Good afternoon, and thank you for joining us at the 45th Annual Canaccord Genuity Growth Conference here in Boston. I'm John Newman, one of the Senior Analysts at the firm on the biotech team. We're very excited to have Adicet with us today and the CEO, Chen Schor. Chen, welcome. Thank you for joining us today. You know, I'm wondering if you could give us an overview on Adicet's allogeneic approach and your current programs, especially your autoimmune initiatives.
Absolutely. First of all, John, thank you for inviting us. It's always a pleasure to be here at this conference. You know the field of autoimmune and cell therapy very, very well, so I look forward to this fireside chat. About Adicet, Adicet is considered to be the leader in the field of off-the-shelf Gamma-delta CAR-T cell therapies. What's unique about our product is that we can provide them off-the-shelf. They have a very differentiated safety profile compared to autologous cell therapies. We can potentially dose in outpatient care settings. These types of cells, Gamma-delta 1-T cells, provide very robust exposure in the blood but also in the tissues. That is very important for autoimmune diseases because many of the autoimmune diseases eventually show organ damage in different tissues, whether it's the lungs or the kidneys or the skin, and that's where Gamma-delta 1-T cells go.
We have a program focused on autoimmune diseases. We're currently enrolling patients for the SLE arm and LN arm, as well as the Systemic sclerosis arm, and this study is also open for enrollment of other autoimmune patients. We also have another program focused on solid tumors, which is a different generation of our program really optimized for solid tumors, and that will go into the clinic next year.
Great. Could you talk about how your Gamma-delta CAR-T cell approach is different from the typical alpha-beta C cell approaches? Now, we've talked about this in the past for the oncology indications, but how might this be important for autoimmune diseases?
Absolutely. I think it's much more important for patients with autoimmune diseases. Let's think about the process of treating a patient with autoimmune diseases. With autologous cell therapies, we need to start, or companies need to start with Leukapheresis. We need to find space in a hospital to do Leukapheresis. Oncology is pretty busy, it's not easy to find space for Leukapheresis. You need to invest the time in personalized manufacturing for the drug product. That could be time-consuming. Some patients might have a very high quality of drug product, some patients might have less quality of drug product. In our case, it's completely off-the-shelf. You just need to bring it from the fifth floor, and it's available to those patients. The second issue is the safety of this drug and what's associated with the safety of these drugs.
Alpha-beta T cells , upon their activation, secrete IL-6 and cause (CRS) and neurotoxicity (ICANS). We've seen these cases for companies like BMS or Cabaletta and many, many other companies. These safety issues are associated with very close monitoring of these patients that is usually done by the hematology department in the hospital. You need very close collaboration between hematology and rheumatology in order to dose these patients. Gamma-delta 1-T cells , upon activation, secrete much lower levels of IL-6, have lower frequency of CRS and ICANS, and less severe CRS and ICANS. We can actually dose patients in outpatient settings by rheumatologists. It's much more available to the patients and much easier to administer by the healthcare system. That's the second key advantage. In terms of B cell , they kill B cells in the same way.
We have shown also data that the tissue penetration of our Gamma-delta 1-T cell into tissues, at least when we measured it, is superior to autologous alpha-beta T cell therapies. In summary, off-the-shelf seems to be potentially safer, provides the same B cell killing activity just like autologous with better activity in different organs.
Okay, thank you. I wonder if we could talk a bit more about your autoimmune program for ADI-001. You know, first of all, I get this question from investors on occasion. Could you talk to us about why you chose to target CD20 versus other targets that have been looked at, like CD19, CD22, in terms of addressing autoimmune indications?
Absolutely. That's a very valid question. The reason for this question stems because historically the proof of concept data in autoimmune diseases has been generated by studies that took CD19 alpha-beta T cells to patients with autoimmune diseases and showed very significant benefits to those patients. We target CD20. The reason we targeted CD20 is actually historically this program started in oncology, and CD20 has a lot of overlap with CD19, not perfect overlap with CD19, but is a very stable antigen on the B cells. Our product is a CD20 Gamma-delta 1- T cells in the blood, and when we measure in the lymph nodes, we actually measure CD19 + B cell depletion. Exactly the same as the autologous CD19 cell therapies.
What we have shown is that both in the blood and in the tissues, the result is the same: complete CD19 B cell depletion, both in the blood and in the lymph nodes. From a functional perspective, we see exactly the same function. It's just that this is off-the-shelf and potentially safer.
Okay, great. Could you talk about the advantages for an allogeneic or off-the-shelf approach in autoimmune disease versus the customized autologous products? What I'm specifically curious about relates to immunosuppression. Can you explain to us why is stopping immunosuppression in an autoimmune patient problematic sometimes, and how can an allogeneic approach potentially address that versus the autologous approaches?
Absolutely. This is also an important point. Right now, the patients that go to get cell therapies in autoimmune patients tend to be patients that tried a couple of therapies, and the disease continues to progress. These patients tend to be on immunosuppressants, sometimes higher doses of immunosuppressants, as well as steroids. In order to provide them autologous cell therapies, many of the companies before the Leukapheresis ask the patients to stop taking their or stop essentially the immunosuppressants and significantly reduce the dose of steroids. That is before the Leukapheresis, during the manufacturing process, and before they take their CAR-T therapy. That could be a pretty long time without immunosuppressants. These patients in many cases depend on these immunosuppressants, so they might not do as well in this period, which could be longer. The advantage of off-the-shelf therapy is that this window is not required.
Essentially, the patients can stop immunosuppressants, you reduce the steroid level, but you can just dose them off-the-shelf. There is no Leukapheresis, and there is no waiting period. That will be an advantage both for the patient and for the treating physicians that do not need to deal with this reduced immunosuppression for a longer time and how to manage the patients in the interim.
Great, thank you. As the field of cell therapy in autoimmune disease generates more data, such as data recently reported at ACA and EULAR, any thoughts that you can share on the difference between some of the studies we've seen in the autoimmune space from companies versus investigator-sponsored studies? Most importantly, what constitutes a meaningful signal and clinical benefit for these patients?
Absolutely. Essentially, there are two questions here: one about ISTs versus company-sponsored studies, and two, what could be beneficial to patients. Both are very important questions. The first question is, what are ISTs? ISTs is Investigator-sponsored study. Essentially, these are usually physicians from academia that run a study in their own site, and their goal, among others, is eventually to publish the results of the study. These studies happen in a single site, the investigator very, very carefully selects the patients that go to Leukapheresis. Very selectively, the investigator selects the patients that receive the drug. There is very close monitoring of these patients when they're in the hospital. Eventually, when you report the disease outcome, these are very subjective outcomes. Some of the outcomes you need to rate headache for the patient, or there is a visual scale marked between this value to this value. Where do you stand?
If you report this value, you publish at Science. If you report this value, you might not publish. ISTs are generally very, very subjective. Company-sponsored studies are much more rigorous. Usually, they tend to be multi-site. All the physicians are trained to do the scoring the same way. The inclusion/exclusion criteria are defined in the protocol and agreed upon by regulatory authorities. Who gets the drug is defined in the protocol as approved by the regulatory authorities. The monitoring is defined by the schedule of events, and the outcome everybody is trained in the same way, and it's multiple sites. There is much less room for bias. When I look at data, I look actually at company-sponsored data to understand what could work for patients.
Just as an example for lupus or lupus nephritis, I would look at data published at the recent ACR/ EULAR by BMS, by Novartis, by Cabaletta, and by Autolus. These are company-sponsored studies in multi-sites. I think that's where investors want to understand what could be the type of data that these patients can benefit from. Now, the second part of the question was, what's a win for patients? These patients with autoimmune diseases take immunosuppressants, chronic immunosuppressants, tend to take high-dose steroids, which have very significant side effects. They flare every now and then, which leads to progressive organ damage. For example, patients with SLE, the mean age of death is 55. I'm 53. The reason they die, it's either an infection because they've been immunosuppressed for years, or cardiovascular because none of these drugs can stop the inflammatory process in their vascular system, or it's a renal function.
They progressed to lupus nephritis. They need something different. The benefit of B cell- depleting therapy is that you treat the patient once, and then if some of the patients have an immunosuppression-free remission or halt of disease progression with no or relatively low dose of pharmacological steroids, that is a huge win. Essentially, you cured or halt disease progression, and there are no meaningful drugs that they take going forward. That's like a CR in oncology. That is a big benefit for these patients compared to any alternative otherwise available.
Okay, great. Thank you. Could you talk about the stage of development for ADI-001 in terms of the lupus nephritis study? Just maybe tell us a little bit about the design of that study.
Absolutely. We started the study quite a while ago. The first arm of the study is currently enrolling for patients with SLE or lupus nephritis. We're escalating the dose from 3E8- 1E9. We had a couple of patients that were also enrolled at 1E8 because of one of the first versions of the protocol. Essentially, you screen patients, and then they get the drug. It's completely off-the-shelf, and we report outcomes at day 28, three months, six months, and up to two years. That's the design of the study. We're enrolling LN and SLE. We're enrolling patients with Systemic sclerosis. Essentially, the design is the same from a practical perspective. It's just that what you measure in terms of disease outcomes is different pending the specific autoimmune disease. It's a pretty standard design consistent with autologous cell therapies.
It's just that it's off-the-shelf, and at some point, we'll likely move to outpatient administration as well.
Okay, great. Are you currently using lymphodepletion in the study? What are your thoughts about that going forward over the long term?
Sure, absolutely. Yes, we currently use the same cycle doses that are being used by other autologous cell therapy companies like Novartis or BMS or those that have been reported by academic studies. In the future, we may have a study to see whether we can reduce the lymphodepletion further. If we can, of course, at some point, we'll reduce it. We don't know how much we need. We're just starting with what was reported to work.
Sure. Are you allowing any re-dosing in the study?
I don't think our protocol allows for re-dosing. It might, but so far, we haven't pursued any re-dosing of patients, so it's essentially once and done.
Okay, great. Can you comment at all on the enrollment for the study?
Yes. We operate the study in multiple countries and multiple territories. Enrollment overall is going quite well. The number of sites has been steadily increasing over the last year. We actually are doing quite well in terms of enrollment, and we expect to report data in the coming month. Data is coming.
Okay. On that last point, I think you had previously mentioned that the initial readout for ADI-001 in autoimmune disease would be sometime in the second half of this year. I just wanted to confirm that that's still perhaps the case.
Absolutely, it is. Yes.
Great. For the initial readout, could you perhaps provide an estimate, just roughly speaking, in terms of the number of patients we might see, maybe a follow-up time, and the types of data that you might look at?
Absolutely, absolutely. We know that investors wanted to see patients with at least three months follow-up. We shared with investors that we expect in the initial update to have at least six patients with at least three months follow-up. Some of them will have much longer follow-up because they've enrolled earlier to the study. That's a nice number. There might be some patients with shorter follow-up, but at least six patients with at least three months follow-up will be included. The type of data that I would expect to see is, one, safety. The other, B cell depletion. Hopefully, we'll get some data to show immune reset in those patients. Hopefully, we'll have it on time. We'll have disease scores, and we'll have renal function for patients with LN.
Of course, you know, we'll see whether they were able to stop immunosuppressants and whether we were able to taper down the steroid doses as well.
Sure. Do you have any sort of a threshold in mind just in terms of what you think would be a significant improvement for autoimmune patients after receiving ADI-001? You know, we talked about this a bit at the beginning of the conversation. What do you think patients would view as a meaningful benefit and clinicians would view as a meaningful benefit? Obviously, we can talk a lot about different measures and details, but what do you think matters to them?
Yeah, I think, instead of my opinion, in this specific case, I would actually think about what the FDA thinks as well because the FDA has visibility to all clinical data by all classes of drugs: small molecules, antibodies, specific cell therapies, they see it all. The question is, what do they think is the right endpoint? There are two recent case studies, one by a cell therapy company that's focusing on lupus nephritis. They agreed with the FDA on a clinical study, a single-arm clinical study in 30 patients where the goal is CR rate at six months. They agreed with the FDA that as long as it's at least 40% CR rate at six months, that's considered the win. That's one example. The other example, there's a different study run by one of the big pharma. People can look it up on clinicaltrials.gov.
It's aimed to be a pivotal study in patients with SLE and LN. The endpoint there is also six months, and it's a dose remission. When you step back and you think about it, this really sounds like the clinical studies in oncology, in NHL or multiple myeloma when this field started. 30 patients- 90 patients, six-month endpoint, CR rate in the case of lupus nephritis, dose remission in the case of SLE. That's what suffices for the FDA for a single-arm study, and it's a big deal for patients. Keep in mind that at least so far, patients that showed a CR rate or a dose at six months, very few of them ever got the disease again.
I would expect that as the field will play out, this is not our data, just to be clear, some patients eventually will be exposed to the same virus that caused them to get SLE, and maybe at some point they'll get SLE again. Six months tends to be a very, very good predictor for a durable response in these patients, and that's what the FDA agreed to twice.
Okay, great. Thanks for that detail. You know, we could talk about ADI-001 in autoimmune for the rest of the day. It'd be great by me, but I wondered if we could talk a bit about another program, ADI-212, which is relatively new. It's in prostate cancer. Could you walk us through the new technology that you're using here and also just how it's different than other products in the field?
Sure, absolutely. Just to summarize, autoimmune we're enrolling to the study. We're very excited about the progress, and I would encourage people to do work and get ready for us sharing the data. The PSMA program is a result of about four years of research where we focused on what else do we need to introduce into our Gamma-delta 1-T cells to make them work better in the solid tumor micro-environment. ADI-212 is a result of these four years. We will share a lot more information about the construct and what exactly we did to our Gamma-delta 1- T cells. It includes gene editing, and it includes another bolt-on technology. What we have shared is, one, we're targeting an epitope on the PSMA that is clinically validated. If you look at the PLUVICTO data, they've shown quite nice data. The epitope is clinically validated.
The gene editing and the bolt-on technology that we added are aimed, one, in enhancing the potency and the cell killing capacity of the Gamma-delta 1-T cells in solid tumors, and two, address the immunosuppressive tumor micro-environment in solid tumors. The data that I've seen in this program, I think, are uncomparable to anything that was seen at least preclinically in the field of cell therapy and makes a lot of sense clinically. We expect to file an IND for this program in Q1, and we're going to get ready to go to the clinic quite quickly. Right now, we may have data maybe even by the end of next year.
Okay, great. Could you talk a bit about the setting for that study, the type of prostate cancer patients that you're going to be looking at?
Yeah, I would love to, but again, I would wait until we get the feedback from the FDA to agree on the inclusion/exclusion criteria because this is not an IST.
Okay. This last question is, you know, manufacturing is everything in cell therapy, and we've seen even the best companies in the autologous setting have struggled over time. They have improved and made progress. Can you talk to us briefly just about the manufacturing process for your product? Specifically, are there any real practical limits on capacity that are going to hold you back on a commercial launch?
Absolutely. The manufacturing process generally is 14 days. We get donor material on a weekly basis from a lot of places around the country. We qualify every donor material to make sure it fits our manufacturing. It moves to manufacturing. We can manufacture in-house at Adicet , and so far, we qualified two other drug manufacturers that manufactured for us clinical material that we dosed into patients. Potentially, we could have three sources of manufacturing. The same release criteria apply for all the sites. I think from that perspective, we're in a very, very good position.
Question from the audience here.
14 days implies a number of population donors, right? One donor does not yield one dose. Can you talk to us about how many doses a qualified donor can yield?
Sure, absolutely. It's a function of what's the efficacious. First of all, thank you for the question. The question is, how many doses can you get from a single donation? It's a function of what's the efficacious dose, but I would expect it to be in the triple-digit zone without any significant scale-up. With just minimum scale-up in the triple-digit zone. The company was started in 2015, so you can imagine 10 years of manufacturing improvement and IP. We know what we're doing. Yeah, great question, which makes it much more commercially viable because we can easily dose a lot of patients, especially in autoimmune, which is a huge market.
Okay, great. That's all the time that we have today. I'd like to thank everyone in the audience for participating, and also thank you to Adicet, and thank you, Chen.
Thank you, John. Good to see you.
Very good to see you.
Thank you.