Welcome to our next fireside chat. I am Robert Burns, I am a managing director and senior biotech analyst at H.C. Wainwright. I am joined by Chen Schor, the CEO of Adicet. Chen, thank you for joining us today. Robert, thank you for inviting us. Always a pleasure. Awesome. Why don't we just take it from a high level, 10,000 ft perspective initially. For those who may be unfamiliar with Adicet, tell me a little bit about the company, its pipeline, as well as the platforms that you are developing. Sure, absolutely. Adicet is considered to be the leader in developing a specific type of CAR- T cell therapy, gamma delta CAR- T cell therapy. It is an off-the-shelf platform that has been so far associated in a quite consistent way across all of our studies with a safety profile that seems to be more favorable than alpha beta T cells. Our lead program is in autoimmune diseases, and we expect to provide a very significant data clinical update this month. Our second program is in prostate cancer and is about to get into the clinic in the fourth quarter. We also have a pipeline of in vivo CAR- Ts, and the first program we expect to put in the clinic in the second half of next year. Expect a lot of milestones in the next 18 months, with the more immediate one is the clinical data that we expect to have in SLE and lupus nephritis. Awesome. Why don't we take those sequentially? Obviously, when we think about CAR- T, a lot of people think about alpha beta CAR- T. Why don't you elucidate the distinctions between gamma delta and alpha beta first before we dive into more specifics about the targets you're going after? Sure, absolutely. I'll use a slide there in a second. The key difference between alpha beta T cells, and there's autologous alpha beta T cells, and there's allogeneic alpha beta T cells, is that these cells, once dosed to patients, are associated with certain safety issues such as CRS and ICANS, and now there's an emerging safety issue called ICHS, which is essentially HLH. In our case, our cells can be provided off the shelf, have shown so far very favorable safety profile, and efficacy has been comparable to autologous CAR- T in the field of autoimmune diseases. Let me walk you through one slide. Before I go there, I'll just say the following. The data set that we expect to share this month will be the largest data set by a cell therapy company or bispecific company in the field of LN and SLE globally. The only two companies that have enrolled comparable number of patients and shared data are two small companies. One of them is Novartis, and one of them is BMS. Both of them are on clinical hold because of safety issues associated with alpha beta T cells. We actually benefited in our enrollment from sites in the same cities that enroll to these studies. Let me walk you through an example why this is the case, and I will use a slide for this. If you are an investigator and there is a patient that comes to you, they tried a couple of different products that are approved for SLE or LN. You really do not feel well. You come to the investigator, and as an investigator, you think, "You know what? You are actually a great candidate for a cell therapy." If you want to go to an autologous cell therapy, this is what you need to tell the patient. "Well, I know you feel really, really not good because the therapies have not been working for you, and your SLE or LN is progressing towards a flare. I need to take you off your drugs now for a couple of weeks because I need to get your T cells to a point that they have good fitness, so we can do leukapheresis. For the next few weeks, you are going to stop taking your drug. Then I am going to call this other department, and I am going to try to get a chair so we can have a leukapheresis, and we will extract the cells from you. Then I will send it to manufacturing. I will send it to a company that has a quite short manufacturing process, maybe three days, but it takes them quite a while to release the cells. So after I send it, at some point, I will get a call, and then I will tell you that you need to" This is literally the case. My mother got CAR- T. I will give you a call, and I will let you know when you need to come for the conditioning. Then we will give you the conditioning. Now, you should know that these alpha beta T cells are associated with ICANS and ICHS. You actually need to sign this form that you know" No, this is true. "That you know that alpha beta T cells have been associated with ICHS, and that can lead to mortality. If you sign it, then we will give it to you. Hopefully, you are not going to get it, and you are not going to get ICANS, and we will keep you in the hospital for at least a week, maybe two weeks, to monitor your safety. But overall, they seem to work pretty well." We actually had cases that these investigators did not want to go through this, and in the same city, we had a site of our program, and they just sent the patients to us. This is one of the reasons you see such great enrollment. In our case, if you see a patient and they seem to benefit from cell therapy, you can tell them, "Hey, why do not we start the conditioning tomorrow, and in five days, you can get a drug." This type of gamma delta on T cells do not have any of these ICHS issues. No ICANS, very low-grade CRS, well-tolerated, and so far, they seem to work like autologous CAR- Ts. It is pretty simple. We have shared our safety profile with the FDA, and they agreed that we can go to outpatient settings in the field of LN and SLE. The safety here has been a big advantage. Yeah. Assuming the comparable continues to be consistent with autologous cell therapies, this might be really a preferred option for patients who are just not doing well on chronic immunosuppressants. Mm-hmm. At least from my perspective, it seems like it would be a natural choice for a patient to choose your type of therapy over the alpha beta autologous CAR-Ts, just given the fact that it can be outpatient. You do not have the safety issues that you are seeing with the little companies such as Bristol Myers Squibb and Novartis. You are getting it within a few days. It just seems like a natural choice there. When a lot of people think about CAR-T in autoimmune as well as oncology, but more specifically for the autoimmune context, they think CD19. All right. Obviously, yours is a CD20. Yep. All right. Do you really see any meaningful difference between the CD19 targeting and CD20 targeting from an efficacy perspective as well as B-cell depletion and pharmacodynamic effect? No. That's the simplest answer you can get, but that's perfect to clarify. The reason it's no, and I want to touch base again on this. I've got one more slide that I think investors will appreciate. We have measured, although we target CD20 in the blood, we measured CD19 B-cell depletion. We see absolute complete CD19 B-cell depletion in the blood. We took biopsies in a different study from lymph nodes of patients. When we take the biopsies and we look for CD19 B-cell, we don't see a single one at day 10. When we look at immune reset, which is the result of a complete CD19 B-cell depletion, we see the same immune reset biomarkers just like the autologous CAR-T. Okay. In terms of the effect that we see in patients, 100% consistent with what we see with autologous CAR-T cells. I did want to touch on safety. This issue of safety that has been recently in the public domain and rose this concern with the autologous cell therapies in general, with autologous alpha beta T-cell therapies in general, with alpha beta T-cell therapies, has been the following, and this is published and the references are on the slide. What happens to alpha beta T-cells, once they start hyper-proliferating, they secrete a certain type of cytokines that are outlined on the top right of this slide. In the seven patients where we published our data a year ago, you can see that these cytokines do not move. Yeah. There's no reason to suggest why, in the next set of 22 patients, you're suddenly going to see these moves and the error bars here on these are really, really small. We don't see these safety issues. We don't see these markers of safety issues, and we don't expect that to change. You presented data. I saw with the update that's coming by the end of this month, maybe help frame expectations with regard to what investors can expect and level set us on the datasets that you presented last year that really exemplify the efficacy and safety profile of prula-cel. Absolutely. Last year in the fall, we presented a dataset in seven patients. Five of them were LN, two of them were SLE. What we've shown in terms of CRR rates and DORIS rates, and I'm going to touch what's the data for competitors. In terms of the CRR rate and the DORIS rate, similar rates of efficacy compared to autologous CAR-T. What we've shown in terms of safety is that while you see with alpha beta T cells a certain rate of CRS, in some cases grade three or grade four, and you see ICANS, we see zero, no ICANS and very low CRS. No CRS beyond grade two. So safety seems to be more favorable than alpha beta T cells. In terms of depletion, we've seen complete depletion of CD19 B-cells in the blood. In terms of immune reset, we've seen recovery primarily by naive B-cells. When you look at the population of the B-cells before, we actually did BCR, B-cell receptor cloning. What are the B-cell populations that the patient has before they got our treatment and after they got our treatment, and essentially everything before disappears, and there is new B-cells that come back that are likely not associated anymore with the disease. The question is, okay, what have we seen in the field of LN or even SLE in terms of efficacy recently? This is something that we've done for ourselves, actually, for our own board, because we want to understand how we fare compared to competitors. Very few companies. We don't look at ISTs because ISTs patients are selected very carefully. The cells are manufactured pretty much next door. They're never frozen. They're provided to the patient on-site, so we can't really use ISTs. We focus on companies that share data. There's few datasets that were recently or in the last two years were made public, and these have been recently updated in EULAR in June. Let's just see these data. One is obe-cel by a company named Autolus. They shared data in six patients, and we're focusing on 12 months CR rate. Why? Because that's what investigators care the most about. No short-term data. Yeah, no three-month datasets. Exactly. Because three months data, they tend not to hold for too long, and we've seen it with many classes of therapies. You look at obe-cel by Autolus. They shared data in six patients. This is autologous alpha beta T cells targeting CD19. They've seen three CRs out of six patients. You look at the Cabaletta with rese-cel. They've only shared data in four patients, and they had one out of the four patients with a CR. These are the same type of products, autologous CAR-T cell therapy targeting CD19, two costimulatory domains. Bottom line, when you look at it overall, 10 patients, four of them achieved a complete renal response, 40%. Let's look at Novartis. Novartis has actually a pretty large data set. They had data in 21 patients. Out of them, 12 patients were LN. Novartis did not share the complete renal response. We are not sure why. What they have shared is their proteinuria. You can see that 100% of the patients, by definition, had proteinuria in the urine. You can see that at 12 months, 50% had proteinuria. At best, Novartis could have had 50% complete renal response. They have not shared their CRR, so we do not know what it is. It is most likely less than 50%. We just do not know the number. The other point, and again, this is all in the public domain on the EULAR poster, you will see that more than a third of the patients continue to take or receive the immunosuppressants during the study. We are not sure if this effect is only due to the CAR- T or some of the immunosuppressants. At best, 50%, most likely less. The other drug that was recently approved for LN is obinutuzumab. Obinutuzumab is a completely different type of a drug. That is a chronic drug. Patients get it essentially four times a year. Two times, then after six months, another two times. This drug is dosed on top of standard of care, which is essentially a cocktail of different immunosuppressants. On this cocktail of immunosuppressants, where patients have essentially no B cells for the entire year, and again, this is all published, the CRR of obinutuzumab was 43%. If they are chronically immunosuppressed, guess what? They are going to have a lot of infections. You see 72% infections, 50% of them were SAEs. By the way, they enrolled patients that were less severe because the median SLEDAI which is how we rate the severity of the lupus, was 10. In our studies and most cell therapy studies, it is more than 12, 13, sometimes 14. If you try to triangulate, you can see that the small autologous CAR- T is about 40% CRR. If you look at obinutuzumab on top of standard of care, this cocktail of immunosuppressants chronically, it is 43% CRR. If you look at the rap-cel, Novartis, we do not know what it is. Probably less than 50%, and quite a few of the patients took immunosuppressants. Overall, it seems like if we are able to show 40% complete renal response that is immunosuppressant-free with something that's off the shelf, available in outpatient settings, simple to administer, and safer. It's really a one and done therapy, too. It is, yeah. We have not dosed a patient twice. Exactly. When you think about potential pivotal trial design here, obviously you've cited the relevant benchmark with which you could potentially receive FDA approval. Talk to me a little bit about the sample size you'll need in a pivotal trial, and with what speed do you think that you could expedite that trial? Sure. Prosecute it? Absolutely. First of all, there's no approved drug that provides immunosuppressant-free remissions. That just doesn't exist. There's really no control. The FDA is perfectly fine with, and there are precedent available, with a single arm pivotal study. The number of patients, if you're focusing on LN, is probably in the range of 35-50 based on precedent that the FDA agreed to, and the endpoint is complete renal response. That's for LN. Pretty simple. Yeah. Can we enroll this study? Absolutely. We actually, six months ago, if all of our patients have six months data, it means that six months ago, we told the investigators and patients, "No more. We have enough patients. You got to wait for the pivotal. I am very optimistic about us being able to enroll these patients quite quickly. The other point, all of LN patients, the 22 patients, most of them will be LN. Quite a few of them will have SLE, but all the patients have SLE. Every LN patient has SLE. We are going to look at the immunosuppressant-free DORIS remissions, and if these present to be reasonable above the bar, and we can talk about what we think is the bar. Then we could expand this pivotal study to include lupus with and without nephritis. Okay. For the entire lupus cohort, the endpoint would be DORIS, and for the LN, it would be. CRR. CRR. Okay. I am actually glad you brought up obinutuzumab because obviously that is in combination with standard of care therapy. There are some other bispecifics in the pipeline for autoimmune. Cullinan is a great example. They are not combining with standard of care, so there is no immunosuppressant. I want to get your thoughts on that. Obviously, incorporation of immunosuppressants seems to be like a non-starter for a lot of these next-gen approaches. I want to get your thoughts there. Obviously, elephant in the room, in vivo CAR- T. Mm-hmm. Sure. Talk to me a little bit about the data we've seen so far. Obviously, there was just an NEJM paper for lentiviral. That one was in neurologic autoimmune. Yes. Talk to me a little bit about those competing modalities, and that's a nice segue into your in vivo CAR- T platform. Yeah, absolutely. Let's step back and review the competitive landscape. We talked about autologous CAR- T. Yes. Let's talk about bispecifics. There's been multiple bispecific approaches that have been explored, whether it's CD19, CD3, or CD20, CD3. They've been in development for now more than two years. So far, we haven't seen a single data set that suggests the efficacy of the bispecifics is even remotely close to the magnitude of efficacy that one can expect from autologous CAR- T. We've seen that sometimes it's one dose, sometimes a couple of doses can show some efficacy in the first few weeks, maybe up to 12 weeks, but then the efficacy disappears. Really what's happening now is that overall, this field is moving towards subchronic dosing. It might be every three months, it might be every six months. We'll see. But to remind you, that sounds like obinutuzumab. It does. It sounds like obinutuzumab. Essentially, this will require chronic dosing and patients will walk without B cells with a bi specifics and will probably have high infection rate, just like we see in oncology. That is no different than oncology. What happens in oncology? Autologous CAR- T is once and done. Bispecifics, chronic until it progresses. There is no reason to believe, based on data so far, that this will be different. All the data that have been published so far support what I just outlined. Yeah. Now, let us talk about the in vivo CAR- T, because we have been looking into and worked on in vivo approaches and analyzed multiple in vivo approaches, not only lentiviral. There are two types of in vivo approaches. One is mRNA nanoparticle approach. Yeah. mRNA nanoparticle approach, and this was published recently in The New England Journal of Medicine. They have quite short time of a CAR- T expansion. You see an expansion for three days, then you need to dose again, another three days. then need to dose again, another three days. If you look at the CD19 B-cell depletion in the blood, you do not really get to full CD19 B-cell depletion in the blood. If you do not get it in the blood, b y the way, rituximab does it in the blood, rituximab you can get pretty good CD19 B-cell depletion in the blood. You are not going to get it in the tissues. I think the mRNA approach is based on data in humans. I am not talking about monkeys or mice. Based on data in humans, less likely that you'll see good efficacy in LN or SLE. Another approach is the lentiviral approach. We do have a pipeline of lentiviral based in vivo CAR- T. With these, essentially what you provide to a patient is essentially a permanent gene therapy that will stay in the system forever, essentially. There is a risk of insertional mutagenesis because that gene therapy might get into the genome in different places. By the way, what do you hit? You hit alpha beta T cells with pretty good fitness. Yeah. The risk that we've seen with autologous CAR- T is probably the same risk that we'll see with in vivo CAR- T. We are developing in vivo CAR- T. The first indication is most likely going to be multiple myeloma. Maybe at some point we'll go to other autoimmune diseases. But I think if you're a patient and you're thinking about something that's a permanent gene therapy with some potential safety concern associated with alpha beta T cells versus this is just off the shelf, I can take it, and it's going to do the same work. Patients will vote with their feet. Yeah. All right, since we're running up on time, last question from me. Maybe walk us through the clinical catalysts for- Sure. Adicet over the next 12- 18 months. Remind us what your cash was as of end 2Q, and what sort of runway that provides. Sure. Absolutely. First of all, we're funded into the second half of next year. These are the milestones that we expect to meet in this period. We'll have data in LN and SLE this month. We expect data in systemic sclerosis in Q4. In the first half of next year, we expect additional data in LN and SLE. We expect data from our prostate cancer program. We also have in Q4 the final protocol, and we start the activities towards a pivotal study. In the second half of next year, we expect to get into the clinic with our first in vivo program, and we may have data in this program. In 2027, we haven't mapped all the milestones. I'm sure every program will generate its own milestones, and we expect to have at least the first readout from the pivotal study. It's just going to be an interim analysis. Mm-hmm. Well, Chen, I certainly look forward to all the data that's going to be coming, especially the near-term dataset in this large sample size. Thank you. Thank you for joining us today. Thank you for inviting me. Good to see you.