Morgan Stanley 19th Annual Global Healthcare Conference

Sep 9, 2021

Great. Good afternoon, everybody. Thanks so much for joining us for the next session. I'm Matthew Harrison, 1 of the biotech analysts here at Morgan Stanley and very pleased to have Cavalata with us for the next session. Before we get started, I just need to read a quick disclosure statement. Please note that all important disclosures, including personal holdings disclosures and Morgan Stanley disclosures appear on the Morgan Stanley public website at morganstanley.com/research disclosures. And so really pleased to have Stephen Knickerbocker, who is the CEO of us. And I thought a good place to start is just obviously, we're going to spend a lot of time on the lead program here. But just to talk a little bit about the company itself, the idea for the founding here and the basis for using CARs to go after inflammation as opposed to and autoimmune as opposed to oncology? Yes. Thanks for the opportunity to join you today. So, Caboleta was formed in order to develop and launch the 1st curative targeted cellular therapies for autoimmune diseases. And the reason we're focused on autoimmune diseases is because the biology suggests that existing technology that was first ever discovered and developed at Penn, our partner in the manufacturing of these products has every reason to support the belief that we can cure these autoimmune diseases, which in most cases today are treated with therapies that are transitionally effective. You might get a response, but it's a revolving door. And there are safety issues. There are real costs. And with new forms of therapy coming to market, those costs are only going to rise. So given the opportunity to take existing approved technologies in cell therapy into a new space, an adjacent space, where cure is possible, we believe, it was compelling. So that was the basis for the company. I apologize, I was on mute still. So I think the best part is, we've got some data and I think we need to go through that. But maybe just for people that are less familiar with the story, just talk about the construct, the antigen you're targeting and why that should lead to a positive outlook in the disease setting? Sure. So the cell therapy, the form of cell therapy that we're developing is a CAA CAR. And it's obviously built on the CAR-nineteen technologies that are now approved and marketed for the treatment of certain hematologic malignancies, right, leukemias, lymphomas primarily. And what we did based on our scientific founders early work is we looked at the CART19 form of therapy and knowing that it could completely and in some cases permanently eliminate the B cell population entirely by targeting the CD19 antigen on the surface of all cancerous B cells and healthy normal B cells. Successful therapy is first created by taking the patient's own T cells, inserting or genetically modifying those T cells and inserting a signaling chain and a targeting domain such that the T cell would be taught to attack all of the B cells that have a CD19 antigen on their surface. Successful therapy results in the complete elimination of all B cells, the healthy ones and the cancerous. Excuse me, our scientific founders said, if you they looked at that data in 2011 and they started a collaboration to explore whether changing the targeting domain from antibody fragments that will recognize a CD19 antigen on a B cell, changing that so that it becomes the antigen that's the subject of attack in an autoimmune disease and allowing for that autoimmune disease target to then attract the B cells that are making antibodies that are causing the disease. So in the CAA CAR technology, everything is the same as CART19, except the targeting domain. The targeting domain is the antigen that's being attacked in pemphigus, in myasthenia gravis, in membranous nephropathy. And that antigen is going to be attractive to the antibodies that would cause the disease in each case. Those antibodies are displayed on the surface of the B cells that are pathogenic and auto reactive. Those pathogenic auto reactive B cells are the ones you want to destroy. The elegant biology here is that only those pathogenic auto reactive B cells have that marker on their surface and they must have that marker in order to produce those antibodies. So by destroying and targeting only 1% of the patient's B cells, we potentially can provide the same sort of cures that you see in cancer, while not affecting the other 99% of your B cell population that's otherwise normal. What that means is that in the clinical setting, we should expect an extremely safe profile, because the number of B cells you kill relates directly to the risk of CRS, the risk of neurotoxicity. And beyond those 2 acute risks of CART19 therapy, the platform of CART19 therapy is fairly safe, I would say very safe, especially over the long run. And so we, as you mentioned, reported out our initial clinical data in pemphigus vulgaris patients, excuse me, where we started with a very low dose, because although the biology suggests our therapy, our form of therapy should be very specific, very targeted and very safe as a result. We reported out safety data that was not surprising, but was comforting to see that at 20, 000, 000 cells and at 100, 000, 000 cells, the first 2 dosing cohorts, both of them very low dosing cohorts, demonstrated no dose limiting toxicities within the 1st 28 days, but more importantly, perhaps, no clinically adverse no clinically meaningful events whatsoever in any 1 of those 6 patients followed until August 17, 2021. So with that data reported out, the trial operation is going as fast as it can possibly go. The sites are enthusiastic and many more are about to open for our Part B and Part C of our trial. The patients are now sufficient in number enrolled in the trial that manufacturing has occurred and patients are now waiting for their turn. Because we and FDA believed this was going to be a low risk form of therapy, this is an outpatient study. Patients can be treated inpatient, but the opportunity is there and primary preference is to treat patients on an outpatient basis. And that was reiterated when FDA provided us the opportunity to have only 1 week between patients. Previously, it was 2 weeks between patients. So where we are to summarize and then we'll go wherever you like in the discussion is we reported out our first 2 of the 4 dosing levels. The 3rd dosing level is 500, 000, 000 cells. The 4th is 2, 500, 000, 000 cells. Because we're treating very few targets, we don't know how many cells will be needed. So we've had this tremendous dose range and we have the possibility of going even higher with this sort of a safety profile if it persists. The data on the first 2 cohorts, the efficacy, the early signals of efficacy, the biologic activity will be reported out in the 4th quarter. And by the time we report out the 3 to 6 month biologic activity data on those first 2 cohorts, we will have, I believe, treated the 3rd cohort at 500, 000, 000 cells. And while that will not be mature enough to talk about the biologic activity, it will inform what we're seeing in the first 2 cohorts, right. So subtle signals could become more important in our conversations if we see that the future holds more profound effects. And as we've said before, the trials enrolling so quickly that the 4th dosing cohort may well start to be treated in the Q4 as well. So very enthusiastic about the initial clinical program and excited to see the near term data on a backdrop of what appears to be an extremely safe form of therapy. Okay, perfect. Thanks, Stephen. So I guess 3 things. So the first 1 is, let's talk about what gives us confidence that ablating these B cells can lead to a clinical effect. And so maybe you could talk about the experience with broad B cell ablation with Rituxan and then why this specific antigen should cover all of the pathogenic B cells related to Pemphigus? Yes. So, we know that CD20 therapy with rituximab leads to transient, but in some cases complete elimination of the B cell populations. So a minority of patients treated will have a good long term response, But the majority, the vast majority of patients will go on to have repeated recurrences through lifetime. And so that proves that long acting memory B cells, which we wouldn't be targeting and which rituximab doesn't target are not necessary in order to achieve a complete norm. So we know we have a target that, again, the biology suggests we should be able to cure the disease. We know that the B cell is at the center of every disease that we seek to treat. We have 7 announced programs, all 7 and another dozen behind that. We believe that B cell is necessary and sufficient to cause disease and therefore its elimination means disease is gone. We believe that the platform of CAR T therapy, the Kymriah platform that we have evolved from our partnership with Penn is known to be very effective in the treatment of cancer. So the signaling chain and the rest of the machinery that is required to work in patients is by design derisked based on other indications. So the question is whether this is safe. We talked about the low dose safety data, the emerging safety data in that 3rd cohort, which we'll report out within the next couple of months. So the safety profile is becoming increasingly clear. We know that the products we make for patients, each of the products we make, we test them in vitro to see if they kill as designed and specifically are killing as designed. And we know that in each case, what we've made for the patients works the way it's designed in vitro. And so the only question remaining is whether the 2 cells will meet in the patient, whether our CAR T cells will bump into, will meet, will seek and destroy the 1% of your B cell population that is causing your disease in pemphigus, myasthenia gravis, membranous nephropathy. If those 2 cells meet, we have the deeply held belief that the T cell will destroy the B cell and will do so in a way that is permanent. And so we're really optimistic and enthusiastic about what's to come over the next quarter or 2 in terms of turning the cards on the more important dose finding results that we're going to see. We are, it's worth noting, not using a lymphodepleting regimen. And I know you know this, Matthew, but for those who aren't familiar, and the reason is this, while it is superficially obvious that CAR T therapy requires lymphodepletion, when you begin to look at it biologically and understand scientifically why you're using lymphodepleting regimens, ultimately to get rid of a cytokine sink, which is all of that tumor that would suck up the cytokines. We don't have tumor in our patients to clear the bone marrow. Our bone marrow in our patients is normal. So, there is no reason to use it. And furthermore, we know that the difference between cancer and autoimmune disease, you've got circulating soluble antibodies. Those antibodies we know from our preclinical studies cause the product to expand. So a monoclonal antibody against DSG3 or a patient serum with pemphigus both will cause our product to expand, to duplicate, to replicate. And that's exactly what you want. That's why you use a lymphodepleting regimen. But why give cancer forms of therapy to autoimmune patients who don't need it? So there's no rationale to use it. We believe the soluble circulating antibodies may be our friend here. And so we're not using. What that means though is that we may not be able to read directly from cancer into autoimmune disease. You may not be able to say that 100, 000, 000 cells is sort of therapy light in cancer, therefore it should be therapy light in autoimmune disease, 500, 000, 000 cells is a routine dose in cancer, therefore it should work in autoimmune. You may need to do what was done in a recent BCMA publication, where they prospectively evaluated BCMA CAR therapy with lymphodepleting regimen versus BCMA CAR therapy at high doses without a lymphodepleting regimen. And what they found was the clinical data were identical in the 2 groups. You couldn't distinguish the clinical outcomes. So we may need to go to very high doses to overcome the absence of lymphodepletion, we may not. And that's why we have such a broad dose range and we reserve the possibility of going even higher and we're encouraged, frankly, to do so until we hit some sort of safety issues because durability is ultimately the final test of whether we are as good as we think we are. And it may be that the highest dose possible to safely administer gives us the best durability over time. We're going to explore the full range as best we can. All right, good. So let's talk about what we're going to get specifically later this year and how we should think about maybe why don't I sort of posit a couple of scenarios and you walk us through. So first scenario is we see some cell depletion, but maybe not enough. So and I don't know what percent range that is, but we see something. What does that mean? How do you think you handle that? I guess the second thing is for the first 2 doses, they're safe, but we end up not seeing anything. And I can obviously think of maybe that's a dose issue, maybe it's something else. So and maybe you have another scenario you want to throw in there, but just I guess talk to us about how we should interpret some of these initial pieces of data we're going to get? Yes, we talk about that a lot inside the company as you can imagine. So our intention with the 4th quarter discussion of the 20, 000, 000 and the 100, 000, 000 cell dose, the first 2 dosing cohort, 3 to 6 month follow-up biologic activity data. Our intention is to give investors a window into exactly what we're seeing without preempting a scientific presentation at a later date. And so that's always a fine line to thread the needle on, but that's the intention. And so there were 4 key parameters that internally our team looks at in addition to a lot of translational data that we don't talk about. The 4 key parameters that we are going to be looking at and discussing are number 1, the DSP3 CAR T quantitative PCR. Do we have persistence of ourselves? Yes or no. Perhaps is there a dose response? Yes or no. Is there reason to believe that we are getting this persistent effect of our CAR T cells? Number 2, the DSG3 antibody titers. The DSG3 antibody ELISA is the proximate cause of the disease. Those antibodies are the cause of the disease. They bind to the DSG3, this desmoglein, the skin glue and they cause the blisters. The level of DSG3 antibody should start to fall and be pronounced in its reduction if therapy is effective by 3 to 6 months. The reason for that is we're killing the factory that's making the DSG3 antibodies. We're not killing the antibodies that are existing. So we have to wait for the existing antibodies to disappear. Their half life is 3 to 4 weeks. So you want to see a few half lives. We don't know how the tissue DSG III versus the serum DSG III play out. So to be safe, we're looking for biologic activity in the 3 to 6 month timeframe where the DSG III level is reduced. And again, we're trying to give investors the best prospective view on what we expect, so that you can judge whether you think it's successful. And so DSG3, we believe will reveal biologic activity if there is a reduction between 3 6 months of greater than 20%. Why 20%? The assay itself using the same sample repeated in the lab in the same day with the same tech is 1% to 2% variability. Different text, different days, different timeline, 20% is real, right? So that's where 20% comes from. There is no science beyond that. So if it's 20%, if it's persistent, not just a blip, if it's across a number of patients, not just 1, then it's real and it's biologic activity. And then we just start to optimize the dose, the manufacturing approach, which can, we believe meaningfully enhance the potency of our product, as well as the patient profiles that we enroll. This is a safety study we're enrolling everybody. So there may be some optimal patient profiles to enroll and we're going to learn that. The third thing we're going to look for is the use of systemic rescue therapy or the absence of systemic rescue therapy. As a reminder for those who are watching, all of the forms of therapy that are given for pemphigus vulgaris today, so I'm thinking of rituximab, I'm thinking of the experimental use of FcRns and BTKs require high dose dexamethasone pulse and a persistent use of steroids. In the case of rituximab in their label, you get 4 months of relief from the disease. There's no guarantee it will stay that way, but at least 4 months within a 1 year period. If you spend 8 days having infusions of rituximab alongside dexamethasone and your total dose over the year of steroids is 3, 500 milligrams. And if you do all that, you get 4 months without disease and off of drugs. That is the bar that we have to hop over to be meaningful clinically. The bar that we are wanting to hop over is cure, which is to say no steroids, no concomitant therapy, no disease. And then the final thing is the clinical symptoms of the patient. Is there pain in your mouth? Are you able to swallow water or not? Do you have more or fewer lesions than you did before therapy? So those are the 4 parameters we're looking at. And I think it's going to be obvious whether there is biologic activity or not. I would say that, how will we think about it was 1 of your questions. If we see a perfectly safe therapy in the first 2 dosing cohorts and we don't see biologic activity, but we see safety in the 3rd cohort, I'm going to feel pretty good about that, because we're still not at the dose level that if it was just a cancer therapy, you would say it probably needs 1, 000, 000, 000 cells, because you need a higher dose than the 500, 000, 000. So I wouldn't be discouraged at all. I would be happy that we've already dosed the 3rd cohort and probably already dosed in the 4th, if not already through it. So the real time we have to be patient, but the good news is the trial is moving very quickly. I would be thrilled if we see biologic activity that indicates target engagement and what we believe is ultimately going to be the case, which is the elimination of these B cells that are causing disease. Okay, perfect. And then I guess just 1 question on optimization, then I want to make sure we talk about MuSK and some of the other programs. I mean, as long as it's safe, it sounds like you'll continue to push dose in an effort to try and eliminate as many B cells as possible, right? Because I think to get to a functional cure, the hope would be that you clear all of the B cells. Agree. And we haven't said anything publicly about it, but I'm very comfortable that internal conversations, we're going to be able to push the dose as long as this is safe and the only limitations are going to be manufacturing in terms of how many cells we can produce. Okay. And even when we hit that as a barrier, there's an opportunity for multiple dosing, right. So there are many different ways to the end game here. And there's no doubt there's risk, but there's also no doubt that having the safety profile that we've demonstrated in those first 2 dosing cohorts followed in the first patient for as many as 6 months, it opens the window, it opens the door for us to pursue whatever is needed to achieve the sort of curative efficacy that we think is possible based on the experience in cancer. Yes. Okay. Okay, good. Why don't we turn to MuSK, since that's 1 of the next programs and maybe just tell people about the target and why that could work in MG? Yes. So, musculiasthenia gravis is a severe form of myasthenia gravis, more difficult to treat. SOLIRIS doesn't work in those patients. Acetylcholinesterase inhibitors don't work. Clinically, they have the same exact symptomatology as the acetylcholine in the majority of patients. But this minority, this subset of myasthenia gravis patients don't have many options. The musk myasthenia gravis protein, which is attacked by these antibodies in these patients, which make up less than 1% of their B cell population. This MuSK antigen, which is on our MuSK CAR T product looks a lot like the DSG3 antigen. And so, the preclinical work, the preclinical data we've reported to date, MuSK CAR T looks an awful lot like the DSG3. The read through from desmoglein and DESCART to myasthenia gravis musk CAR T, we believe is profound. The IND is on track to file this year as we've said long ago. We are making changes to our clinical plans for musk myasthenia gravis based on conversations with our investigators or future investigators as well as based on what we're seeing in the DESCART trial. So for example, a question that's on the table is why do you need a 20, 000, 000 cell dose, right? Other questions, do you need to fractionate each patient's dosing regimen into 4 fractions? Can you go with 2? Can you do 3? There's all sorts of good questions. Do you need 3 patients per dose? All sorts of questions. If we ask them prior to IND filing and we incorporate a more rapid approach, we get to the finish line faster even if the IND is filed later in 2021 than it could have been. So we're taking that approach to the filing of the Musk IND and we're excited to see what that can do. Okay, perfect. Yes. No, I mean, I think that's obviously a good approach to be informed by what you're seeing with DSG3 And also I think everybody can appreciate that if you can start at a higher dose or move quickly more quickly through dosing cohorts that that can have a real material impact. 2 other points I just want to quickly make, Matthew. 1 is, the manufacturing for the Musk program is being done in collaboration with Wuxi. We have dedicated room and dedicated people working at Wuxi supporting this program. The strategy partnering with Wuxi and moving out of Penn is very thoughtful and purposeful. If and when we see biologic target engagement with DSG III CAR T and if Part C of our ongoing study becomes a potentially registrational study, Wuxi will be in a position to receive the tech transfer from Penn. The Wuxi plant is probably 10 miles away from the University of Pennsylvania. We have already set up and have the ability to quickly tech transfer from Penn to set up that relationship with Hudi, expand our existing relationship and commercial supply could come out of the Wuxi facility potentially. So that's how we're thinking about the upside scenario of accelerated market approval from a really positive data set. And again, neither my good or bad statements are intended to forecast anything about the 4Q data. It's really just to let you see how we're thinking about continuing to efficiently manage our capital, but also take advantage of every opportunity that we're given. Okay, good. Good. And then maybe in the last minute or 2 that we have here, maybe we should just touch on you obviously talked I think about 8 sort of antigens that you've identified. I think you started to talk about PLA2R. So maybe we could just touch on that. And I guess more importantly, sort of how you think about the cadence of INDs and new programs coming into the clinic? Yes, sure. So PLA-two ARC is the next in what I consider to be a boatload of indications that we've been working on for a long time, boatload of products, we've worked on since inception. The read through to PLA2R is as profound as it is to Musk. The antigens are similar. The biology is similar. The design is straightforward for us. The early data are as we would have predicted. We expect that we'll hear back from FDA by the end of the year regarding pre IND questions we had and that will allow us to communicate an IND filing timeline for that program. But as a reminder, from concept to IND filing, the Musk program, maybe just concept, we didn't have a program up and running, didn't have anything. Maybe it was 3 years at most from concept to IND filing. And we've got 7 programs underway. So you can reach whatever conclusions you would like around how quickly INDs could file. But listen, this biology is really elegant. The clinical need is important. It is very much an engineering problem. And as soon as we did as soon as we reveal biologic activity and clinical data from the first program, it won't be lost on any of the many folks in the industry who I know follow us closely that they need to figure out how to address the opportunity. And therefore, we need to have the IP in place. We need to continue to expand what is currently a profound lead in this entire space of CAR T as it is applied to autoimmune disease. At the same time, while we're going for cure on everything in our platform today in the autoantigen space, we're beginning to open our eyes to the broader opportunities of cell therapy in autoimmune disease and watching what's going on in terms of the scientific advances being made. But first things first, clinical data from the CART T program at DESCART is top of mind for us and we're looking forward to the Q4 data and then the data in the first part of next year from the higher dose cohorts. Okay. Well, good. Thank you, Steve. Thanks for being here and look forward to the day as well. Yes. Thank you, Matt. Appreciate it.