GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - ADICET BIO INC

One of the biotech analysts here at Guggenheim, and it's my pleasure to introduce our next company Adizet Bio, and with us we have the CEO, Ken Shore. Welcome Ken, and its a pleasure to have you here. So maybe just to set the stage, why don't you tell us the story about the company for people who are not really familiar with that, and the latest updates, what shall we look for over, you know, the next 12, 18 months. Sure, absolutely. So first of all, Delma, thank you for inviting us. Always glad to be here in the conference and look forward to a productive Fireside Chat. So AdiCET is a leading cell therapy company. We're focusing on a specific type of cells called gamma-delta-1 T-cells, and we also have an in vivo CAR-T pipeline that we expect to update the market about in the very, very near future. On the cell therapy side, what's unique about gamma-delta-1 T cells is that we can dose them completely off the shelf. These are allogeneic cells that can be dosed to patients. And gamma-Delta-T cells, unlike alpha-beta T cells, tend to home to tissues. So a very low percent of our T cells in the blood are gamma-delta-1 T cells, but rather a much higher percent in the tissues is gamma-Delta-T cells, which makes them ideal for autoimmune diseases and potentially also for solid tumors because that's where the tissue presents itself. And for example, in autoimmune diseases, we have these B-cell islets that are associated with the disease. The other key advantage of gamma-delta-1 T cells is they're generally very, very well tolerated and have less events like CRS and ICANNs and other type of events that are very predominant with the alpha-beta CAR-Ts as we've seen in different data sets. We recently announced a data set that included quite a few patients at 12 months, not all All of them were 12 months. We expect to have a data update in the very, very near term, in the next few months, with all the patients completing at least 12 months, and an update following our meeting with FDA regarding the design of the pivotal study. We also expect in the few months to update the market about our in vivo CAR-T pipeline, And we have another program in solid tumors for prostate cancer that we expect to start dosing in Q1, and we'll have data over the next year. Thank you for that great overview. So maybe stepping back to the platform, as you were saying, it's a pretty differentiated platform compared to the classical A-beta CAR-T cells, in vivo CAR-t. We have the T cell regulators as well. So how shall we think about the implication of this difference? So what are the advantages in terms of efficacy and safety? Yes, absolutely. So that's a very broad question. So essentially, the question was, how do you compare? And let's focus on LN and SLE. I think that's probably going to make it more relevant. How do you prepare Prula cell versus other alpha-beta T cells, bispecifics, in vivo CAR-Ts, there is lentiviral approaches, and there's mRNA, yeah, this will be specific, and mRNA nanoparticles. So let's kind of go, I'll start with the bottom line. I believe the data suggests so far that for autoimmune diseases, the therapies that can provide immunosuppressant-free remissions are either T-cell, whether it's alpha-beta or gamma-delta, or lentiviral approaches. In between, it's less likely that we're gonna see. So let's first focus on the in between. Now there's room for everybody, let's not be confused about it. So let for a second focus on in between, if you look at T-cell engagers or B-specifics in the field of LN and SLE, we haven't seen, these have been developed for quite a few years, I just came back from ACR, We haven't seen any data set that suggests that B-specifics can cause an immune reset and provide immunosuppressant-free remissions. When you talk with ACR, in ACR with investigators that are experienced with B- specifics, I haven't found one that told me you're not gonna need chronic dosing with B specifics. Will it work? Yes, but it will be another version of immunosupressants, probably, maybe a little bit better than immunosuppressant, than obinutuzumab, maybe, but I don't think there's data yet to suggest that it's better than obunutuzimab. So B-specifics, more like chronic immunosupressants, like antibodies. If you talk about mRNA approaches, again, no data to support the efficacy, but they're overall predicted and what we've heard from people that have clinical experience to perform in the B-specific range. With alpha-beta T cells and when you look with gamma-delta T cells, what you see is immunosuppressant-free remissions. So when you at our data set, we've seen approximately 50% to 54% either at 12 months, complete relapse response or DORIS that are immunosuppressant free. Generally all the patients stop taking their immunosupressants and they went off their steroids except for one and you know they don't take any drugs. They feel much much better. That's consistent with the alpha-beta what you see and the key advantage that we have is that we're off the shelf and we're much better tolerated and we understand why we're much better tolerated compared to the alpha-beta T cells. The lentiviral approach I think will eventually produce the same type of data sets just like the alpha beta T cells but it's gene therapy and I'm not sure if you're an immune patient if gene therapy is the first choice you're gonna go after if you can take a cell therapy approach. Got it, that's really helpful and maybe zooming in on the data that you have recently shown so we have seen like 12 months data can you help us contextualize the denominator you know that we received a lot of questions on that like compared to all the patients that you had enrolled how many did you follow up and can you contextualize that number that you saw absolutely our efficacy of valuable population is 22 patients will LN or SLE 16 of them of them 16 of them had the LN and six of them SLE. By definition all the L and patients also have SLE so out of those 22 patients all the 22 patients had reached their nine month visit 13 of the 22 patients reached their 12 months visit at a 12 month endpoint which is also what we expect for a pivotal study. Out of those 13 patients, what we have seen is that in the lupus nephritis, 50% of them had a complete renal response. And out of the entire population that had the lupUS, which is 13, 54% of the patients had a DORIS remission. And both CRR and the DORIs are immunosuppressant-free remissions. We have follow-up up to 21 months for these patients. all the patients but one complete continue to be in remission we had one Ellen patient whose proteinuria increased their threshold for complete response is 0.5 it increased to 0.65 in one of their visits but they're all continued to be immunosuppressant free nine patients have reached their nine months visit and they'll reach their 12 month visit very very shortly by definition, the data cut was, I believe, end of August. So you can imagine that by the end of the year, we'll have the data cuts for all the patients reaching 12 months. Got it. So pretty solid data. And when we look at the durability of these responses, how does the immunophenotype of these patients help you to predict how long is that going to last? So in other words, did you see signs of immune reset? Yes, thank you for asking. We absolutely saw signs of immune reset. So what you see is upon dosing of a prolocell, you see complete depletion. We actually, although we target CD20, we actually measure CD19 in the blood and we find the same findings as you see with autologous securities. You see complete depletion of CD19 B cells from the blood for about 28 days. All the patients, 22 out of 22. If you look at CD19 B cells in the blood, complete depletion. And then once you see the immune, the B cell compartment starts to recover, it's really primarily naive B cells. In a prior data set, we also did some BCR clonings, trying to understand what were the BCR clones before dosing of pulocell versus after. And you see essentially all the clones before go to zero, and the clones after, once the B-cell compartment recovers, there's a completely refreshed and new BCR clone. So we truly see signs of immune reset, and only that can explain the quality of the data that we have with essentially all of the patients but one continue to be immunosuppressant-free, and such a significant percent of the patients at 12 months having these major responses. Yeah, I agree. That's really supportive of that potential durability. And as you add more patients, so do you expect those efficacy responses to remain constant over time? And what's going to be the longest follow-up at the next update? So last time it was 12 to 21 months. We're going to move probably three, four months. So you can just do longer in terms of follow-up. One thing we can do is move time faster. But that's a very... There's always a possibility there. Yeah, maybe I can do that. Maybe I can't do that, so that's going to be... But that is a very significant follow- up. When you look generally of data with T-cells that show immune reset, you see pretty good durability for this type of therapies. And how many patients do you expect for the next update, roughly? So we actually, about nine months ago, we felt that we do not need to enroll more patients prior to starting the pivotal study. So it's going to be the same number of patients because we have not enrolled for the last nine months, but we rather focused on a follow-up. So it will be 22 patients. All of them will have at least 12 months follow-up that we will report. So just zooming in on that point, can you clarify why did you stop enrollment? Will that be just because you will enroll them directly into the Pivotal? Yes. There was just no need. When you look at all the companies that enroll patients, in terms of number of patients that we enrolled, we're in a pretty good company with companies like BMS and Novartis. We had a lot of interest in joining our study and as we continued enrolling we had more and more interest but like 22 patients is way more than even Novartes and BMS had before they started the pivotal study. So there was just no reason to enroll but rather wait and enroll to the pivotal studies. Okay perfect and the The Pivotal Study is the next key milestone for the company. So where do you stand there with the conversation with the FDA? What are they waiting for? And what are the latest updates? Sure, absolutely. So we had one meeting already with the FTA. We expect to have another meeting with FDA this quarter. The meeting that we had with FDA initially focused on LN. And when we discussed with FDA about the endpoint in LN, they agreed that it's complete real response at the time point for the endpoint will be 12 months so essentially it's immunosuppressant free CRR at 12 months that's the endpoint in terms of number of patients we haven't finalized the number of patients for LN but you can see the number of patients in other studies in the range of let's say about 50 patients the reason we want to meet with FDA this quarter is because when you look at our Doris rate it's you know 54% it's really in line with autologous cell therapies and we can talk about some of the data sets from ACR so it really makes sense to include SLE in this pivotal study so the goal of that meeting is to agree with FDA on the endpoint for this study and if we are able to include them in this pivotal studying together with the LN and what's the best way to do this we will have that meeting this quarter and once we have data we'll share with the market. So what's going to be the bar of success for that pivotal study, both in LN and in non-renal SIU? Sure. So among the approved therapies that are currently in the market, there is actually no therapy that provides immunosuppressant-free remission. So the bar for this type of study, it's tough to find something to compare it to. So we don't have a good answer. What we've heard is that, for example, for LN, people want to see at least 40% complete urinary response. When you think about SLE, the therapies that we currently have have very low, even, dory rate in 12 months so the Doris rate is somewhere in the range of 10-15% you know we've seen 50% immunosuppressant free Doris permission so I think the bar is not going to be an issue and this will be small studies with double-digit number of patients I agree and in terms of safety requirements so where are you standing like what's the request from the FDA and where do you stand sure so We haven't discussed this with the FDA. We can see what other companies have done. Generally, what the FDA wants to see is at least 100 patients exposed to a Prula cell. We do not expect to have any issues with this. In our autoimmune data set, I believe we already have 45 patients. The size of the pivotal study will definitely roll it up. If it's LN, let's say it's 50-ish, so maybe it's five more. And if it's LNS, it's going to be higher. Usually it's 100 patients. That's what we've seen in other therapies. And that's going be a single-arm study, right? Yes. Where do you stand with the site activation and general preparation of the Pivotal? Sure. So we're in startup activities. The sites that I literally just set in a table in an event we had at ACR with investigators from U.S. and from Europe and from Canada, you see, first of all, a lot of interest in participating in the studies, especially given some of the news with alpha-beta T-cells and given the safety profile and the efficacy that we've seen. So certainly a lotof interest in our study. And we've heard from one of the sites that they just happened to sit next to me that they would love to enroll and they have many, many more patients that they want to dose with Prolocell. So consistent with our track record so far for enrollment, I think in the Pivotal study it's gonna be even more so because it's now established, we have the efficacy, and we have their safety data set. And when can we expect the next update for the Pivoter? Like will it be after the- Yeah, we will have it in Q1. That has been our guidance because by then we'll have the 12 months data and by then we'll have the feedback from the FDA. Got it. And how are you thinking about the commercial opportunity in LN and the non-renal SLE? Sure, absolutely. So when you step back and you think about the number of patients that could benefit from a drug like Pruracel, in Ln we estimate that essentially the efficacy, the patient population that we expect to enroll are patients that were diagnosed with LN and failed at least two prior therapies. I would expect it to be the same for SLE. When you look at the number of patients that could potentially benefit from Pruracel, in LN, we estimated at around, in the U.S. alone, at around 35,000 patients that would benefit from this therapy in LN and qualify for this type of therapy and when you look at the SLE although SLE is a larger indication we expect that fewer patients would want to take a cell therapy this would be the more severe patients and it's we expected to be around the same number 35,000 patients so a total of 70,000 patients the way we define this patient population is not inconsistent with some of how some of the big pharma guided for the size of these population so that is very meaningful it's actually much higher for example when you think about the NHL cell therapies in terms of the number of patients I agree and one key point for all the CAR T therapies out there is obviously manufacturing so that's a big part of the equation also when we think about profitability scalability so what's your strategy there and how does it compare with the autologous approaches. Absolutely. So autologues essentially you have to manufacture per patient and then you have two release per patient, and it's quite costly. In our case, from a single manufacturing run, it takes the same time as an autologus curtee, about 14 days, but we have many many many more doses. We have manufactured inside at Adicet and with two different CDMOs, we've used the same release criteria within our studies multiple different donors there's no magic donor in our studies the cost of manufacturing is well below 20% it's a little more consistent almost with an antibody a little higher than an antibody so cost of money factoring is not an issue here and we have a lot of stability how to wear how to price and you know follow up to that is also the lymphodepletion which that's another and are you trying or planning to run a lymphodeplation free trial and based on your feedback that that you receive you know from physician yeah let's walk through let's work through the existing information what we know about whether a lymphodeplication is necessary or not so let's think about I'll mention different companies this is about the field not about the specific company. But I think we can all learn from others. So if you think about companies like Encarta, initially they started with the Cy-only and they did transition to Cy-flu. Maybe there's something we can learn from that. If you think companies like Allogen, they've just shared data at ACR, they tried no-lympho depletion, they tried, I believe, Cy-only and Cy-flu. If you look at the B-cell depletion profile, where they saw the best B-Cell depletions was in the Cy-Flu. If you at the autologous cell therapies, some of them tried to go without lymphodepletion at all, and certainly you see that efficacy is compromised or they need dosing every six months if it was in oncology. Generally, it seems like in order to see this great type of efficacy, CyFlu is required. These are low doses of CyFflu. The Cy is not associated with fertility concerns. There's more and more publications that suggest that these low doses of Cy are not associated. They're not associated with fertility issues. In our case, I believe we had a couple of women that got pregnant. They're disease-free. They feel good. They got pregnant, so no, there wasn't a concern. So I believe that CyFlu will be required. We're running a small study in RA with Cy versus CyFlo, just to confirm that that's the case with gamma-delta-1 T cells, but I would say generally as a field, CyFle is probably something that will be necessary. Thank you for that. And in these last few minutes, let's turn to the pipeline. So, I think you're guiding for an update in systemic sclerosis in the first half of next year what shall we expect how many patients roughly will have data and what's the longest follow-up sure so i think we have around 10 patients with the systemic cirrhosis and we expect the update in the second quarter of next and we expected to have all the patients who have at least 12 months follow-up it sounds like that's what the market there would prefer um so that's our expectation we also expect during this time to update the market about the in vivo cart pipeline we've invested a lot in this uh there's a lot of excitement on that yes a lot of excitement and we get a lot questions from investors about it um so we we essentially what What we have been focusing on is a cell therapy that is very potent, that engages T-cell in a very, very specific and selective way so that the doses that will be required will be low. We developed different bolt-on technologies for that, and we also selected targets and SCFEs that can engage those targets in a differentiated way, so we will update the market. It might be a mono car, it might be dual car, but it's a lot of work. That's going to be interesting to know, yeah, exactly. And where do you stand with that program? Are you in the IND enabling studies? Not yet. The IND is not yet in IND. Got it. And any update on the cancer program? Sure. So our oncology program is for prostate cancer, ADI 212. So I'll define ADI212 is a gamma-delta-1 T cell that targets PSMA and the right type of pyridic site of PSMA, very consistent with Pluvicto, that is shown to work. We introduced two additional bolt-on technologies to this therapy. One is a member-bound IL-12, and during CITSE you see more and more information about the IL- 12 as a strategy to turn the hostile microenvironment of the tumor into a more friendly and engage more type of immune cells to fight the tumor. So membrane-bound IL-12 is a part of this product. It's being expressed on the membrane upon activation of the CAR, so it's really selective to the tumor, so that was one bolt-on technology. And the other bolt-to-technology is the MET-12 knockout. What the M-12 knockout does, it enhances the potency and the serial killing capacity of the gamma-delta-1 T cells in a very, very significant way. So you see essentially the cells continue to kill and kill and kill until we end the experiment. The combination of both MET-12 knockout and memory-bound IL-12 has a lot of synergies and shows very, very promising preclinical activity, and hopefully this will translate into activity in patients as well. That's really interesting. And maybe the last question from me. What do you think is generally not appreciated enough about, you know, Adi's story? Yes, absolutely. I think the cell therapy as a field is a field that suffered from investors that lost money on certain companies. And general investors are a little more careful about this. Where I think The Market Got Burned is primarily in oncology. and there were a couple of disappointments on on data from some autoimmune companies and i think where the market could benefit and where can people really be smart and be have something that's uncorrelated is really dig into the data and understand the efficacy and safety of different modalities and pick what's the winner so it's much easier to say hey this class or that class, but actually not all therapies are created equal. Gamma delta 1 T cells are completely different than alpha beta T cells. Very, very different. NK cells, completely different from gamma delta and alpha beta. It might be that if people really do their work, they realize that actually with gamma delta T cells, they have the efficacy like alpha beta C cells because they proliferate and they deplete B cells really good, but they secrete these other types of cytokines so they don't have all these safety issues with alpha-beta T cells and it's just a single dose. So I think people should just spend their time and understand and if they're interested, we can walk through other data sets from ACR and they'll find out that that is the case. Thank you so much for that perspective, Ken. I enjoyed the conversation. Thank you for being here with us. Thank You so much. Good to see you.