Cabaletta Bio, Inc. (CABA)

39th Annual JPMorgan Virtual Healthcare Conference

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Jan 14, 2021

Hello, everyone. I'm Nader Sarabi from the JPMorgan Healthcare Investment Banking team. On behalf of JPMorgan, it's my pleasure to introduce Doctor. Steven Nick Berger, Chairman, CEO and Co Founder of Capital Data Bio. As a reminder, we'll try to reserve a few minutes at the end for Q and A. So if you have any questions, please submit them online using the Ask a Question feature at the bottom of your screen. I will now turn it over to Doctor. Nick Berger. Thank you. Thanks, Nader, and thanks to our friends at JPMorgan. I appreciate you guys spending a little time with us today. So, Caboleta was spun out of the University of Pennsylvania in order to develop and launch the first curative targeted cellular therapies for patients with autoimmune diseases. And while the biology suggests that we might provide a deep and durable response, perhaps even a cure for patients with these autoimmune diseases, Make no mistake about it. To be successful, we simply have to be better than the best available therapies for these patients. So we're developing these highly specific CAARCART products to treat B cell mediated autoimmune diseases. We're focused on diseases where there's a biologic opportunity for deep and durable responses and perhaps cure. And we're leveraging the work that has been done over the past 15 years at the University of Pennsylvania to leverage their design and their manufacturing expertise in the development of Kymriah and many other cell therapies. Their support and our work has brought us into our 1st in man study for a lead clinical program targeting patients with mucosalpemphigus vulgaris. The first patient in this trial was dosed at the end of last year. And during the first half of this year, we expect to be able to report out the top line data on the first low dose cohort from the trial. That acute safety data is on track to report out in the first half of this year. Our lead preclinical program is directed at patients with the MuSK form of myasthenia gravis. The IND for that program is on track to file in the second half of this year. Our product portfolio includes the 5 additional products, 3 of which have not yet been publicly disclosed. Our patent portfolio includes a patent for our lead program targeting pemphigus vulgaris patients, which includes any or all of the necessary elements in the targeting domain in order to use a CAR T therapy approach for the treatment of these patients. We're really thrilled with the outcome of that initial issued U. S. Patent and we hope that as we file additional patents for additional programs, we'll follow in that same paradigm. We have a substantial cash runway that takes us at least to the end of Q3 of 2022. And if things go sideways and we don't have multiple programs moving ahead into the clinic, we have the ability to stretch that runway well into 2023. So the foundation that we built shown on Slide 5 in 2020 really sets the stage for these milestones in 2021. The launch of the DESCART trial with FDA fast track and orphan drug designations, opening multiple clinical sites and now enrolling patients in an effort to report a top line milestones, the top line data from the clinical trial in the first half of this year on that low dose cohort, the initial cohort. And as that matures through the 2nd part of the year, additional longer term follow-up, including any observations that we might make on target engagement in the latter part of the year. In addition to the DESCART program, the MuSK program directed towards myasthenia gravis patients is progressing off of a foundation of in vitro and in vivo studies that have been presented with successful specific target engagement and those programs are now on track for an IND filing in the second half of this year, including partnership with a CBMO rather than partnership with an academic institution to support the manufacturing process in that program. So let's talk a bit about what our platform is all about. So our platform is leveraging clinically validated CAR T technology, as I said, that has been originally developed at the University of Pennsylvania. The product candidates are designed to be very selective and specific to eliminate only the pathogenic autoreactive B cells, representing something less than 1% of your normal B cell population, while we leave the rest of the population alone. So the way we do that is we start with the history. And so by way of history, for those who are not familiar, Kymriah or similar CD19 directed CAR T therapy for cancer is developed by taking the patient's T cell as shown on the left of Slide 6 and including in that CAR T cell a signaling domain and a co stimulatory domain. In addition, there's a targeting domain. That targeting domain in CD19 directed Part T therapy involves the antibody fragments that are directed towards CD19 antigens that are shown on the B cells on the screen. Normal healthy B cells have this CD19 antigen as do leukemia and lymphoma and certain other B cells. Effective therapy results in elimination of all B cells in these patients. And while that's a great outcome if you have cancer that is hard to treat, it is not an acceptable approach if you have an autoimmune disease. And so our scientific founders, 1, an inventor of Kymriah working in Carl Joon's lab and the other a B cell mediated autoimmune disease expert got together in 2011 when the first data was published in the New England Journal on CD19 directed CARs. And they asked whether they could do only 1 thing to change the CAR T paradigm so that it becomes a very specific killing instrument, so that it directs itself only to the pathogenic auto reactive antibodies. And to do that, they said, let's keep the signaling domain in the T cell. Let's keep this co stimulatory domain in the T cell, but let's change the targeting domain. Instead of antibody fragments, as shown on the right side of slide 6, the autoantigen, the antigen that is the subject of attack in an autoimmune disease is the targeting domain that will be used. And that autoantigen is going to engage with the B cell receptor, which is only going to be found on the B cells that would do you harm, only found on the pathogenic auto reactive B cells. So a very elegant biologic marker exists in any cell that wants to secrete antibodies that would be pathogenic. And for the disease that we are targeting, we can identify the B cell receptor specifically by simply putting the target of their design onto our targeting domain. Effective therapy in these patients will result in the elimination of the disease causing cells, but not elimination of the normal cells. And the outcome could well be a specific and a deep and a durable response similar to that which you see in cancer without the side effects. And so our platform, when we first formed the company, we had to make some choices. Those choices revolved around the many autoimmune diseases that we could go after. The target selection is very important here. We have a very an elegant biologic tool only if used in the right patient populations. And so we chose our targets through scientific, clinical and commercial assessment, looking for regulatory pathways and precedents, needing to understand whether the epitopes are able to be identified and included in our targeting domain, so that all of the patients with the disease regardless of which flavor of the antibody they possess or antibodies that they possess would respond to our therapy. We then optimized the CAR design and I'll take you through that in a moment. Once we optimize the CAR design, we move into preclinical in vitro and in vivo testing and the MuSK CAR is now in the pre IND or IND enabling studies along with manufacturing buildup to be able to launch into that IND filing later this year. Of course, we're in clinical studies with our lead program directed towards pemphigus. Slide 8 shows our entire portfolio, including the 4 disclosed programs and 3 programs mentioned at the bottom, which have not yet been disclosed. So, let's focus now just on this PEMFEGUS lead program. Pemphigus is really an optimal lead indication for CAR T therapy. The desmoglein 3 desmoglein is skin glue. The desmoglein 3 antibodies are widely considered to be necessary and sufficient to cause pemphigus. Therefore, their elimination should result in a clinical outcome that is desirable. So walking through these 5 elements, the serum anti DSG3 antibodies are used in the clinical assessment of the disease and they're 98% to 100% sensitive and specific for the disease. So we can specifically identify the right patients. Depletion of the B cells by rituximab or antibody plasmapheresis transiently improves the outcomes for patients. And that proves the idea that the B cell is at the center of this disease. Incomplete B cell depletion by rituximab results in a reliable expectation that this is a revolving door disease. The disease is going to recur. And that recurrence is with identical clones as were there before. This has been proven. And as a result, what we know is that rituximab and other pharmaceutical approaches are not going to get deep into the tissues where they need to go. But T cell therapy, particularly CAR T therapy has proven its ability to do so in the treatment of cancer. The B cell repertoire is well understood for pemphigus vulgaris, including all of the antigenic epitopes. And so we could design our CAR optimally. And finally, there's published animal data on the Pemphigus condition and the use of the CAR in those animal models. So taking a look just at Slide 11 now, it's sort of an overview of the current state for pemphigus patients. There are 2 forms of pemphigus. 1 of them affects only the mucosal membranes, desmoglein 3 is the culprit there. And for those patients, they have sores on their mouth in their genitalia, their eyelids and so forth. And some of them when you talk to them will describe that drinking water when they have an exacerbation of disease, which could last for months, drinking water can feel like drinking shards of glass. On the right of this chart, you see the other form of pemphigus vulgaris, which includes the mucosal membranes, but also includes blisters on the skin due to desmigliin-one antibodies. The current treatment landscape for both forms is identical. It is a broad immunosuppressive approach using steroids, perhaps high dose steroids followed by other T cell toxic therapies cyclophosphamide. Rituximab was recently approved, a real breakthrough for these patients. And so let's look at what the bar is here. If you take rituximab plus steroids with an average of 2, 800 milligrams per year, what the rituximab label says is that you'll have a 40% chance that you will achieve 4 months with no lesions and off of your medicines. Unfortunately, the vast majority of patients who respond will have a recurrence. It is a revolving door disease. While taking rituximab, the risk the annual risk of a severe infection, perhaps hospitalization as well is about 5% to 10%. Real world data suggests that about 70% of patients can actually get to a complete remission for a transient period of time. Unfortunately, a third of the patients are going to have a recurrence in the 1st year and another third in the 2nd year. And so a lifetime of this revolving door disease demands that patients have better, more effective, more durable and deeper therapies that they can rely on. To design our products, this Slide 12 is an example looking at desmoglein 3. So the protein, the desmoglein 3 protein shown on the upper left, there are 5 extracellular domains in that protein. The 5th is known to be inert in humans. It does not cause disease when it is present in humans by itself. When we take EC1 through 4, any 1 of these extracellular domains might have generated an antibody response and you can see the percentage of patients with pemphigus who have an antibody present to any 1 of those domains. When you take the right side of the slide and look at our product, we've integrated EC1 through 4 and shown to the right are the antibodies that would be appropriately addressing the epitopes shown underneath each antibody that could have caused the antibody response. And so the conclusion on this slide is that the desmiglen 3 CAR T product encompasses all known pathogenic epitopes. If you have this disease and desmoglein III antibodies, we know that you'll have the clinical disease and we know that we should be able to address the patients who have the disease as defined by a desmoglein 3 antibody. This preclinical data, I will summarize very briefly because there's nothing worth spending a lot of time on here. Very comprehensive program, no signals that would have directed us to design our clinical studies differently or with a focus on any particular toxicity. The tolerability and the target engagement were as expected across a series of animal models as well as in vitro studies and screens for any interactions. These data are published in science as well as in JCI more recently and more comprehensively. So this is the clinical program that's underway, the DESQUART trial. It's a Phase 1 clinical trial in mucosal dominant pemphigus vulgaris patients. It's an open label study. It's a 3x3 design, fairly classic. And it's looking to determine the maximum tolerated dose and fractionation regimen for desmigliptin 3 CAR T. To be eligible for the trial, a patient must have active disease and they must have failed therapy. There is no specific criteria required that you have a severity of disease of any particular sort, only that you have tried therapy and failed. That reflects the vast majority of all patients with the disease. The trial starts it has 3 parts. The first part is dose escalation. We're starting with a low dose that we wouldn't expect to have efficacy, but it could. And so the reason we say it could, in cancer patients, some of them will respond to this very low dose that we're using as the first of the 4 doses in Part A. We're administering the dose as a fractionated regimen and we're elevating the dose after each cohort until we get to a dose at the highest level, which is higher than is commonly used in the treatment of cancer. So a very broad dosing spectrum. Part B is to consolidate from 4 fractions given within a week down to maybe 2 or a single fraction of the dose given at 1 time. As noted in the footnote, Part C, although it's an open label design and as discussed and presented with FDA in the IND filing process where they changed nothing that we submitted, they did make some comments about the clinical trial and particularly Part C. They asked the company to consult with them using our Part A data once it's known in order to optimize the design of Part C. And specifically, we asked for a discussion a live discussion during the IND filing process. They said, look, this is just our advice. It's strong advice. And the reason we give you this advice is because if you do eliminate the desmiglen 3 antibodies and you see the treatment effect, This trial cannot be the efficacy part of your label nor can it be part of the efficacy in your label without a comparator arm in Part C. And so we'll consult with FDA. We've agreed to consult with them and they've agreed to provide us a rapid turnaround once we have the Part A data in hand. Slide 16 I'm sorry, Slide 15 is a timeline for the clinical study as well as some of the risks and how we will measure efficacy. So the safety is being assessed at day 8. The most important side effects with CAR T therapy are CRS and neurotoxicity. From there, it goes down to a 3rd, 4th or 5th side effect that are not prevalent enough for there to be consensus about what they are. And they're not serious enough to rise to attention. So these first 2 are the story. And so we're focused on day 8 within which the 8 days 95% or more of the CRS and the neurotox that we expect could be seen would be seen in that short window. And that's the data we'll report out in the first half of this year on that first dosing cohort and on each subsequent dosing cohort. As a matter of approach, we are going to be presenting top line data when we see it. We will not discuss individual patient data unless there is a material change either good or bad to our clinical trial design or to our timelines. After the 8 day data, we follow patients and as shown on the slide, the desmoglein-three titers, they do not spontaneously remit or disappear. Our patients are not expected to be on multiple additional therapies. And as a result, if we see a decline in these desmiglen 3 titers within the 3 or 4 months after treatment, we know what caused that to happen. And so as we see that in a dosing cohort, we'll be reporting that out. In each case, these side effects, which I don't have time to go through in detail today, but I urge you to review them, each 1 of these, we have reduced the risk that it could occur. CRS and neurotox were only killing 1% of your B cells. We're not killing 100% of your normals and a tumor burden that is huge. Of course, the tumor burden, as classically discussed, is the greatest predictor of severe CRS. We're starting with this very low dose and fractionating it, again cutting the risk. We're not lymphodepleting because patients have soluble circulating antibody. Lymphodepletion increases the risk of severe CRS. So with each of these, you can walk through and see how we are mitigating these risks. The soluble antibodies are important. While we don't have excessive tumor, we don't have bone marrow packed with tumor that needs to be cleared out with lymphodepleting regimens, we do have soluble circulating antibodies. We've studied these extensively and a bit of that data is on this slide. The soluble circulating antibodies when exposed to our product from patient serum can either enhance the activity, the target engagement or diminish the target engagement or they could have no impact on the target engagement of our product. In taken as a whole, the net impact is modestly more or modestly less, but it never goes below that line. It never goes below the dotted line on slide 16 on the left side. And that is the minimum that we believe we need in order to reach and destroy the B cells. So we feel pretty good about the soluble antibody. Potential barrier to our reaching the target, those B cells. Shifting over to the right, there's another side to this story. When exposed to our product, the patient serum as well as antibodies to desmiglin-three monoclonal antibodies cause our cells to expand. Lymphodepleting regimens are designed to help your product expand and engraft. While we don't know if we need engraftment or if a 1 time destruction of all of the targeted B cells will be sufficient, it sure is good to see that the soluble circulating antibodies have an impact on our cells, which is desirable. They expand the cell population. So we don't know what happens in the clinic yet and we're going to wait and see. We'll of course be analyzing it carefully, but these are pretty good indicators of things yet to come. In the red box at the bottom is a very important piece of information that I would again urge you to look at the JCI paper or look at our website for more information. There was an active immune model that was developed and was studied using our product. And what we found was despite soluble circulating antibodies that would be comparable to those you would find in a human with pemphigus vulgaris, We were able to demonstrate in that model the histologic, the serologic and the clinical outcomes that you would want to see in patients. Moving to slide 17, the desmoglein IIIone CAR T, which would be for the other portion of the pemphigus population, relies on having the desmoglein 3 as well as the desmoglein 1 antigens in the CAR. And while I don't again have time to go deep here, the fastest way to get across the finish line with this program is to take all of the wisdom that we get from the desmiglien 3 program to integrate it into a proper dosing regimen, a proper fractionation regimen, the right endpoints and to quickly start and finish that trial in a more rapid cycle time because we started after we know what we're doing from the Desmaguen 3 program. The design of the car is very similar, but different. Each of them is specific as shown on the right of slide 17. Each is specific to being cytotoxic against its target and they do not interfere with each other. I want to shift quickly now to the MuSK CAR T program for patients with myasthenia gravis. Slide 19 shows that myasthenia gravis has a pretty high unmet need and is very similar to the pemphigus vulgaris paradigm. All of the known extracellular domains for this disease that are triggering an antibody response in this disease are integrated into the design of our CAR. Similar to desmoglein 3, the musk CAR, it has 4 extracellular domains IG-one, 2, 3 and Frizzle. Those 4 are shown here. Those are all integrated into the design of our CAR. We've talked about that. Rituximab gives transient responses in these patients and the pathogenic B cells are incompletely eliminated. So very similar paradigm. About 6% or 8% of all patients with myasthenia gravis have the MuSK form. And it's important to recognize that when we're talking about a cell therapy for musk myasthenia gravis patients, they cannot even take Soliris. It doesn't work in this very hard to treat patient population. They cannot use acetylcholinesterase inhibitors to improve their functionality. They're stuck with steroids and cytotoxic And so as I said, the design of our CAR on Slide 20 is designed to include all of the known epitopes. And when you use any of the antibodies that we've studied, we get specific killing and we have no toxicity membrane protein array that we used covering 6, 000 human membrane proteins, the same 1 that we used with our DESpart program. This is the in vivo data, a snapshot of that, which also has been presented in scientific sessions to neurologists actually importantly and highlighted at their meetings. And here what you see is that the musk CAR is able to destroy its target in the musk column day 1 to day 13. The CART19, which kills all B cells also destroys all of the target as well as all of the B cells. However, the DSG3, the pemphigus targeted CAR does not have an impact on the target cells in this model, neither does the non transduced group shown on the left. In terms of manufacturing, we were able to go from a standing start, formation of the company first financing in 2018 to an IND acceptance with manufacturing in hand a year and a few months later because we were partnered with the University of Pennsylvania as I mentioned. We were also partnered with the Children's Hospital of Philadelphia. We're using the manufacturing processes that were used in the discovery and the development the early development of Kymriah. Those processes were integral to the success of that program, ultimately getting across the finish line to FDA approval. And by partnering with Penn, we have people who have deep and longstanding experience with the manufacturing processes supporting our DESCARP trial and that partnership is going exceptionally well. At the same time, we've been working with partners on the vector side as well as on the cell manufacturing side. We have now entered into an agreement with WuXi Aptech in order to have them work with us and collaborate to support the MuSK myasthenia gravis program, the MuSK CAR T program. And we expect that their work with us will support the IND filing for the Muscar Part T product later this year. And finally, Stage 3, as we start to see more data, as we start to feel a sense of insight into the direction that each of these programs will be going, the duration of time to get across the finish line here. We'll start to think about both leasing the space and then building out the manufacturing facilities that will be wholly owned and controlled by Caboleta. And to do that, our Head of Science Technology and myself have both built commercial scale manufacturing facilities for cell therapy previously, quite unusually 2 of us completely independently. And so we're very comfortable that we understand both how to do that and when to do that. The manufacturing processes I've already mentioned and for time I'll summarize by saying that we have cross referenced the IND for Kymriah that the University of Pennsylvania still owns. And as a result, we have a really de risked manufacturing process going into the clinic in our lead program. So to summarize, I would say our team is extraordinary. They're exceptionally team oriented. We have a scientific advisory board that is wise in its counsel and diverse in its perspective. And we're surrounded by partners and associates that are not listed here, but that make up the village that it's going to take to achieve our 2021 milestones, which include in the DESCAR trial reporting out the top line data from the initial dose cohort as well as the initial data following the additional cohorts throughout the rest of this year. In addition, the MuSK program we expect to finalize our manufacturing processes, run the engineering runs and be prepared to initiate that trial as soon as the IND is accepted and that IND is on schedule to file in the second half of 20 21. I want to thank you for taking the time to hear a bit about our company and we'd be happy to take any questions. Thank you, Doctor. Mick Berger. I am not seeing any questions at this time. I think we can wrap up now. On behalf of the JPMorgan team, I'd like to really thank you for speaking at our conference and being here. It was a real pleasure to have you and we wish you best of luck in 2021 as you execute on your plans. Great. Thank you so much. Take care.

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