Cantor Biotech Equity Research Team. Pleased to be joined by Steven Nichtberger, Chief Executive Officer of Cabaletta. Steven, maybe give us a quick snapshot of Cabaletta, where you are with your CAR T programs in immunology, and what we should be looking for in the next 12 to 18 months.
Oh, my gosh. So, first, thanks for the invitation, and thanks everybody for investing a few minutes with us. So Cabaletta, as most of you know, was formed in 2018, with the sole purpose of developing and launching the first targeted curative cellular therapies for autoimmune diseases. We have a lead asset now called CABA-201, which is a 4-1BB containing CD19- CAR T, directed towards four different indications in the clinic currently in phase I/II clinical trials. Each trial uses the same exact starting dose of our product, because that dose is the same dose that was used by Professor Schett in his clinical trials. Our product, we believe, is the only one that has been exclusively designed for patients with autoimmune diseases, and specifically designed to be as similar to Professor Schett's compound as possible.
It's essentially the fully human binder equivalent of his murine binder. Otherwise, nearly an identical construct. So knowing that we believed we understood the dose, we went to FDA and requested permission to go forward without a dose-finding study, which differentiated us from just about everybody else who was focused in the, industry, and we've proceeded with those trials. Thrilled to report that as of today, we have 28 clinical sites open across the United States in our four programs for lupus, myositis, myasthenia gravis, and scleroderma. The 28 clinical sites opened across the U.S. is crucial. Clinical sites are reaching their limits as to how many CAR T products, how many cell therapy products they can possibly take on.
And to the extent that you need clinical sites to enroll patients, our team started two years ago on the journey of recruiting sites, and we lead the world in terms of the number of clinical sites that are actively enrolling for our cellular therapy in autoimmune patients. The logical extension of that should be that we are now enrolling at a pace that we believe is at least as fast as any company in the world when it comes to, and this is really important, FDA-cleared, company-sponsored clinical trials. I don't know of any example where anything other than a company-sponsored clinical trial formed the basis of a dataset to get a drug approved.
And in the field of autoimmune CAR T and in CAR T in general, enrolling patients in IITs and compassionate use has value for an initial understanding of where you might have safety or efficacy and how your drug might work. But if you're talking about developing and launching the first targeted curative cellular therapy in the industry, you need clinical sites within your company-sponsored, IND-cleared clinical trials. We have 28. Bristol Myers, according to ClinicalTrials.gov, has 17 in the U.S. They're in Europe as well. I believe they have 13 or so in Europe. And it's not that we started first, 'cause we didn't. We've been doing this since 2018, and we have a world-class clinical trial operations group. The next step is gonna be the enrollment.
It took us eight months, painful eight months, much longer than we anticipated it would, to enroll our first five patients. It took us eight weeks to enroll the next four. We were enrolling at a pace between June and August of approximately one patient every two weeks. Back then, we had about 20 clinical sites open. We reported an ICANS event on August 10th, after reporting at EULAR two very safe patient administrations. So we had a lupus patient we reported at EULAR, and a myositis patient reported at EULAR. Both of them had no ICANS and no CRS.
We subsequently reported the patient number three, which is a lupus nephritis patient, who had a very biologically active case of lupus with pericarditis, swelling around the heart, shortness of breath, that caused her to go to the hospital yet again for the same problem within two weeks of the time she was administered CABA-201. In the moment, both the site, the rheumatology, and the infusion specialist, as well as the company, saw the patient go to the hospital, get treated. They went home. They looked and felt great. They wanted to be treated with their cells. We delayed by an extra day or so out of caution, administered therapy, and for four days stayed in the hospital, as is usual for our product.
I believe we're the only company in industry that started with a four-day required hospitalization, as opposed to 10 or 14 days, again, reflecting the belief in our safety, lo and behold, this patient at day nine came back with CRS grade 1, followed by seizure activity in the brain, not movement of the muscles and the body, but seizure activity in the brain. That seizure activity was triggered by excessive cytokines being released on day nine, and that led to a decline in mental status that we call grade 4 ICANS. They didn't have swelling of the brain. They didn't have any other sequelae. They just had the seizure activity that caused them to essentially lose consciousness, if you will. They had routine therapy that rapidly reversed their seizure activity, and their mental status was restored completely.
Within three or four days, they were discharged with no sequelae at all. While I can't give you the medical case report that we intend to publish very soon, as soon as we can, we'd love to be able to include three-month follow-up, efficacy, safety, translational data, a full set of information, because in talking to our SAB members, called Carl June and others, this is a seminal case for autoimmune CAR T. This was not about CABA-201, in our opinion. This was about a patient who was clinically stable from their pericarditis event, but the appearance was deceiving. They were treated with steroids and other medications that made them feel great, but biologically, they still had cytokines that were a tinderbox waiting to be ignited by the infusion of activated T cells, and I think you'll see when we publish it, this is tantamount.
This is similar to a heavy tumor burden in a CAR T cancer patient, where the CAR T cancer patient is at higher risk of side effects because a lot of B cells that then explode in a lot of cytokines. This is a patient who was waiting on the activated T cells, and they had an excessively high response to the activated T cells that were infused, and they had the side effect. That was unfortunate for the patient. The great fortune is they were discharged without any sequelae, and they were managed beautifully well. I wanna close out the opening comments that are longer than I would have liked, but I wanna close out by saying we went. The most important thing is to know the data and to, more importantly, maybe, what was the reaction?
What was the reaction of that investigator, and of the DSMB, of FDA? What was the reaction of other clinical sites that wanted to open or of patients who might have enrolled subsequently? Since that event, we went to the DSMB. The DSMB said, "change nothing. We believe this is about the patient circumstance. Do not slow down. Do not change your dose. Don't change a thing." The FDA, we went to them, and we said, "You know, DSMB said, 'change nothing.' We would like to include seizure prophylaxis, a simple pill before, during, and for the month after administration." Not because CABA-201 is somehow different or toxic in some unusual way, but because Professor Schett always gave every one of his patients at Erlangen the same seizure prophylaxis that we recommend at this point in all of our trials.
Not because CABA-201 is different, but because in the interest of patient safety, the downside of administering an oral medication to prevent seizure activity can maybe, just maybe, prevent a grade four ICANS. There's been some debate in the investment community whether Professor Schett really did administer it because a junior person or two at Erlangen said it was not administered. Just for the record, we've spoken to him as recently as last week to confirm what we knew all along. His first publication of five patients included the disclosure about seizure activity prophylaxis being administered. The same five patients presented in The New England Journal of Medicine. It wasn't in The New England Journal of Medicine. They didn't write it there. Whether they'll correct that or not, I don't know, but I assure you, every patient at Erlangen with cancer and CAR T administration gets it, and all the autoimmune patients got it.
So all the data that excites us used seizure prophylaxis. We should use it, so we are. And the second thing is, wait longer after, wait two weeks at least, after you have an event like pericarditis and don't administer therapy 'cause the appearance of clinical stability and calmness can be different from the biologic activity beneath it. So we hope to publish that very soon. FDA's response was, "keep going, change nothing. Yeah, those are good changes. Do that." So we did. In addition, remember that our trials, we have the permission of FDA to go two- and three-fold higher in dose than we currently are. There was no change in any of that. Next, all the investigators were made aware, all 20 of them. What happened? The 20 of them said, "we're still enrolling.
Thank you for telling us," and another eight sites have opened in the last eight weeks. What happened in terms of patient enrollment? We went from five in eight months. We added four more in the next seven weeks, and that pace of enrollment, which appears to be about one patient every two weeks, is not slowing down. Now, we're not gonna give interim, interim patient updates on how enrollment is going, but at the end of this, by the end of this year, I am hopeful that we're able to report, number one, a sufficient number of cases with up to six months follow-up from our program, demonstrating the safety of CABA-201, which we believe more than ever is what we always thought it would be. Number two, the efficacy and activity associated with that to be reported out.
Number three, the pace of enrollment, which I expect will not be any less than any company in the industry for U.S.-based enrollment of IND-cleared, company-sponsored clinical trials. And then finally, remember, we're enrolling, and last we said a, a number, it was nine, and I'm telling you, we're not near nine anymore. We have cohorts of six patients in each of the four trials, and within the four trials, we have different subtypes. There are nine subtypes. Any subtype of the disease, lupus or lupus nephritis, for example. We get six patients. We go back to talk to FDA about registrational design. So my aspiration is that sooner than anticipated, we're starting to talk about that design with FDA. So I'll pause there, Josh, at seventeen minutes.
Super. Are you done opening trial sites? What are your target numbers?
I would say we have not even begun. So to the contrary, I know from multiple sources, investors and companies, that there is a very important challenge that companies are running into, which is they're knocking on the door of the most prolific sites, and those sites are saying, "regardless of what you have, less preconditioning, no preconditioning, allogeneic, some future, the NK, not whatever. I'm sorry, I can't even begin to think about taking on another trial with cellular therapy. And I understand it's gonna be simpler, there's no apheresis needed or what, it doesn't matter. I don't have the nurses, I don't have the clinical capacity." Think about it. You have Novartis, Bristol, us, you have every flavor of every company that ever had a cancer drug trying to repurpose towards autoimmune. We knew this was gonna happen.
October, 2022 , look back at our staff meeting notes, that the gold is going to be drilled or is gonna be found, the oil is gonna be drilled, the gold is gonna be found on the land that you have to own, and the land that you have to own are the clinical sites. Investors completely do not understand that yet, right? And I think this discussion is intended to highlight the importance of clinical sites. Without clinical sites, you can't enroll patients. Without clinical data, you can't create value. And while, you know, many will argue which, who's gonna win the CD19 race, at the end of the day, you need data.
We are as guilty as anybody of not delivering as much data as fast as we would have wanted, but from here forward, nobody's gonna do better than us, and it's because we have the sites that we can do that.
How have you prioritized then, the sites to start with? And, you know, where is that target optimal number of sites for enrollment?
The last two drugs approved for the treatment of lupus in the United States, Benlysta and Saphnelo, were developed by GSK and AstraZeneca. The head of the medical function in each of those two phase III programs was our Chief Medical Officer. David knows that each of those programs in a pharmaceutical development program for lupus required about 100 clinical sites worldwide. We knew that in October 2022. When you think of how many sites, I don't think 100 is a limit, I think 100 is kind of the ante. I think to be in the game, that's where you need to start thinking.
Now, we have a clinical trial design program that is purposely built so that these major differences of a complete drug-free, disease-free follow-up period in patients, which is our goal, that can be demonstrated as a truly effective outcome versus almost any standard of care today, with far fewer than, like, a hundred patients. But you need safety, and the safety will come from all nine of our cohorts, all four of our INDs, all at the same dose, driven to the same patient type. Within the efficacy standard of approval, we need to demonstrate beyond a shadow of a doubt, statistically, that there's a difference between a complete responder, measured by FDA acceptable milestones and endpoints, and those who either have no care or in some cases, there is a standard, we would compare against that standard. So that's our expectation set.
Open as many sites as you can. We have plastered the U.S., right? We currently probably are talking to over a hundred sites in the U.S. alone, and, you know, in due course, we will start talking more about a long-standing effort that we have ongoing in Europe, to expand globally with our program, because you must have global clinical sites to achieve the sorts of numbers that we need to achieve in the industry.
Are the sites that you're enrolling at different than the ones that Bristol and Novartis?
Sometimes there's overlap, sometimes there's not. The investigators, you know, if they have the capacity, like to have two, if they can. I'm not familiar with many, if any, that have three. And if they have the opportunity to fulfill, you know, early to create an early data set with you, that's the most motivating thing you can offer them because of the prestige that comes with the data that you would generate early in a trial. Our trials are all designed, and it's really important. Our trials are all designed... Yes, it's a cohort of six with lupus, right? And I think we have 16 or 17 lupus sites currently open. It's a cohort of six that we need to fill.
Once that's filled, we go to FDA, and we talk, and we have fast track for nearly every indication at this point, so we're gonna have a very fast turnaround with FDA, we believe. If the data are supportive, while we're talking to FDA, our trials are all designed, and we haven't until now said this out loud, although it's self-evident, perhaps, if you look deeply, every trial has the capability to enroll substantially more patients while we're talking to FDA. We're not gonna turn away a patient simply because we're somewhere between phase II and phase III. The objective is treat and enroll as many patients as can show up. Our conversations at the leadership team table until June were about how do we make sure awareness and in education and communication about our trials is widespread? Those conversations have now shifted.
Yesterday's discussion was entirely centered on clinical supply, because the demand is clearly there, and now it's a question of clinical supply. You know, I'm thrilled with the prospects of the company, and I think my view is shared both by our leadership team, which I would say I'm even more thrilled. It's the same leadership team that's been around this table since two thousand and eighteen, and our stock price has seen, as most of you know, the highest of highs and the lowest of lows. It's not about that for us.
It's about developing and launching the first targeted curative cell therapies for autoimmune disease, and there is no more exciting thing to see than patient after patient enrolling and giving us the very near-term prospect to talk about what our real profile is with investors, with patients, and then to see the ball continue to roll.
So you talk about the strategic positioning of having as many sites open as you do have. I guess if sites can double up, and there's well over a hundred sites to choose to pick and choose from, why wouldn't, you know, a competitor program, an Allogene program, be able to find plenty of sites for themselves?
You'll have to ask them. So they've been open for over a year, and on ClinicalTrials.gov, there is not an allogeneic company that has more than two clinical sites open. I don't know why. I understand what I hear from investigators. I understand what I hear from investors in those companies. I understand what I hear from strategics who come to us and say, "hey, can you develop our drug for us? Because we're not gonna be able to open that many sites." So I hear that, but I don't know why they haven't opened up more sites.
Can you elaborate the opportunity you have to expand the portfolio with it... of product offerings within the sites that you're working at? How easy-
Yeah
... is that for you to do compared to a new company just coming in and-
You always ask the next question. Not our intention to highlight, but I will respond to the question by saying, companies are now approaching us with their potential therapies earlier in development than the most advanced of the allogeneic products. These are allogeneic or other forms of therapy where you don't have preconditioning, and they, the investors and the companies, look at these products and opportunities, and they look at what we are doing, and they fully appreciate how hard it is to open a clinical site. Look, Bristol Myers opened 17 of them in two years, not for lack of trying. They are slaying it. They're doing a great job compared to everybody else, except Cabaletta. That's not lost on everybody else who's trying to do what we're doing.
And so they come to us, and they say, "for a lot less money and a lot faster than we can do it, you can develop our drug." And the reason they say that is this. About four months ago, we had a choice. We saw the early activity, biologic activity and efficacy of CABA-201 with preconditioning, and we have a long history of talking about the value of preconditioning. We believe, with very good scientific rationale, that Flu/Cy provides no benefit to clinical outcomes at the doses used for preconditioning. The early signal in that would be the myositis patient that Professor Schett saw when he retreated with a CD19- CAR T that was murine. There were antibodies that blocked the cell expansion. The cells never expanded. The patient's symptoms didn't change. Oh, wait a minute, they got Flu/Cy.
Flu/Cy didn't change symptoms in myositis patient who had an exacerbation. That's the first evidence. It's early. It's one patient. It's the first evidence that Flu/Cy does not have direct clinical benefit in these patients. If Flu/Cy doesn't have benefit, and if CABA-201 can benefit patients with Flu/Cy, it isolates on the question that we all want to know the answer to, which is: Can CABA-201, at usual doses and at higher doses with no preconditioning, change the world for a patient? Can you get not only an acute, but ultimately a durable, complete response with no medications but the cell therapy? That trial was something we filed with FDA. We had two choices.
We could either file it as a new IND, which we've done many times and done it within thirty days, repeatedly and successfully, and then wait nine months to open your first site, 'cause we and every other company in the industry takes that long to open the first site after an IND is filed. So we could either do that, or, credit where credit is due, Gwendolyn Binder, our President of Science and Technology, with the deepest history in this industry and an awesome teammate, recommended that we explore the following: Go to FDA and say, "we have 10 clinical sites," not among the 28 that I'm talking about. This is 10 additional sites that we've been working with for years.
These ten U.S. sites are enrolling patients or have enrolled patients with DSG3- CAAR T, this other product that we were using in the past for pemphigus. Pemphigus is a pure B cell-mediated disease. It's the perfect disease to study no preconditioning CABA-201. Let's put a sub-study recommendation. Let's do a sub-study, a new arm in that trial. The contracts are already negotiated. The budgets are already agreed. The sites are already open. The IRBs are already happy. Why would we wait nine months, and there's ten of them. All they have to do is the IRB reviews the new sub-study. FDA said, "go right ahead." All ten clinical sites are now reviewing the protocol.
The first one of those sites, which is going to be enrolling, and, you know, just listen for a minute, pemphigus of any form, you show up, you have your blood drawn, and 30-45 days later, your cells are infused. We're gonna know if your T cells expand to a level of activity or not, if your B cells are eliminated, and if your antibodies start to decline. We're gonna know that in a very near-term way, and I don't mean to create undue expectations. We won't talk about any of this until next year, right? In fact, we may not even talk about it next year, because the first thing we're gonna do if we see the activity at the starting dose or at the higher dose, is replicate sufficient numbers of patients.
The first site already opened four months after we filed the IND with the FDA, not nine months. The second and third sites are gonna be opening in the coming weeks. This is the most important trial in the entire industry right now, because if cell therapy alone with no preconditioning works, every allogeneic product currently in clinical trials has to ask themselves what their value proposition is for patients. It changes the game, it moves the cheese. Cabaletta has been and will continue to be a leader in this field in ways that are not at all evident to the world yet, but the opportunity to leverage our clinical portfolio, to leverage our clinical trial designs, to bring in new products if we want and need to, where we think there's benefit. By the way, allogeneic might be the perfect approach for MS.
Autologous for MS, that's a tough, tough. Imagine, what, how many patient therapeutic units can you manufacture for the 1.3 million patients with MS? And even a less effective allogeneic product might be a better alternative for those patients. So we see it as entirely compatible with CABA-201 and its success to have these sorts of products. And all of us are going to sit behind the bispecifics. So today, you have to fail two or three therapies to be able to be in our trials. We never imagined a world where we don't get anything other than the 5%-30% most severe patients. The fact that they got a bispecific that took them out of our market, that's fine.
There's still 5%-30% of the patient, unless you believe that bispecifics are permanently, durably, single dose, single regimen, curing all patients. Perfect drugs with no side effects. Unless you believe in perfection for bispecifics, there needs to be something for the patients who either can't tolerate, don't respond to, or have continued organ decline, or frankly, don't wanna spend $250,000 a year forever just maintaining their disease while they are immune suppressed. And we are among those who believe that something has to come after bispecifics, and it doesn't matter that it's bispecifics or it's rituximab. They're gonna get something first, these patients. There has to be something that is a reliable, durable, curative treatment. We think we can be that for patients. We need to get the clinical data. We need to have the efficacy and safety documented.
We hope that comes this year. The no preconditioning is a complete game changer for everybody, and all of that, combined with discussions with FDA that we hope are triggered by data permitting, a cohort of six patients or two or three being filled, you know, we feel great about our prospects right now.
When do you think you'll be in the registration trial? What do you think your first two registration indications are gonna be, and are they gonna need to be controlled trials?
So if I answer your first question, it becomes a milestone for the company, and we haven't said anything, so I'm not gonna answer the question. But suffice it to say that that is what we're talking about. We are internally, in-house, designing the registrational cohorts with very deep detail at this point for at least two of the indications that we know are starting to fill. I do think that with 17 clinical sites opened and the largest of the markets that we're currently looking at available to us, lupus, a place where nobody can get sites and nobody can get patients, but we've always said we're gonna compete there, and it may be the first way to get a phase III program up and running.
But it's not the first product that's gonna get approved, in my opinion, in our opinion, because the clinical trial required for lupus will necessarily be more patients against comparators with more data required. The IMNM subtype of myositis, there is no treatment, and I'm a great believer for a lifetime, that when patients show up in your clinical trial, you can tell the marketing people where the unmet need is. And our first patient was IMNM. That's what we've said publicly. I'll leave it at that, but IMNM is a really great place for us to go. The only approved therapy in myositis is IVIG for dermatomyositis at a cost of $500,000 per year. The IMNM subtype is extremely difficult to treat. It is notoriously challenging compared to the others, and there are no treatments. So those would be the first across the launch timeline.
The first two phase III might be lupus, but I never know who's gonna show up for enrollment, so I don't know the answer to the question.
Are you expecting ACR to be the next major update?
Um-
How do you think about framing it?
Yeah, we haven't announced anything in particular, but it wouldn't be illogical to think that ACR would make sense. We were manufacturing five patients simultaneously in August, and you can work the numbers from there to understand what data we might have. Six months, three months, and one-month follow-up on a full cohort of patients.
We'll look forward to seeing you again in November, then.