one of the biotech analysts here at Guggenheim, and it's my pleasure to introduce our next company, Adicet Bio. And with us, we have the CEO, Chen Schor. Welcome, Chen, and it's a pleasure to have you here. 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 the next 12, 18 months?
Sure. Absolutely. 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. 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 1 T cells, unlike alpha beta T cells, tend to home to tissues.
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 1 T cells, which makes them ideal for autoimmune diseases and potentially also for solid tumors, because that's where the tissue presents itself. 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 ICANS and other type of events that are very predominant with the alpha beta CAR Ts, as we've seen in different datasets. We recently announced a dataset that included quite a few patients at 12 months. Not 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 the FDA regarding the design of the pivotal study. We also expect in the next 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. Maybe stepping back to the platform. As you were saying, it's a pretty differentiated platform compared to the classical alpha beta CAR T cells, in vivo CAR T, we have the T cell regulators as well. How shall we think about the implication of this difference?
Sure.
What are the advantages in terms of efficacy and safety?
Yes, absolutely. That's a very broad question. 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 compare prula-cel versus other alpha beta T cells, bispecifics, in vivo CAR Ts, there's lentiviral approaches.
T cell engagers.
and there's mRNA. T cell bispecific , that's the and mRNA nanoparticles. 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 going to see. Let's first focus on the in between.
There's room for everybody. Let's not be confused about it. Let's, for a second, focus on the in between. If you look at T cell engagers or bispecifics 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 dataset that suggests that bispecifics can cause an immune reset and provide immunosuppressant-free remissions. When you talk with ACR, in ACR with investigators that are experienced with bispecifics, I haven't found one that told me, "You're not going to need chronic dosing with bispecifics." Will it work?
Yes, but it will be another version of immunosuppressants, 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 obinutuzumab. So, bispecifics, more like chronic immunosuppressants, 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 bispecific 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 look at our dataset, we've seen approximately 50%-54%, either at 12 months, complete remission response or DORIS that are immunosuppressant-free. Generally, all the patients stopped taking their immunosuppressants. They went off their steroids, except for one. And they don't take any drugs. They feel much, much better.
That's consistent with the alpha-beta, what you see. 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 datasets, just like the alpha-beta T cells, but it's gene therapy.
I am not sure if you are an autoimmune patient, if gene therapy is the first choice you are going to go after if you can take a cell therapy approach.
Got it. That is really helpful. Maybe zooming in on the data that you have recently shown. So we have seen 12 months data. Can you help us contextualize the denominator? We received a lot of questions on that.
Sure.
Compared to all the patients that you have enrolled, how many did you follow up, and can you contextualize the number that we saw?
Sure. Absolutely. Our efficacy evaluable population is 22 patients with LN or SLE. 16 of them had LN, and six of them SLE. By definition, all the LN 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-month visit. At the 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 have the lupus, which is 13, 54% of them had a DORIS remission. 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 continue to be in remission. We had one LN patient whose proteinuria increased.
The threshold for complete renal response is 0.5. It increased to 0.65 in one of their visits, but they all continue to be immunosuppressant-free. Nine patients have reached their nine-month visit, and they will reach their 12-month visit very, very shortly. By definition, the data cut was, I believe, end of August.
Yeah
You can imagine that by the end of the year, we will have the data cut for all the patients reaching 12 months.
Got it. Pretty solid data. 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? In other words, did you see signs of immune reset?
Yes. Thank you for asking. We absolutely saw signs of immune reset. What you see is upon dosing of prula-cel, you see complete depletion. Although we target CD20, we actually measure CD19 in the blood, and we find the same findings as you see with autologous CAR T's. 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. Then once you see the B cell compartment starts to recover, it is really primarily naive B cells. In a prior dataset, we also did some BCR clonings, trying to understand what were the BCR clones before dosing of prula-cel versus after.
You see essentially all the clones before go to zero, and the clones after, once the B cell compartment recovers, has a completely refreshed and new BCR clone. We truly see signs of immune reset, and only that can explain the quality of the data that we have with essentially all the patients but one continue to be immunosuppressant-free.
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. As you add more patients, do you expect those efficacy response to remain constant over time? What's going to be the longest follow-up at the next update?
Last time it was 12-21 months. I think we are going to move probably three, four months.
Three, four months longer.
We can just do longer in terms of follow-up. One thing we cannot do is move time faster. That is a very
There is always a possibility there.
Yeah, maybe AI can do that. Maybe AI can do that. That's going to be... But that's 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.
How many patients do you expect for the next update, roughly?
We actually, about nine months ago, we felt that we do not need to enroll more patients prior to starting the pivotal study. 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 follow-up. So it will be 22 patients. All of them will have at least 12 months follow-up that we will report.
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.
Oh, yeah.
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 are in a pretty good company with companies like BMS and Novartis.
We had a lot of interest in joining our study.
Exactly.
As we continued enrolling, we had more and more interest. 22 patients is way more than even Novartis and BMS had before they started the pivotal studies.
Got it.
There was just no reason to enroll, but rather wait and enroll to the pivotal study.
Okay, perfect. The pivotal study is the next key milestones, I feel, 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. We had one meeting already with the FDA. We expect to have another meeting with the FDA this quarter. The meeting that we had with the FDA initially focused on LN.
When we discussed with the FDA about the endpoint in LN, they agreed that it is complete renal response. The time point for the endpoint will be 12 months. So essentially, it is immunosuppressant-free CRR at 12 months. That is the endpoint. In terms of number of patients, we have not finalized the number of patients for LN, but you can see the number of patients in other studies in the range of, let us say, about 50 patients.
Yeah.
The reason we want to meet with the FDA this quarter is because when you look at our DORIS rate, it is 54%. It is really in line with autologous cell therapies.
We can talk about some of the datasets from ACR. So it really makes sense to include SLE in this pivotal study. The goal of that meeting is to agree with the FDA on the endpoint for this study, and if we are able to include them in this pivotal study, together with the LN, and what is the best way to do this. We will have that meeting this quarter, and once we have the data, we will share with the market.
What is going to be the bar of success for that pivotal study, both in LN and in non-renal SLE?
Sure. Among the approved therapies that are currently in the market, there is actually no therapy that provides immunosuppressant-free remission.
The bar for this type of a study, it's tough to find something to compare it to. 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 renal response. When you think about SLE, the therapies that we currently have very low even DORIS rate in 12 months.
The DORIS rate is somewhere in the range of 10%-15%. We've seen 50% immunosuppressant-free DORIS remission. I think the bar is not going to be an issue, and these will be small studies with double-digit number of patients.
I agree. In terms of safety requirements, where are you standing? What's the request from the FDA, and where do you stand in that?
Sure. 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 prula-cel. We do not expect to have any issues with this in our autoimmune dataset. I believe we already have 45 patients. The size of the pivotal study will definitely round it up. If it's LN, let's say it's 50-ish, so maybe
Yeah
Five more, and if it's LN SLE, it's going to be higher. Usually, it's 100 patients. That's what we've seen in other therapies.
That's going to be a single-arm study, right?
Yes.
Where do you stand with the site activation and the general preparation of the pivotal?
Sure. We are in startup activities. The sites, I literally just sat at 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 have seen. Certainly, a lot of interest in our study. We have 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 prula-cel.
Consistent with our track record so far of enrollment, I think in the pivotal study, it is going to be even more so, because it is now established, we have the efficacy, and we have the safety dataset.
When can we expect the next update for the pivotal?
We will have it-
Like, that is the after the-
Yeah, we will have it in Q1. That has been our guidance.
In Q1. Okay.
Because by then, we will have the 12 months data, and by then, we will have the feedback from the FDA.
Got it. How are you thinking about the commercial opportunity in LN and non-renal SLE?
Sure, absolutely. When you step back and you think about the number of patients that could benefit from a drug like prula-cel, 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 prula-cel, in LN, we estimate it at around, in the U.S. alone, at around 35,000 patients that could benefit from this therapy in LN and qualify for this type of therapy. 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 we expect it 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 how some of the big pharma guided for the size of this population. That is very meaningful.
Yeah.
It's actually much higher, for example, when you think about the NHL cell therapies in terms of the number of patients.
I agree. 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—
Yes
—about profitability, scalability.
Yes.
What is your strategy there, and how does it compare with the autologous approaches?
Absolutely. Autologous, essentially, you have to manufacture per patient, and then you have to release per patient, and it is quite costly. In our case, from a single manufacturing run, it takes the same time as an autologous CAR T, about 14 days, but we have many, many, many more doses. We have manufactured inside at Adicet and with two different CDMOs. We have used the same release criteria within our studies, multiple different donors. There is no magic donor in our studies. The cost of manufacturing is well below 20%. It is a little more consistent almost with an antibody, a little higher than an antibody. The cost of manufacturing is not an issue here, and we have a lot of flexibility how to price.
Got it. A follow-up to that is also the lymphodepletion
Yes
approach. That is another. Are you trying or planning to run a lymphodepletion-free trial? Based on your feedback that you receive from physicians, —
Yeah, let us just walk through
how important is that?
Let's walk through the existing information, what we know about whether lymphodepletion is necessary or not. Let's think about I'll mention different companies. This is about the field, not about-
Yeah, sure.
—a specific company. I think we can all learn from others. If you think about companies like Nkarta, initially they started with a Cy only, and they did transition to Cy/Flu.
Maybe there's something we can learn from that. If you think about companies like Allogene, they've just shared data at ACR. They tried no lymphodepletion. 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 depletion was in the Cy/Flu. If you look at the autologous cell therapies, some of them try 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, Cy/Flu is required. These are low doses of Cy/Flu. 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 with fertility issues.
In our case, I believe we had a couple of women, they got pregnant. They are disease-free. They feel good. They got pregnant.
Yeah
No, there wasn't a concern. I believe that Cy/Flu will be required. We are running a small study in RA with Cy versus Cy/Flu just to confirm that that's the case with gamma delta 1 T cells. I would say generally as a field, Cy/Flu is probably something—
You think that's still needed
—that will be necessary.
Okay. Thank you for that. In these last few minutes, let's turn to the pipeline. I think you're guiding for an update in systemic sclerosis—
—Yes
in the first half of next year.
Correct.
What shall we expect? How many patients roughly—
Yes
—will have data, and what's the longest follow-up?
Sure. I think we have around 10 patients with systemic sclerosis, and we expect the update in the second quarter of next year, and we expect to have all the patients who have at least 12 months follow-up. It sounds like that is what the market would prefer. That is our expectation. We also expect during this time to update the market about the in vivo CAR T pipeline. We have invested a lot in this.
There is a lot of excitement on that.
Yes, a lot of excitement, and we get a lot of questions from investors about it. Essentially 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 scFvs that can engage those targets in a differentiated way. We will update the market. It might be a mono CAR, it might be a dual CAR, but—
That is going to be interesting to know.
—a lot of work. Yes.
Yeah, exactly. Where do you stand with that program? Are you in the IND-enabling studies?
We're not yet.
Not yet.
The IND is not yet in IND-enabling.
Got it. Any update on the cancer program?
Our oncology program is for prostate cancer, ADI-212. I will define ADI-212 is a gamma delta 1 T cell that target PSMA, and the right type of binding 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 membrane-bound IL-12, and during SITC, 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 is being expressed on the membrane upon activation of the CAR, so it is really selective to the tumor. So that was one bolt-on technology, and the other bolt-on technology is the MED12 knockout. What the MED12 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 MED12 knockout and membrane-bound IL-12 has a lot of synergies and shows very, very promising preclinical activity. Hopefully, this will translate into activity in patients as well.
That is really interesting. Maybe the last question from me, what do you think is generally not appreciated enough about Adicet 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.
Yeah
Where I think the market got burned is primarily in oncology. There were a couple of disappointments on data from some autoimmune companies, and I think where the market could benefit and where people can really be smart and have something that is uncorrelated is really dig into the data and understand the efficacy and safety of different modalities and pick what is the winner. So it is 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.
Yeah, there are a lot of nuance.
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 T cells because they proliferate and they deplete B cells really good, but they secrete this other type of cytokine, so they do not have all these safety issues with alpha beta T cells, and it is just a single dose. I think people should just spend their time and understand, and if they are interested, we can walk through other data sets from ACR.
Yeah
They will find out that that is the case.
Thank you so much for that perspective, Chen. I enjoyed the conversation. Thank you for being here with us.
Thank you so much.
Thank you.
It's good to see you.