-conference. My name is Kelsey Goodwin. I'm one of the research analysts here at Guggenheim. With me, we have Chen Schor, President and CEO, Schor. Welcome. Thank you. Uh- Thank you for inviting us. Yes, thank you. Let's start off kind of big picture and then for everyone in the room. You're obviously one of the most advanced, if not the most advanced company in the gamma delta T-cell space. Walk us through the differences between gamma deltas and alpha betas and what are the potential advantages, disadvantages of using one or the other? Sure. Absolutely. Let's focus for, on NHL as an example. If we wanna treat a patient, our goal from a cell therapy is to provide a cure to as many patients as possible. When you think about the alpha beta T-cells and specifically CD19 as an example, alpha beta T-cells proliferate very well. They would kill all the tumor cells that express CD19, if there is a tumor heterogeneity, then most likely they will not kill the tumor cells that do not express CD19. From an efficacy perspective, they proliferate well and they provide about 33% CR rate at six months in, for example, advanced LBCL settings. From a safety perspective, alpha beta T-cells secrete a lot of IL-6, and IL-6 is associated with the CRS and ICANS. When you think about the alpha beta T-cells, quite significant percent of the patients, up to 33% of the patients, end up in the ICU because of the CRS and ICANS, which makes it quite expensive for payer and tolling, on patients. Gamma delta T-cells, from an efficacy perspective, one, they proliferate equally well, if not a little better compared to alpha beta T-cells. We published this data. Two, they provide antitumor activity both for the tumor cells that express the target for the antigen, but also for tumor cells that do not express the target for the antigen because they have innate antitumor activity, which is relatively potent because gamma delta T-cells do not have inactivating receptors unlike NK cells that have quite a lot of them. From an efficacy perspective, we have the benefit of innate antitumor activity and good proliferative capacity. From a safety perspective, gamma delta T-cells do not secrete IL-6, so we don't see, so far, actually any grade 3 ICANS or CRS. They're off the shelf, so the patients don't need to wait in the case of autologous cell therapies. Great. The gamma delta T-cell space has obviously gained more interest from the field in recent years, probably in part due to your initial clinical data. What differentiates Adicet from the other companies now looking into the gamma delta T-cells? Sure. Absolutely. We're, I wanna say probably one of the only players. We started in 2015, we took a very fundamental approach to gamma delta T-cells. We can expand any type of gamma delta T-cells. One, two, if you want a combination of alpha, of one and two, just tell us what proportion you want of each, and we could do also bispecifics. We chose to focus on gamma delta T-cells after comparing them for three key reasons. One, we see better cytotoxicity for gamma delta 1s. Two, we see much better proliferative capacity without exhaustion and these type of cells home to tissues. For these reasons, we focused on gamma delta 1s. We're the only company with CAR gamma delta or gamma delta in the clinic or CAR gamma delta 1. We have very strong expertise, an expertise in IP and manufacturing of those cells. Great. your lead program, ADI-001, you provided some clinical updates over last year with the most recent at ASH across dose levels 1 through four. I guess maybe remind us what the key clinical learnings have been so far in terms of response and durability. Sure. Absolutely. As of ASH, if you step back and you summarize the data, I would say it's the following. One, in terms of the patients that we enrolled, these are patients with aggressive lymphomas with median number of lines of therapies of four. A little more advanced compared to autologous cell therapies or bispecifics. When you look at the CR rate, overall it was 69% CR rate, a little better than other alternatives. When you look at the durability, we do not have a lot of patients that reached six months durability, which in cell therapy is what we all look for. When you look at DL2 and then you look at DL3, one out of three patients are at CR at six months. It's 33% in both DL2 and DL3, quite comparable to YESCARTA when you look at their six months CR rate. From a safety perspective, very encouraging data. No significant CRS, ICANS, and grade 3 infections. A little lower than advanced setting in cell therapies. Overall, nice activity, reasonable durability so far, and good safety. The interesting thing about our cells is that we show also very nice activity in post-autologous CAR T. In patients that progress following autologous CAR T, the CR rate that we've seen there was actually even higher than 69%. The durability seems to be also very encouraging in that patient population. Currently, that patient population is growing, and it's a salvage setting. There's nothing approved for these patients. All right. I guess, now kind of looking to advance your pivotal study, what do you need to see from the existing patients or maybe with new patients to choose your recommended phase 2 dose? Sure. Absolutely. Since ASH, we continued to enroll to three dose level to DL3. To DL3, day 1 and seven, and to DL4. When we share more data in the first half of this year, we'll see more durability on the current patients, more CR and durability on these additional patients. I don't think we're gonna be able to see a lot of difference between DL3, which is 3E8 CAR positive cells, to DL3, day 1-7, which is 6E8 versus DL4, which is 1E9. Almost look at all of them together, and based from all these doses, we'll select one recommended phase 2 dose. I think it's gonna be a tough decision, and it's not gonna matter too much which dose we'll choose because they're so close. In terms of the follow-up, given Dose level 4 started, you know, towards the back half of 2022. Yeah. I guess, how much follow-up do you think you need to feel comfortable, you know, if you were to choose Dose Level 4, for example? Yeah.Six months is what people look for. We expect to start the first pivotal study around the middle of the year, plus, minus. By definition, by then, you know, if you think from ASH, we'll have more data about the 6-month durability from dose level 4 as well. Okay, got it. One area of investor discussion and focus is kind of lymphodepletion, what's being used, what doses, et cetera, how they compare across the products. I guess maybe just remind us what doses you use, and what you've seen to date, with respect to the safety profile of ADI-001. Absolutely. From the first version of the protocol, we enabled physicians to select one of two lymphodepletion. One is the standard lymphodepletion, one is enhanced. The key difference between enhanced and standard is mainly the dose of cyclophosphamide. In the standard, it's 500 mg per meter squared over three days, in the enhanced, it's 1,000. That's the difference. The first two patients that were enrolled in the study were in standard lymphodepletion, physicians kept choosing enhanced lymphodepletion. Some of the concerns on enhanced lymphodepletion is infection rate, actually, when you look at the infection rate that we've seen in our study, it's comparable, if not more favorable, to YESCARTA. It might be because gamma delta T-cells have been known to play some role fighting infections, so probably you see some mitigation from the cell type. Got it. As you said, you're looking to start your initial pivotal trial, middle of this year. I guess you've disclosed that it will be in the post-CAR-T setting. Maybe just remind us what exactly is the efficacy bar there. Sure. How should we think about the potential commercial opportunity as, you know, the CD19 autologous CAR-T start to gain more steam? Absolutely. Let's start with the efficacy bar. Right now, there's multiple publications that show that we try whatever products for these post autologous CAR T patients, the overall response rate is about 10%-20% and mostly PRs, the PFS is about two months. There is real unmet medical need. The next data set that might be somehow interesting for those patients are actually the bispecifics. The bispecifics show a CR rate of 34%-35%. They haven't published their durability, but if you look at the durability in the entire patient population of the bispecific, you assume it's gonna be the same for the post autologous, it's probably gonna go down to about 15%-20% long-term durability. From 35% to 15%-20%. I think that's the bar from a commercial perspective. From the FDA perspective, there's nothing really approved. Even those bispecifics are accelerated approval, you can't use them as a bar. When you look at our data, the CR rate that we've seen in post autologous CAR-T, it's actually in LBCL is 86%. I think these are small N, it doesn't really matter if it's 86% or 70% or 60%. It's more than the bispecifics. It's more than any other alternative that we're aware of. In terms of durability, so far when we look at the durability, it's quite encouraging. The 1st patient in dose level 1, I believe it's post five lines of therapies, including autologous CAR-T. Keep in mind the median overall survival for these patients is six months, is now 14 months into the study. When we invite them to scan, like, sometimes we can't find them because they're, like, in the Caribbean on an island, and they're saying, like, "Leave me alone. Yeah. you know, it's really, it's amazing to see what happened to patients. Yeah. Not a bad problem to have. Yeah. You've also guided to, planning additional pivotal trials for this program. Yeah. I guess what indications make the most sense? Mm-hmm. Are there potentially additional accelerated approval pathways, or will post-CAR-T probably be the accelerated path, and then maybe the confirmatory would be? Um- a little earlier? Actually, I'm not sure that I see a good reason for the post-CAR-T to go accelerated. Mm-hmm. I think if you just do the standard study, it's probably double-digit number of patients, and you can submit for full approval. I haven't been persuaded that accelerated would buy us anything in the post autologous CAR-T. For the earlier line of therapy, we haven't finalized the that study. Once we'll finalize, and when I say finalize, we wanna hear what the FDA say, then we'll update what's the design of these studies. Okay, got it. Then at last year's R&D Day, you, kind of unveiled. Mm-hmm ...some of your new kind of gene edits and ways you're modifying next gen programs in your platform. Yeah. Maybe just walk us through kind of what you unveiled there that you have in your toolbox and you plan to use moving forward on some of your next gen assets? Absolutely. Our next program that we're gonna move into an IND and then to clinical study, the IND is in the second half of this year, and then we'll follow up with the study, is a first-in-class. It's actually not a CAR-T. It's a CAD, chimeric adaptor, gamma delta 1 T-cell. The presence of gamma delta T-cells in tumors correlates very well with overall survival. Actually, a little more than alpha, beta, and NK cells. Why? Because they have very good innate antitumor activity. We took the innate antitumor activity of the gamma delta 1 T-cells, and we upgraded them to a signal just like a CAR signals. Now they signal through 4-1BB and CD3ζ. Now we go after eight, at least eight stress antigens, and we can go after multiple tumors. If one of the stress antigen is downregulated, then we catch them by another stress antigen. The preclinical data have been very, very favorable. We expect to start with AML as the first indication, and then we'll move to solid tumors that again, gamma delta T-cells in those tumors correlate with OS, and they express those stress antigens like TA, like triple-negative breast cancer or ovarian cancer or hepatocellular carcinoma. Got it. I guess how might that be, like, targeting various stress ligands? How might that be differentiated from, say, you know, targeting just a more traditional target or a dual target? How do you think about that? The key is that you have a bunch of them. You have eight of them. Different tumor types that we can characterize, we know which stress antigens they're most likely to express. Even if one is downregulated, you catch them using a different one. It's very different than an alpha/beta CAR T would only target one, the, the target for the CAR. A gamma delta would have very potent antitumor activity against the CAR, but about 25% of the antitumor activity seems from the innate. Now we made the innate work just as potent as the CAR. It's the data preclinically, if you compare CAR to CAd, you can't tell the difference. Okay, got it. It sounds like you're gonna go into AML first, and then will there be a basket trial for the solid tumors, or do you plan to kind of-? Yeah. hand, handpick? We haven't shared more details. Probably a basket, but, you know, we haven't finalized that design. Okay, got it. Then another asset you're pursuing is a CD70-targeted- Correct. CAR, I guess maybe remind us how this asset was designed and how it might be differentiated from some of the other CAR Ts we see that target CD70? Sure, absolutely. It's designed in the following way. One, we're targeting CD70 in a different way. We added bolt-on technology, and it's a different cell type. Why is that important? CD70 as a target has shown some clinical activity both in AML and in renal cell carcinoma. In low antigen density CD70, you see very little activity with the CD70 targeting. We actually are using CD27, which is the natural ligand for CD70, to target CD70. It's been published by others, not Adicet Bio, that using this targeting, we can go after low density of antigen malignancies. Indeed, that's what we see. One, going after low antigen density. Number 2, we address the tumor microenvironment by adding dominant negative TGF-beta. Number 3, we're using gamma delta 1 T-cells, which are tissue resident. They go to the relevant tissue to begin with. Half of the problem in cell therapy is make sure you get there. Gamma delta 1 T-cells are much more likely to get there and show activity. Got it. For clinical development plans for this asset, is it again maybe starting in Heme and then moving into solid tumors or? Yeah. Yeah, you see a common strategy. It's actually a strategy that takes into account mitigating risk for investors and patients. First program is Heme, which is clinically validated. Second program is Heme and solid without bolt-on, but we'll have a backup with the bolt-on potentially. Third program is Heme solid with bolt-on technology, and fourth program is solid. We're, if there is a cell type that will show efficacy in solid tumors, gamma delta 1 T cells is one of them because it's the only cell type that really goes to tissues, and that's where they reside in humans. We're mitigating the risk for investors and patients. Mm-hmm. Got it. I guess kind of thinking about moving into solid tumors. How do you think about the lymphodepletion dosing strategy and the cell dosing strategy? Do you think, you know, there's any kind of read-through to from the Heme learnings, or do you think solid tumors will kinda be its own animal? It's actually tumor dependent. You're asking a very good question. It's actually tumor dependent, and it's dependent on what's the status of the immune system in those patients. It might not be the same lymphodepletion as we see in Heme as a function of the tumor. We're actually, we're thinking about this as we think about the design in solid tumors. Okay, got it. It might not be one lymphodepletion. It might be two lymphodepletion in solid tumors, just two doses. We don't know. Got it. All right, is that something that, I guess, in solid tumors, you know, do you think that two doses would maybe be enough? Or is... How do you think about, you know, solid tumors obviously being one that's been historically difficult? Yeah. Is it something where cell therapies might just need, you know, more of, like, sequential dosing, not necessarily chronic, but maybe more than just one or two that we've tried in Heme? We don't know. Honestly, that's the answer. I'm hopeful that one or two would be enough. Certainly, when you look at the activity that we have in Heme, which, yeah, it's not a solid tumor, but eventually you have, you know, a bulky tumor and sometimes, like, very large bulky tumors that we were able to essentially eradicate with a single dose. We don't know. We're planning either one or two doses potentially, but we haven't finalized the design there. Right now, we're not thinking more than two. Got it. Thinking about the catalyst lineup for the year, it sounds like an IND for ADI-925, and then an updated data from ADI-001. I guess maybe just remind us or help us kind of gauge expectations there. We'll get an update, I believe, in the second half, but you'll start to pivotal in the middle of the year. No, we expect, at least one update in the first half of this year- Okay, got it. ... for, 001. Overall, in this, first half of the year, we expect to report, more data on the current patients in the study and more durability, CR rate and durability for additional patients enrolled in the study. Feedback from meeting with the FDA regarding the design of the first, pivotal study, and the recommended phase two dose. We expect to start the study around the middle of the year. Mm-hmm ... everything should fall into place in the next, in this half of the year, hopefully. Okay, got it. As of now, are you enrolling new patients into that phase 1, or will we just get kind of the same patients we saw at ASH with longer follow-up? We have enrolled more since ASH. Okay, got it. Yeah, yeah. In dose level four? Dose level 4, dose level 3, day 1, 7, and dose level 3. Okay, got it. Those are the three in the running for recommended phase 2 dose? Correct. Got it. Okay. All right. I don't think we'll be able to tell the difference, but we'll see. Okay, got it. I guess, maybe with our last couple of minutes, is there anything else in your pipeline that you feel, you know, we didn't spend enough time on talking or something that you're particularly excited about for Adicet that investors are maybe just not getting? First of all, there is more pipelines, product in the pipeline that we really like the PSMA as well. Overall, investors, eventually data should play out. If I try to summarize the data that we've seen so far with this potential class of drugs, with ADI-001, CR rate seems to be more favorable than autologous or bispecifics. Durability, small data set, looks to be pretty comparable to YESCARTA, which is the best therapy out there. ICANS and CRS don't seem to be an issue with gamma delta T-cells. Grade -3+ infections seems to be a little more favorable compared to YESCARTA. It's off the shelf. We think this can play a significant role in patients and, you know, we look forward to reporting more data. Great. Maybe just remind us cash runway? Yes. We're well-funded. We had $280 million in cash as of the end of Q3 this year, and that should take us into the first half of 2025. We're very well capitalized. Great. Okay. Well, I think we're running out of time here. Thank you so much for joining us, Chen. Thank you everyone in the room for joining, and we'll see you at the next session. Yeah. Thank you. Good to see you.