, but maybe the Goldilocks dose for autoimmune patients, and if we have that kind of safety record and we go to FDA with a cohort of three, six, whatever patients in a subset of a disease where, as we presented at ACR, you have compelling clinical responses where every single patient has stopped every immunosuppressant for the entire duration of follow-up and nobody has had an exacerbation causing any restart of any medicines, you could say whatever you want, drugs like that don't exist, and we think that's going to be a compelling opportunity for us to partner with the sites who, by the way, are signing up left and right. You have to ask yourself, why are they continuing to sign up with an autologous company if there are so many other better opportunities on the horizon?
And for sure, they're getting the door knocked on. It's not like they have to sign up with us. And half of those sites have signed up in the last few months. So I think there's a different view of autologous CAR-T and of Cabaletta in the physician leader, investigator, key opinion leader community. In the patient community, patients are showing up increasingly quickly. And so we're seeing a lot of enrollment. And our pace of enrollment and the execution, frankly, is just completely different from every other company that we see. And I think investors just don't see that yet. I think we'll give every opportunity for investors to understand it more and more. And that's why we're here today.
I think it's worth touching on the Pemphigus study, the sub-study that you're running, including an arm without conditioning.
Yeah.
I guess the question is, how can you integrate those learnings into your other studies? You have a lot of those studies, a lot of those sites up and running already. Couldn't they enroll really quickly?
Yes.
How important overall to your strategy is moving away from?
So there are seven clinical sites enrolling patients in a pemphigus program that does not use any preconditioning. We presented data from our legacy portfolio demonstrating that with a CAR that was directed to only the pathogenic B-cells causing pemphigus and myasthenia gravis, two separate products. From that legacy portfolio, we learned two things. First, preconditioning with Flu/Cy does not affect clinical outcomes in and of itself. So in other words, if the cells don't expand, Flu/Cy doesn't change things. The second thing we learned, which is really important, is that without preconditioning in myasthenia gravis patients who have the MuSK form, when they are administered a MuSK-specific CAR, we get pharmacokinetic T-cell expansion of our CAR. We get biologic evidence of activity, and we get clinical evidence of activity that is durable.
So we know at higher doses, if you have a clean safety profile at the start, refer back to my comments a few moments ago, the frequency of CRS, the IL-6 levels, very, very modest with our dose. If we increase that dose meaningfully to a level where we can do without preconditioning, it changes the game for everybody. And we will have insight into that data early in 2025, the first half of 2025. We'll see the first few patients. And we'll know in a month whether we have PK, PD, and biologic and clinical effect or not. If we do, the next step is going to be to set up an arm without preconditioning in every one of the nine cohorts of clinical study that we are pursuing and to start enrolling there. But we will not interfere with speed to launch on the first of those nine.
Whatever our first product is across the finish line, we're not going to bring in the whole blood, the blood draw that replaces apheresis. We're not going to bring in anything that will slow down being the first to launch because that at the end of the day is what strategic partners value the most, and it's what we value the most, and we think investors will value the most, is getting out to patients first and doing it in a way that you have compelling safety and efficacy data.
That puts us right on time.
Ooh, look at that.
Thanks so much for joining, Steven. Really appreciate it.