Good morning, everyone. My name is Anthea Li, biotech analyst at Jefferies. Welcome to day two of our healthcare conference in New York. Really great to have Adicet here. President Chen Schor, welcome.
Anthea, first of all, thank you for inviting us. Really glad to be here today and look forward to a great fireside chat.
Absolutely. Maybe before we get into Q&A, would love to have you give some opening remarks about Adicet for those who are not too familiar with the company, and kind of key catalyst to look for in the next six-12 months.
Sure, absolutely. Adicet is a cell therapy company. We're focused on a specific type of cells, gamma delta 1 T cells . Gamma delta 1 T cells have some key advantages, both in autoimmune diseases and in oncology. The key advantages are, first of all, they can be dosed completely off the shelf. There's no GVHD and no need to gene edit the cells in order to dose them in an allogeneic manner. That means that there's no need to schedule leukapheresis, and that's a significant bottleneck. Most of the sites cannot do leukapheresis, and cell therapy is very limited to very few centers. There's no need for the leukapheresis itself. There's no need to wait for the manufacturing and get the cells. These are simply completely off the shelf for the patients.
The other key advantage is that gamma delta 1 T cells present with a very favorable safety profile compared to alpha beta T cells or even bispecifics. I can elaborate why we believe this is the case, but this has been our experience across clinical studies. Essentially, they provide potentially the same type of therapeutic benefit, potentially in autoimmune diseases and in oncology. We currently have one program for autoimmune diseases in the clinic. We have another program focused on oncology, which is a very much significantly more advanced generation of our gamma delta one platform, I'm happy to share more details about the oncology program. We have some other, I believe, very exciting research program focused on in vivo CAR T as well.
Great. I think maybe first starting with prula-cel, can you just give us an overview of the asset, the mechanism, also all the indications that you're going after in the autoimmune program?
Absolutely. prula-cel or ADI-001, is a CD20 targeted gamma delta 1 T cells . It was initially developed for NHL, and once we saw the data in autoimmune, we switched to autoimmune diseases. In autoimmune, we started a study that has multiple cohorts. The first cohort that we started was lupus nephritis, then we expanded to SLE, the n we expanded to systemic sclerosis, then to myositis and ANCA vasculitis, and we have another very small study on RA focused mostly on testing different lymphodepletion regimens. Most of the data that we expect to have in the next data cut are going to be focused on the, or will be the indications that we started enrolling with. It's going to be primarily LN and SLE, as well potentially systemic sclerosis.
Got it. I think one of the key pushback that I get is that prula-cel is going after CD20 versus a lot of the data generation in lupus has been in CD19. What would you say to that? How do you think the efficacy compares there? Are there any disadvantages to CD20?
Absolutely. All we can talk about is maybe two important points. Number one, although we target CD20, when we look at CD19 depletion in the blood in our patients, we see complete depletion of CD19 B cells. When we look at lymph node biopsy, we see complete depletion of CD19 B cells. So far, both in autoimmune patients and in oncology, we haven't seen any difference. When we looked at adult autoimmune study, when we look at the immune reset, we see exactly the same type of immune reset as we've seen with the other autologous CD19 companies. When we look at the efficacy overall, it looked in the same ZIP code of the efficacy of the alpha beta T cells.
So far, we haven't seen any changes, and we expect to do another data cut with significantly more data in patients. It hasn't been that much of a concern. I'll point out, when you think about Artiva. Artiva is an NK cell that is combined with rituximab. That's a CD20, and they announced data a couple of, I think it was about a month ago, and they showed quite potent data in RA. I'm not sure if there is a big difference, but the future will tell.
Right. Got it. I think, yes, very important to note that in the clinical data that you have in SLE and LN, if you plot everything together, it trends right in line with CD19. On a clinical perspective, it seems to be similar. I think the mid-year update is definitely the most near term. Talk about how many patients you're expecting, 20+ in six months, six months plus, what you're expecting from that data, and what would be good data?
Sure, absolutely. Indeed, we expect to have a little more than 20 patients. All of them with at least six-month follow-up. Some of them will have nine months follow-up, some of them will have 12 months follow-up. We expect at least in LN, look at the SLEDAI, look at all the relative kidney function. In SLE, we expect to take a look at the SLEDAI. We are going to look at are patients still taking immunosuppressants, are patients still taking any steroids. We may also have the systemic sclerosis data set. It is coming very soon. We might just combine them all into one clinical update. In terms of what we want to see, we want to see overall efficacy in the same zip code of the autologous cell therapies.
The key advantages that we see from prula-cel is the fact that it's off the shelf, the fact there is no manufacturing, no leukapheresis, the fact that it's very well tolerated, and it can really be dosed in outpatient settings to so many more patients compared to the very few centers that can do cell therapy and leukapheresis.
Got it. Given that this is a much larger data update, 20-plus patients, how are you thinking about how to interpret that? Understandably, with the five-patient data, you would look on an individual basis. Do you feel like this is critical mass to be able to see this on a mean basis? Or would you still be watching out for patient data more so?
You're absolutely right. Once you get to this type of number of patients, you want to look at everything and understand the totality of the picture, not incomparable to other larger data sets that have been reported by some of the bigger companies.
Got it. In terms of that SLEDAI curve, is there a slope or a score that you're hoping that most patients reach? Just talk a little bit more about the thresholds of mild, medium, severe, and remission, and what you're looking there numerically.
Sure, absolutely. That is a very good question. In terms of where you expect, it's a little different between SLE versus LN. The magnitude of the reduction in the SLEDAI score is usually correlated to how many years the patient had the disease, most importantly, the chronicity of the patient, because sometimes they have damage that is really irreversible. You sometimes see that in LN patients. If LN patients had a high chronicity score, their kidney might be so damaged that the proteinuria you're going to see for long-term, and you might never see it disappear. Most of the reduction that we expect to see in the SLEDAI usually happens within the first three months, and then it continues to decline over time. Again, overall, we expect the same type of data that we've seen from the autologous.
In terms of how quick responses are, would you say that LN is also slower given that that disease is very different from non-renal SLE?
Absolutely. When I mentioned the SLEDAI, you see most of the markers go down in the first three months and then continue to slowly decline. You're absolutely right. In LN, in many cases, the proteinuria takes much more time to resolve. Absolutely.
Got it. Okay.
Yeah. Consistent across many data sets.
Understood. Should we see this data set as LN on its own and then non-renal SLE on its own? Do you feel like this is good enough to be able to see it as a whole and look at the clinical profile in both indications?
Sure, absolutely. We're going to have most of the patients will be in LN. We'll have a very good picture about the LN. We will have some patients with SLE. I don't remember exactly the number, but it's going to be in the single digit, and potentially we'll have patients in systemic sclerosis. We'll be able to take a look at all these data sets.
Okay. What are you looking for in terms of determining which to go forward to or going forward with both?
Absolutely. Initially, we expect to consider LN as a first indication. We've seen examples by other companies where they started from LN and then they expanded to SLE as they enrolled more SLE patients. It certainly has been done even in a pivotal study context, essentially extending from LN to SLE. In systemic sclerosis, it seems like a pretty small single-digit number of patients can potentially lead to starting to think about the pivotal study.
Got it. This is also a much longer follow-up data, six months, nine months, 12 months. At what point is data enough to be able to assess durability, and what kind of signals are you hoping to see? Is it additional decline, as you kind of mentioned, or is stabilization good enough?
It depends on the indication. When you look at the endpoint from a regulatory perspective, it seems to be that six months is the right timeframe for LN and SLE. When you look about systemic sclerosis, not a lot of data out there, but it might be 12 months. It looks like single-arm studies are possible. The longer the durability, the better. When you talk to physicians, if they can get one treatment and they see 12 months, essentially patients getting rid of most of their symptoms, if not all, stop taking immunosuppressants, stop taking steroids, or reduce the steroid dose to something that's very, very low. Essentially, the patient is symptom-free and doesn't take drug that take a big toll on their lives. I think six months is from a regulatory perspective, and the longer, the better.
Got it. Okay. I guess going back to the thought about moving forward in SLE in addition to LN, it sounds to me like LN will be the first to go. There's more patients. You'll have a clearer picture. SLE will be a decision on whether or not to expand. What is gating that decision? Would you look to enroll more patients and then have more critical mass before you move forward? Just talk us through your thinking there.
Sure. Absolutely. In SLE, that's the case. It's potentially expanding the data set and understanding better the durability of the data set that we have, because it's just smaller. I'll just expand, also in systemic sclerosis, again, it's understanding the data set and seeing when do we want to consider moving to a pivot.
Okay. Systemic sclerosis, just remind us the endpoints that you're watching out for. What is clinically meaningful there, and also how much data you provide at this update.
Absolutely. Systemic sclerosis is very, very different from SLE or from LN. First of all, in both cases, there is unmet medical need. In systemic sclerosis, the unmet medical need is very, very significant. The drugs that are approved today do not improve the skin score. They barely reduce the reduction in lung function. You see some of the patients that walked into our study, their skin is so thick and stiff they can't hug their own family members and they can't climb stairs. It's really a terrible disease, and there is no available therapies. What we're looking at in the study is, one, lung function, and there the hope is pretty much to stabilize the lung function so it does not continue to deteriorate. The other is the skin scores.
Now gamma delta 1 T cells have tropism to the skin, quite significant tropism. We really look at the MRSS score. Of course, we're going to look at the CRISS, which is a combination of a couple of data points as well. We'll have all this data when we report data.
Got it. Can you talk about how many patients, or roundabout, that you expect to provide an update on and how long?
Sure. Single-digit number of patients. How long? It's going to be I don't want to guide you on how long. I'm waiting myself for the data cut. I have a sense, but I wouldn't want to mislead you.
Okay. Absolutely. Stepping back a little bit, how do you feel that prula-cel's efficacy looks like so far compared to the autologous CAR T? Do you feel like, given it's off the shelf and there's manufacturing efficiencies relatively, that there is potentially a discount on efficacy that prula-cel can take compared to auto CAR T?
Absolutely. So far it looks quite similar to the autologous CAR T efficacy. Whether there is some room for difference, I think there is. I think there is. When you think about the cell therapy, they're really available to very few patients in few centers. When you think about something that's off the shelf, you can dose it in outpatient settings, so many more physicians can prescribe the drug. The commercial model is completely different. The cost of manufacturing is completely different. Where you stand in the formularies is completely different. It's really the difference between a specialty drug in few centers versus something that could be much more available.
Understood. How are you thinking about COGS and pricing, understanding that it is kind of far away, but is there also an opportunity to differentiate on price when you eventually launch?
Absolutely. We don't have all the liabilities of autologous cell therapies and manufacturing. When you think about the cost of manufacturing an autologous cell therapy and release, it's not that much different than what it costs us to manufacture one in an off-the-shelf manner, and it's available for so many more patients. Our COGS is significantly lower and much closer, I want to say, to the antibodies cost of manufacturing. In terms of pricing, very premature to discuss about pricing, but I think there's going to be a lot of flexibility.
Right. RA data in second half. Talk us through kind of what you're looking in that cohort. What gives you confidence that you could see good data there? Also kind of what signals you're looking for to move forward.
Absolutely. Yeah, I've been asked this question a couple of times recently. I want to remind people that the RA study was really positioned to understand whether prula-cel requires Cy/Flu or Cy only. Essentially, we are enrolling, I believe six patients in one dose level and six patients in the higher dose level, 3e8 and 1x10^9. In each case, we're comparing Cy/Flu versus Cy only. Do we see difference in the B-cell depletion? Do we see difference in how patients with RA in terms of their symptoms? It's a very small study, and the goal of the study is to understand whether fludarabine is necessary.
Do you have kind of any early data or work that you've done to point to whether you think that flu would be necessary here?
We just started. Actually, we started the study a couple of months ago. It's still enrolling. It's now enrolling at the 1E9 dose level. We just need to get the data.
Yeah. Understood. Also many other indications for prula-cel as well. Just talk us through kind of how those cohorts are enrolling?
Where we could see additional updates.
Absolutely. We had to focus at some point from an execution perspective. The focus on enrollment has been LN, SLE, and systemic sclerosis. The other indications haven't enrolled in any significant way, and we haven't focused on enrollment in these indications. Really it's LN, SLE, and systemic sclerosis that has been the focus.
At what point do you feel like you could kind of shift your focus a little bit and accelerate more of that enrollment? I think LN, SLE, understandably, maybe when you move forward to your additional trial, but maybe when do you feel like you could put more focus into indication expansion and feel comfortable with kind of the core indication moving forward?
Sure. At this point, we think that LN and SLE and systemic sclerosis are pretty big indications when you think about the number of patients. That's the reason we didn't focus on the other indications. I believe there is a lot more room to expand to other indications, but we wanted to first get a good read on these indications, see the path to potential pivotal studies. As we go there, we can start thinking about what indications we want to expand. Focused on data first.
Yeah. Makes sense. Speaking of indication expansion, have you thought about maybe expanding into MS as well, just given that there are CD20 therapies there?
Yeah. MS is a great potential for cell therapy, autoimmune. A little longer endpoint, and the studies generally are much more expensive because they require MRI, but definitely something that we've been thinking about. In terms of ability to execute, when you think about how we were able to execute, we're probably one of the very, very few companies that have been able to enroll this number of patients. Most of the smaller companies have very small data set in the single digit. That required focusing, and we focused on sites that are either rheumatology sites or nephrology sites so we can find these LN, SLE, and systemic sclerosis patients. Moving to MS would require more focus on neurology.
It's something that we can certainly consider in the future, but in order to enroll so far, we had to focus on these centers.
Understand. If you had to rank the remaining indications outside, I know it's a difficult question, outside of LN, SLE, and SSc, how would you think about that?
It's a very tough one to rank. I would love to hear how you would rank them, actually, and opine on that. No, I think it's a very tough one. Each indication is so unique from an unmet medical need perspective, from a regulatory perspective, from a competitive landscape perspective. You really want to think about each indication.
Got it. Safety, another very important topic. Talk about what you've seen so far and how you feel or what you're kind of looking for in the additional update?
Absolutely. I'll start with a problem. The problem with making cell therapies available to many patients, one is you need to make sure that facilities can provide the therapy. The second one is actually the safety. When you think about alpha beta T cells, whether it's an alpha beta T cell or even a bispecific, a part of the activation profile of alpha beta T cells is secretion of IL-6. That secretion of IL-6 is associated with CRS and with ICANS, which essentially is neurological toxicity. We don't know who is the patient that would get CRS and ICANS because if I, for example, I'm blessed to have great T cell fitness and I'll get the therapy, they'll proliferate great, they will secrete a lot of IL-6, and I'm much more likely to get CRS than ICANS.
That's an issue with alpha beta T cells. With gamma delta 1 T cells , and we have learned this during our clinical studies, the increase in IL-6 is not significant in any shape or form compared to alpha beta T cells. That indeed tr anslated across all the indications into a lower rate of CRS, a very low rate of ICANS, and significantly lower severity of CRS and ICANS. The FDA knows our data. When we showed the FDA our data, they were perfectly fine with us moving, at least in LN and SLE, to outpatient dosing, and we don't need to hospitalize a patient. That presented itself as well.
In terms of the broader landscape, how are you thinking about CAR Ts and lupus in general, given that you have bispecifics, you have T cell engagers coming and pursuing this indication as well?
Sure. Absolutely. First of all, it's a huge market, and there's room for everybody. Focusing on data, T cell engagers in oncology have shown efficacy that's a little subpar compared to autologous cell therapies. When you look at the data reported so far for T cell engagers, this is the case again. It looks like the T cell engagers would require some kind of a semi-chronic dosing, or I've heard it called as immune dimming. Essentially what it's a new potential class of immunosuppressants that will continuously deplete the B cells for patients. When you think about the unmet medical need of these patients, this long-term immunosuppressant leads to many problems for these patients. One of the causes of mortality, for example, in SLE and LN is infections.
While they definitely have room in the market in terms of the magnitude of efficacy and in terms of the potential long-term toxicity, I think that might be an issue. Definitely for some patients, a new class of immunosuppressants might be something that's very, very viable and desirable. For many other patients, they would rather take a one-time therapy that will relieve them from symptoms and from the need to take those therapies for whatever their median durability is.
Understood. I think we have a couple of minutes, so maybe we should move over to ADI-212. Talk a little bit about that program, what types of enhancements you've made to the asset.
Absolutely. I am very excited about the ADI-212. We recently changed the guidance that we'll file the IND in Q3. It's coming very soon, we'll enter clinical studies. The reason I'm excited about ADI-212, it's a result of more than four years of research at Adicet. The question that we were asking ourselves is, how can we make cell therapy work much better for solid tumors, leveraging the advantages of ADI-212? Let's just think what we've done. ADI-212 is a gamma delta T cell targeting PSMA with two important bolt-on technologies that were designed to enhance its efficacy. Let's go one by one. First of all, the target that we're engaging is PSMA, and there's been programs that have been more successful versus less successful targeting PSMA.
We're targeting essentially a binding site in the PSMA that is clinically proven and is a little consistent with Pluvicto. We know that patients that take Pluvicto, as an example, most of them maintain their PSMA, and that's how you enroll them. The binder is pretty validated or the binding mode. Number two, we knocked out a gene called MED12. When you knock out MED12, the cytotoxicity and the repeat killing capacity of the cell is significantly enhanced. Essentially, the cell keeps killing and killing and killing and don't get tired. That is incomparable to any cell therapy that I've seen, whether it's gam ma delta or alpha beta or anything else that we have seen. It's a little bit like the commercial for Duracell, the Duracell that keeps killing.
The other bolt-on technology, we added a membrane-bound IL-12 that is presented on the cell once it engages PSMA. We know that IL-12 reshapes the tumor microenvironment of the tumor to something that's much more friendly to cell therapy. It brings other cytotoxicity mechanism to the therapy, and it really synergizes with the MED12. When we look at the overall profile of the program, we think it's quite promising. We've had some early meetings with FDA. We received some great feedback, and we expect to initiate the study very soon.
Okay, great. Just very quickly, what are the kind of feedback that you've gotten from the FDA so far, how quickly can you move into phase I?
Sure, absolutely. We're actually starting to work on the phase I now. We expect to start enrolling potentially in the fourth quarter of this year and have data next year in this program.
Okay, perfect. Lastly, remind us of your cash runway and the path to the many catalysts ahead.
Sure, absolutely. In terms of catalysts, we expect to have data in LN, in SLE. We expect to go into the clinic with PSMA, potentially have data in PSMA. We're well-funded into the second half of next year. The only thing we haven't covered, and you might hear something and it will create a lot of noise, is an in vivo program that we haven't unveiled. We've seen one program in the in vivo space that has been unveiled recently, and this is something we've been working on for a while. We haven't talked about it, once we do, it's going to be meaningful.
Ending on a very exciting note. Thank you, Chen.