Hello, everyone. Thank you for coming. My name is Zachary Conti. I'm a member of the J.P. Morgan Healthcare Investment Banking team. It is my pleasure to announce Cabaletta Bio. There will be a short presentation, followed by a Q&A. I would like to introduce Dr. Steven Nichtberger, Chairman, CEO, and Co-founder. Thank you.
Thanks, everybody, and good morning. Appreciate everybody investing some time to learn about Cabaletta this morning. Cabaletta exists to develop and launch the first targeted curative cellular therapies for autoimmune diseases. We were founded in 2018. This slide has been with us ever since. We're pursuing these cures for a broad range of autoimmune diseases using two strategies, the CAR-T strategy and the CAR-T strategy. The CAR-T strategy is led by the CABA-201 product that we announced in October. That product is on track for an IND filing in the first half of this year. We're excited about CABA-201 because it builds on the history of a publication in September of last year, where an academic clinical study demonstrated that five out of five patients with refractory systemic lupus were cured, had a complete response within three months.
All serologic and all clinical markers of disease were resolved within three months. Their immune systems seem to have been reset by the therapy, a single infusion of CAR-T therapy resetting the immune system of an autoimmune patient. We expect to accelerate CABA-201 through an exclusive translational research partnership with the author of that paper. In this exclusive translational research partnership, we receive samples from all of the patients in that publication and in future patients treated by this leading physician. Our translational research team, that's been at this for five years, works on and develops data around those patient samples, returns that data to Professor Schett for his evaluation as he shares the clinical findings from his study with us in order that together we can advance the field of CAR-T therapy for autoimmune disease.
CABA-201's been specifically designed for use in autoimmune patients, specifically engineered to be able to be safe and deliver the efficacy that we've seen in this Nature Medicine publication. We use a 4-1BB costimulatory domain that is, as you may know, the safest form of costimulatory domain when used in cancer patients as it typically is. It provides a much lower risk of neurotoxicity and of CRS in those patients versus the alternative costimulatory domains. It's the same domain that Professor Schett chose to use in his study. CABA-201 has a fully human version of the CD19 binder that was used by Professor Schett in that study. His animal version, his murine version of the targeting domain, is the same, it targets the same epitopes as our fully human version. The binder that we use has clinical data.
In 20 patients in a CD19, CD22 product, 20 patients were treated. The tolerability and the safety of that product, including our binder in those patients, demonstrated what we believe to be a tolerability and safety profile that is perfectly well suited for use in autoimmune patients. We're really excited about CABA-201 and the opportunity that it provides to address a broad range of autoimmune diseases, starting with lupus, of course, as was presented by Professor Schett, but he has also publicly spoken about his ongoing efforts in patients with myositis, in patients with scleroderma, and aspirations to address patients with rheumatoid arthritis. Turning for a moment to the CAR-T strategy, our legacy strategy as a company, we have 2 products in clinical trials currently. The first one is DSG3-CAART, the second is MuSK-CAART for myasthenia gravis.
The DesCAARTes study with DSG3-CAART for pemphigus patients is currently dosing patients in a combination regimen with cyclophosphamide and IVIg. We're in that phase of the study after a long-standing experience with monotherapy where we delivered a beautiful tolerability and safety profile, but insufficient efficacy to demonstrate the full capability of the platform in this case. We're excited to see that data later this year. The MuSK program in myasthenia gravis has similarly been designed. We start with a much higher dose. We go through a monotherapy regimen in only four patients if it is deemed to be safe in those four patients, and then we move into a combination regimen if it is appropriate. Really thrilled with what's gonna happen in 2023.
Our plan is to reveal clinical experience, clinical data with all of our programs as we get through the next year, into early 2024. Our cash runway is about two years and two and a quarter years from now, we have plenty of capital to be able to implement on the promise of these strategies. Just to dive in for a second to be clear, the CAR-T strategy and the CAR-T strategy, both of them in the CABA platform. The CAR-T strategy, chimeric antigen receptor T-cells for autoimmunity, CAR-T for autoimmunity, seeks to reset the immune system.
I guess the way to think about it is we're eliminating all of the B cells in a patient who is genetically predisposed to disease, and the patient who's genetically predisposed to disease doesn't get that disease until some environmental insult occurs. That environmental insult results in a B cell response that triggers a disease cycle that causes the patient an awful lot of suffering and pain. That stays. The patient stays in that state. It doesn't revert. The B cell may or may not be at the center of that pathology. It doesn't seem to matter. What we do when we treat with the CAR-T platform is we believe we will be eliminating the B cell compartment.
In addition to a transient elimination of the B-cell compartment, we see on its reconstitution, the B-cells are immature, and that immature B-cell population comes back in a patient who is now predisposed to the disease perhaps, but no longer has the spark plug that's required to get the engine of disease going. If this is true, the potential for CABA-201 to treat a remarkable broad variety of autoimmune diseases is just profound and it's terrifically exciting for patients, for physicians, and of course, for the company as well.
On the other hand, a very specific and elegant platform, the one that we co-founded the company on, is the CAR-T platform, where the antigen that's the subject of attack is engaging with only the 1% of B cells that are causing the autoimmune disease. In this case, we're seeking to eliminate only 1% of your B cells. The normal B cells are never touched, so they remain intact. We've demonstrated in this platform that the therapy is very safe, but it has yet to demonstrate the sort of efficacy as monotherapy that we would've liked to see. As I've told you on the prior slide, we're moving ahead with combination regimens, and we expect to deliver data on that in the coming year.
This is sort of a sampler of the disease states that could reasonably be addressed with these two strategies. In dark blue, you see the ongoing or recently completed clinical trials that are underway at Cabaletta or in Professor Schett's experience. Our specific pipeline, two programs in the clinic at this point, myasthenia gravis and pemphigus. For the CABA-201 platform, we have yet to reveal the specific clinical indications that we will be pursuing, and the reason for this is very simple. We believe that after five years, we understand an awful lot about CAR-T in autoimmunity. Our partnership with Professor Schett provides us with the opportunity to have insight into what's coming.
It is of strategic importance that we use all the data that we have at our disposal to be able to make informed choices about which indications and how we will pursue them. In due course, we'll reveal the undisclosed indications, but that's why it's currently remaining undisclosed. Let's dive deeper into the CABA-201 product in this CAR T platform. These are the academic clinical data that got us so excited and frankly, have struck a chord with, I think, the whole industry at this point, more broadly. 5 out of 5 refractory lupus patients treated with a 4-1BB containing costimulatory domain in a CART19 product. The administration of the product results in a rapid, deep, and transient depletion of the CD19 positive B cells.
The graphs on the right show you the CAR T cells expanding and resolving within 30 days, the B-cells disappearing within 10 days, and the white blood cell count only transiently for a very short time, going down and then back up with the result of preconditioning. The B-cells, however, don't recover as quickly, and we'll talk about that in a moment. By three months at the bottom of this slide, you see that the symptoms measured by the SLEDAI scale are resolved. Like this is data that in a pilot study, you know, you don't have to squint to see the data, and if you do squint, you still can't avoid seeing the data. It is a profound initial experiment experience in patients with this form of therapy.
Every serologic and clinical marker of disease seems to be resolved, consistent with the belief that we have reset or that in this case, Professor Schett has reset the immune system. More importantly, the safety profile reported in this paper showed that only three out of five patients had any CRS, and the CRS that they had was grade one CRS. The worst of the cases was a patient who had so much fever that they needed to have a single dose of tocilizumab to resolve the fever. Other than that, there were no side effects reported. That's not surprising in an autoimmune population where fewer B cells are being killed than in a cancer population, and frankly, where he's using a lower dose than is typically used in cancer.
The safety profile, really remarkable. Compounding all of this, as I've discussed, the B cells are repopulating with a naive set of B cells. You have no mature B cells, reappearing. Instead, you have naive B cells that are waiting to create the new B cell portfolio in that patient. We've seen that the patients here followed for as much as 17 months, have no need for medication and have no disease. There's one patient here who shows a little bit of a signal. That's a renal disease which was documented by biopsy to be unrelated to lupus. Really thrilling data. On the back of this data, we designed CABA-201, a CD19 targeting CAR T therapy. It contains a 4-1BB costimulatory domain.
Let me remind you that that is documented, well accepted in the literature based on all of the cancer experience to be the safest form of a costimulatory domain to use in a field where this is not cancer, this is autoimmunity, and the patients suffer every bit as much as cancer patients. Their prospects, though, are different. They're not going to usually die in the next 48 hours or the next month. The safety has to be exquisite. Choosing the safest costimulatory domain matters, and that's why we chose it. It is also, by the way, the one that Professor Schett chose to use, not surprisingly. Our fully human anti-CD19 binder is the fully human version of the murine binder that Professor Schett used.
Professor Schett's binder is shown on this slide, and you can see that we compare favorably to the binder that he used with in vitro and in vivo evidence of comparable activity biologically. Cabaletta Labs has now repeated both the in vitro study and the in vivo study. We're highly confident that our binder has similar activity to the one that delivered the clinical results that you've now seen. Our binder has data in 20 patients with cancer. We're developing a product that's already been in the clinic, right? Not in a monotherapy, but in a combination form of therapy, a CD19, CD22 form of therapy for cancer patients. Those 20 patients had no evidence of side effects that would preclude use in a population that requires a very safe approach. We're really thrilled with the opportunity to advance CABA-201.
When you start with a great product, you need to do much more than that to win, and this will be a highly competitive field. We are a small company. We have fewer resources than most of the companies that will come after this because the opportunity is so attractive. Why will we win? Well, it starts with a product that's properly designed, that's closely aligned with the product that has demonstrated clinical efficacy and safety in those five patients. It's so much more than that. We're in a position where for the last five years, we're the only company on Earth that has spent five years filing two INDs successfully with a 30-day clearance, CAR-T products in autoimmune patients. We understand what preclinical data FDA needed. We understand what clinical programs FDA was accepting of, what clinical designs were attractive or desirable.
We understand how to implement manufacturing with a 100% success rate over the last five years, working with the University of Pennsylvania to do so. We understand how to implement in the clinical operations sense. Just imagine for a minute what we have to do. The oncologist is administering therapy. The dermatologist is loading their patient for a day so they can be treated. The side effects are treated by the oncologist acutely, but more chronically, it's the dermatologist once again who steps in. The same is true for the neurologist in the myasthenia gravis population. The same is gonna be true for the rheumatologist in many of the indications we're talking about. This is not simple, and we are very good at it. We have 12 sites in the United States that currently are open in our trials. We know how to do this.
We will convert a number of those sites into the CABA-201 program very efficiently. The duration of time required to get a site open after an IND is accepted is underestimated by most everybody, companies and investors. It is hard work. We have an advantage because we know exactly who to talk to. We have existing contracts, existing budgets, all we need to do is modify a few of them. We're feeling very good about the ability to implement successfully. I come back to the design of our product and equally importantly, the opportunity to partner with Professor Schett.
To partner with Professor Schett in a way that is not about simple announcements that he's an advisor or he's an SAB member, which he is, but a true scientific partnership whose purpose is to advance the field using our translational research expertise and his clinical program. Together, we believe we will advance the field. For Cabaletta, we believe we will design and implement the best product in a very important field. We expect, again, the IND for CABA-201 to be filed this half of this year. I would say we are at the IND writing stage. We're not at a point where we have data-driven risk, and we feel, again, highly confident that we'll be successful in our efforts here.
Let me turn my attention just for a couple of moments to the DSG3 CAAR T and the MuSK CAR T program. Pemphigus, really severe disease. You talk to patients who are on rituximab, on steroids, and still not really responding. You can see here that despite 3.5 grams of steroid per year combined with rituximab administered multiple times throughout the year, patients are still two-thirds of the time gonna suffer from failure of therapy and disease within the two-year period. These are patients who they tell you when you talk to them, if you go to their patient meetings, when they swallow water, if they have a sore in their mouth, it's not like a cold sore. It's like swallowing glass, like shards of glass when you drink water. There's a really important unmet need here.
We believe that the CAR T platform, DSG3 CAR T, can address these patients and their unmet need. As I've discussed over the last few years, we've escalated in a dose escalation trial from 20 million up to 7.5 billion cells. The safety and tolerability is exquisite. It's fabulous. With that said, there has not been the level of biologic activity or clinical response we would have liked to see. That informed the decision to move into a combination sub-study. Shown on the right here is the dose response curve as we escalate from 20 million cells up to 7.5 billion cells. A beautiful curve until we get to that 7.5 billion, it plateaus. Where it plateaus is really important.
The pink shading at the top of these graphs reflects the pharmacokinetic measurements that are associated in cancer with efficacy of CART19 therapy. If we can't get into that zone of efficacy, we can't expect our therapy to be effective. We believe that we have a couple of strategies through the combination sub-study to allow us to get into that zone of efficacy. Specifically, we believe that IVIg can diminish the circulating soluble antibody. We don't have evidence. In fact, we have checked, and there is no evidence that those antibodies are in the way, that the antibodies are prohibiting our activity. We don't have evidence of that. Nonetheless, it may be the case that we're not detecting it, that something's going on we don't understand, so we're adding IVIg to the regimen.
In addition, cyclophosphamide to reduce the cytokine sink to give the therapy, the DSG3 CAR T, the best chance of hitting that zone of efficacy. This trial will read out later this year. We'll talk about the data. The early efficacy influence of the preconditioned regimen will be out of the way, and the literature is pretty clear on this. IVIg and cyclophosphamide will have a transient but not a permanent effect on the disease. By six-nine months, it'll be cells, our cells that are doing it or nothing. There's also a lower priority, 15 billion cell dose, where we don't put a high probability of success, but we thought it was worth trying because the safety of the product is so profound. Flipping quickly to the MuSK myasthenia gravis program.
In myasthenia gravis, we have a starting dose of 500 million cells, not 20 million. Experience working with FDA, understanding what they'll accept and not. We have a two-by-four design. It's no longer a three-by-three design. That means with two patients, we're going through each dose, 500 million up to 2.5 billion cells. Those are the two monotherapy doses. The fifth patient treated, if therapy is safe, the fifth patient treated is going to be a combination patient, one who gets preconditioned regimen. Very quickly, this is going to help us answer the question. In myasthenia gravis, a disease that has many characteristics very similar to pemphigus, this will tell us whether the difference, the lower antibody titer in a typical myasthenia gravis patient than a pemphigus patient, whether that matters.
Excited to evaluate and hopefully to be able to successfully declare an effective treatment for patients who really need one in this MuSK myasthenia gravis program. Our manufacturing strategy has allowed us to succeed through the two years of cold winter that the biotech industry has had. We didn't hire the 80-100 people that you would need to say that you have your own manufacturing, and it didn't matter. It only mattered because we spend very capital efficiently, about $10 million a quarter historically. We've elevated a bit with CABA-201, but we have always been very intentional about our manufacturing strategy. We started by working with Penn and having the variable cost associated with that very reliable provider of our product.
In 2021, we engaged with Oxford Biomedica and WuXi AppTec on vector and cell manufacturing, both of which could take us into commercial use for any of our programs. At the right time, Cabaletta will make investments in its own manufacturing facilities and capabilities. Our leadership team, you know, I used to talk about how fabulous the team is and so forth. Team's still fabulous, I think the results speak for themselves. Right? We have done the right studies. We've done no harm to patients. We've yet to deliver on the efficacy promise. We're prosecuting that as planned. We have been incredibly capital efficient and spent where we needed to.
That put us in a position back in the fourth quarter to in-license CABA-201's binder, which has really been the beginning of the next chapter in this story of how this team is gonna achieve that first slide. Curing autoimmune diseases with cell therapy is possible. These data will help us understand how quickly we'll be able to do it, which strategies will work, and the team has plenty of capital to be able to implement on these milestones. Really appreciate your being here this morning and your attention. Happy to take any questions.
Well, thank you for that presentation. Very insightful. I guess I have a few questions to start. You had mentioned that you guys are filing the IND filing for CABA-201 in the first half of this year.
Mm-hmm.
You know, what work, or other obstacles remain before you can successfully file?
Thanks for the question. We feel highly confident about the IND filing. And the reason is, we have the overwhelming majority of all of the data in-house. And it's really just now a matter of writing the IND and submitting it. The lead, the coordinating lead on the IND is the exact same person who, while working for Carl June in... 20 years ago, wrote and filed the IND for Kymriah, which of course at that time wasn't Kymriah, it was the University of Pennsylvania CART19 program. The similarities between that CART19 product 20 years ago and now are profound, obviously.
Really, those facts and the fact that the same individual at Cabaletta led the IND filing successfully for DSG3 CAR-T and MuSK CAR-T, two CAR-T products in autoimmune patients. I love our odds.
That's great news. Another question is, there's a lot of competitive interest from larger and smaller biotechs. You know, how do you guys think that you're gonna be successful when competing against these players?
Internally, we talk about this every week at the leadership meetings. We are smaller and we have less money than all of the big pharma, all of the biotech, you know, the big, the big players who already we know are very interested in this field. The reason we believe we will win is, we do have all the characteristics of a delta force. We have more experience, we are better trained at implementing and executing on the promise of autoimmune CAR-T therapy than anybody on Earth. In fact, our chief medical officer actually, to complement that, has been responsible for leading the development and then approval of the only two drugs that have ever been developed in the last 65 years for lupus. There are two products approved for lupus in the last 65 years.
Our chief medical officer ran the program for both of those in their Phase III state. That's just one sampling of. The other I would mention because I've already mentioned is the IND filing and the manufacturing. Our President of Science Technology started back in Carl June's lab writing that IND on CART19. We just have terrific people who are passionate about executing, knowledgeable as much as anybody on Earth, I believe. That collaboration of incredibly knowledgeable and trusting people with the experience we have as a company, and I guess all of it compounded by the knowledge that we have designed the right product and we have the right partnership. The right people, the right product, the right partnership. We know this is possible. There's clinical data.
Mm.
We just have to go do it.
Yeah. No, also those are great reasons why hopefully you will. That's good. Earlier this week, you know, Autolus announced that you had licensed their RQR8 safety switch technology.
Yeah.
How do you envision using that technology in the future?
We've been talking to Autolus for a year and a half, learning about the RQR8 technology and understanding how we might use it. We decided to bring it in through that agreement, not for CABA-201. I wanna be really clear. CABA-201 is moving ahead as a program, as it has always been spoken about. RQR8 is a tool in our toolbox. This category of product, right? This approach to elimination of B cells as a form of perhaps curative therapy for autoimmune disease, is gonna have a lot of twists and turns along the way. We, as a leader in the field, need to be ready for the second, the third, and the fourth phase of what's to come. We historically have had a gene editing partnership.
We have that capability in-house now from a few years ago, we announced a partnership with Artisan Bio. We continue to talk with them and work with them, collaborate with them. Here too, the RQR8 technology, we have the access to the technology for our programs. To the extent that the safety switch that it provides is something that would be useful in a portion of the patient population or in a particular indication, where you'd want to get rid of the product that you've inserted into the patient, you've administered to the patient. This would be an approach to a safety switch, where the safety switch is already in the clinic. We know that it's safe, and it frankly uses rituximab as its trigger.
If you wanna get rid of that product, if we did include it in a future product, it would just simply allow for the administration of rituximab dose in a patient who doesn't have B-cells because maybe they have you know, more permanent or prolonged B-cell aplasia. Administer a drug that gets rid of B-cells, there are none, so it will have no effect that way. It will get rid of the T cells that have that receptor for rituximab on it, this RQR8 receptor. It was a beautiful tool to insert in our toolbox for future use if needed
As a reminder, the data from Georg Schett show us that 5 out of 5 patients had a full reconstitution of a brand-new B-cell compartment, all of it immature B cells and all of it healthy. No evidence of recurrence of disease. We may not see any problems.
Good.
If we do, we wanna be ready.
Yeah. No, it's good to have that backup plan. Anyone have any other questions? I guess I have another question. You know, you had mentioned in your presentation that CABA-201, you're obviously starting with lupus, and you have the opportunity to expand to scleroderma and others. Could you just walk me through that process and, you know, how you would potentially expand to other diseases and what's the timing on that?
Yeah. Just for clarity, we haven't announced which indications we will. prioritizing first, second, third in the clinic. You know, it's hard to look at the lupus data and not have a point of view that that should be developed. We have additional insights into the future of this form of therapy that are still confidential to Georg Schett and to the company through our partnership. That influences our thinking, exactly who we treat, how we treat them, where are the pitfalls, where can we enhance outcomes, you know, which portion of the patient population would be the right portion to go after first, second or third, which indications and in what order. Those are gonna be ultimately gain time decisions that we'll make as we file the IND.
Mm.
We would expect to announce, you know, the indications in due course later this year. For now, we believe we have, you know, frankly, more experience in the past with working with FDA and as I've discussed, and going forward into the future, and looking and peering into the future through our partnership with Georg Schett. All of that is actionable data that we're considering as we think about how to prioritize our clinical assets.
No, that's excellent. I guess, does anyone else have any other questions? That's it. Well, thank you for coming.
Thank you.
It's very, very insightful and excited to see the future.
Yeah, us too.
Thanks.
Thanks. Appreciate it.