Good morning, everyone, and thank you for joining us at the 44th Annual Canaccord Genuity Growth Conference. I'm John Newman, one of the senior biotech analysts here at the firm. We're very excited to have Adicet with us today, and the CEO, Chen Schor. So, Chen, welcome. Adicet is developing gamma delta CAR T cells for both autoimmune indications and cancer. I wondered if we could start with autoimmune and then discuss your oncology pipeline. So most people are familiar with alpha beta T cells from the original customized CAR Ts, but some people may be less familiar with gamma delta T cells. Could you discuss the advantages of gamma delta T cells here versus alpha beta for autoimmune diseases?
Absolutely. First of all, John, thank you for inviting us to our conference. Great timing, because we just issued our quarterly results, and we updated about our autoimmune program, so we actually added a couple of slides to walk you and the people here regarding the update. So, gamma delta T cells have a couple of key advantages, and I'll probably talk about it in the context of ADI-001. When you think about autoimmune diseases, what's important is the reset of the B-cell compartment, whether it's in the blood or in the different organs where the autoimmune disease presents itself.
So one of the nice things about the gamma delta T cells, and specifically about ADI-001, is that the PK or the exposure that we see for ADI-001 is consistent with the exposure that we've seen with autologous alpha beta T cell approaches, like the one presented by Dr. Schett in a multiple autoimmune setting. So you wanna make sure that the potential drug gets the same exposure in the blood. Number two, it's important to deplete the CD19 positive B cells. The data they provided proof of concept showed very nice depletion of CD19 positive B cells, both in SLE, in systemic sclerosis, and in the myositis. The B-cell depletion, and we measure B-cell depletion based on CD19.
B-cell depletion in the blood is very, very consistent with the B-cell depletion that has been demonstrated in autoimmune patients by Dr. Schett. So we have the same exposure and the same CD19 positive B-cell depletion. So far, that's overall comparable. Now, let's talk about a couple of the key advantages versus alpha beta T cell approaches. One is tissue trafficking, and I'm happy to cover this point in more details if there are interest, but certainly, tissue trafficking is very important in autoimmune diseases. The second one is safety. In autoimmune diseases, as was mentioned in a prior fireside chat, safety is very important, and we know that alpha beta T cells are associated with secretion of certain cytokines and lead to CRS and ICANS.
In fact, last week, we've seen an event of ICANS Grade 4 in an autoimmune patient by autologous alpha beta T cell. It's just the biology of alpha beta T cells that is associated with CRS and ICANS. With gamma delta T cells, we don't see secretion of the same cytokines that are associated with the CRS and ICANS, and therefore, it's a significantly lower risk compared to alpha beta T cells. The other issue with the, especially autologous alpha beta T cells, is the CAR T cell malignancies, and given that gamma delta T cells are off the shelf, this is also a very reduced risk. So from a safety perspective, we have the advantages of significantly less CRS or ICANS risk and essentially no CAR T cell malignancy risk.
Gamma delta T cells or ADI-001 is off-the-shelf. We manufacture and release with the same potency and release criteria on an ongoing basis, and given its safety profile, it's available in the community setting. I wanna move to another slide, which I think is important, because one of the questions that we received: "001 targets CD20 versus the proof of concept has been observed with CD19, so how is your B-cell depletion profile different, if at all, compared to a CD19?" And the key point is that actually, all the data that we have suggests that we completely deplete CD19 B cells exactly like we've seen with alpha beta T cells approaches. The next slide talks about plasmablasts. So this is not our data, the next slide. It's actually data by Roche, Obinutuzumab.
So Obinutuzumab is a CD20-targeted antibody. It's been tested in 125 patients with lupus nephritis. It was dosed on week 1 and week 2, and take a look at what happens to the plasmablasts. Essentially, they go to absolutely zero following Obinutuzumab, a CD20-targeted antibody. Then it's a biologic, it's not a cell therapy. You can see that it starts to recover. It also recovers on cell therapies. And then again, the patient got two doses on week 24 and 26, and you see again a reduction in plasmablasts. So bottom line, you see external data that show that with a potent CD20 antibody, you can essentially reduce plasmablast essentially to zero. Now, the limitation, this is an antibody.
We know that generally, antibodies have not optimal tissue penetration, and that's why their activity is likely not as potent as is being presented with the cell therapies. So that was, you know, probably a long answer, but probably provide both on efficacy and in safety some of the key advantages.
That's great. Wondered if we could talk about the work that you're doing in autoimmune disease. What would you say are the key data to date to support the expected efficacy in autoimmune disease for zero zero one?
Sure, absolutely. So far, all the data that we have are from our patients in the non-Hodgkin lymphoma study. First, when you look at the PK profile, we see Cmax and day 28 persistence. That is very consistent with the data, for example, for Yescarta. Actually, in our highest dose level, the Cmax and the day 28 concentrations are actually even higher than Yescarta. So same PK. When we look at the CD19 positive B-cell depletion, exactly the same profile. When we look at the CRS and ICANS, we see significantly lower risk of CRS and ICANS. So all these data support this potential efficacy in autoimmune diseases, given the B-cell depletion and the PK profile.
I'm wondering if you could talk about the trial design-
Mm-hmm.
-for ADI-001 in lupus nephritis.
Sure, absolutely. We actually announced this morning that we're expanding to a couple of additional indications. So we expanded to SLE, systemic sclerosis, and ANCA vasculitis. Some of the key reasons we selected these diseases were, one, because these diseases are efficacy in these diseases is associated with B-cell depletion, reason number one, and reason number two is our advantage in terms of tissue tropism. When you look at the data in the literature, so this is a summary of, I believe, more than 10 publications. This is not our data. You can see significant tropism of gamma delta T cells, for example, to the kidney. So lupus nephritis kind of makes sense. You see significant tropism of gamma delta T cells to the lung.
Systemic sclerosis kind of makes sense because many of the patients suffer from the disease in their lung organ. We chose ANCA vasculitis. ANCA vasculitis, in many cases, presents itself also in the kidney. So as you can see, we're trying to reduce the risk by going after diseases where there is some proof of concept, but also these diseases can benefit from our tissue tropism and reset or also the B-cell islets in those tissues. When we look at preclinical models, and I'm focusing on tissue tropism for a second. So if you take, this is just a gamma delta 1 T cells. There is no CAR or some other modulation inside the cell. So this is gamma delta 1 T cells. You dose it to mice. You can see that it distribute to the different tissues.
Over time, by day 14, it gets out of the blood, and look where it stays. It stays in tissues, and it continues to proliferate in the tumor, or in this case, there is stressed cells. So we picked our indications based on the efficacy, the expected efficacy of B-cell depletion and the benefits of tissue tropism. The trial design is outlined on this slide. Essentially, these are different arms that enroll these patients, the starting dose is 3E8. Initially, we thought about starting with 1E8, and then we made a protocol change to 3E8, so there might be 1 or 2 patients that may be dosed with the 1E8 because the amendment is not effective in that specific site.
But bottom line, the starting dose is at 3E8, where we've seen all the data that support efficacy. We lymphodeplete the patients, same protocol overall as the Schett protocol. We provide a single dose of ADI-001. The DLT window is 28 days, and then there is the follow-up period. In terms of endpoints, it's the cellular kinetic of ADI-001, the dynamic of the B-cell depletion and reconstitution, and, you know, some additional endpoints outlined on this slide, including, most importantly, the disease activity scores in the different diseases, whether it's SLE, lupus nephritis, systemic sclerosis, and ANCA vasculitis.
Each of them comes with different metrics to measure the efficacy, but the core thing they all have in common, these are primarily B-cell-mediated diseases, and if we can reset CD19 positive B-cells in the blood and have superior tissue tropism to tissues, patients may benefit potentially for a long time.
... Okay, great. Thank you. Chen, we've recently seen some data for autologous CAR T cells in lupus nephritis from two different biotech companies. And although those data are early, one observation was that T cell expansion after infusion can vary between patients, and this is something that's been seen with autologous approaches as well. Just curious if you think that this might be less of an issue for your gamma delta CAR T cell product?
Sure, absolutely. So with autologous, we need to remember, by definition, it's a personalized medicine. So we do the leukapheresis. We're doing allogeneic, but autologous approaches complete the leukapheresis process. They take the alpha beta T cells. Now, one patient might have great fitness of the alpha beta T cells, and they'll manufacture, and they proliferate really great, and you'll provide it to the patient, and you're gonna see efficacy, and they will expand very well. Another patient might have not as good T cell fitness, and when manufacture, you get lower yield, and then you provide it to the patient, you see lower expansion, and you might see less of an efficacy. And in some patients, they have phenomenal T cell fitness. They manufacture it very well. You dose them to the patients, and guess what?
They secrete a lot of IL-6, which is associated with the CRS and ICANS, and in that patients, you're gonna see ICANS. So the limitation of autologous CAR T is that you manufacture per patient, you count the cells, and assuming you have enough of them, and there is a certain release test, you dose them to the patient, and, you know, we'll see the response. With allogeneic approaches and specifically with gamma delta-1 T cells, we worked over the years to have a potency assay and a specific release testing, where every lot we test in the same way, and overall, we expect a more consistent efficacy versus a personalized approach. So I do think it will be less of an issue for gamma delta-1 T cells.
Okay, great. And manufacturing for off-the-shelf CAR Ts has long been viewed as an advantage versus the customized autologous CAR T therapy. I'm wondering if there might be additional advantages specifically in lupus nephritis, and what I mean by that is, could there be challenges manufacturing functional autologous CAR T cells in immunosuppressed autoimmune patients?
Yeah. First of all, there could. I mean, the n of manufacturing for different patients is quite small, and from academic studies, there might have been some patients where the cells didn't yield the right amount, and maybe they were not appropriate to even receive the CAR T. So we don't have the full picture for the autologous cells. For allogeneic approaches, such as ADI-001, the benefit that it's completely off the shelf, and if there is a patient with lupus nephritis that can benefit from the therapy, essentially the physician can tell him, "Hey, why don't we start the lymphodepletion?" And in five days, they'll take it, you know, from an off the shelf, essentially from a freezer, thaw the cells, and provide them to the patient, and they're just more consistent in terms of their availability and their potential benefit to patients.
Overall, I believe that's a significant advantage that we have with 001.
Okay, great. For potential timing on data for ADI-001 in lupus nephritis, and for the autoimmune program overall, how should we be thinking about that, just generally speaking, in terms of, timing there on data?
Sure, absolutely. So, the study will start enrolling very soon, lupus nephritis patients, and, in the fourth quarter, it's gonna start enrolling patients with systemic sclerosis, SLE, and, ANCA vasculitis. Our current guidance is that we expect data in all these diseases. Maybe we're not gonna have data in ANCA vasculitis because it's so rare, but we're gonna open enrollment for all these diseases in the coming month, and we'll have data in the first half of next year. We might start reporting data earlier this year, but right now, our guidance is for the first half of next year across the different diseases.
Okay, great. And in terms of the types of initial data for ADI-001 and lupus nephritis, I wondered if you could discuss what you might be focusing on. There's obviously been a lot of different tests and characterization that's been done for some of the autologous studies. A lot of things that have been looked at. Just curious as to what you might be looking at and what you think investors should focus on there.
Sure, absolutely. I think some of the more important endpoints are B-cell depletion, autoantibody levels-
Mm-hmm
... disease scores. I think these are probably the more important. Other factors that people will probably look at is the B-cell reconstitution, maybe complement levels, but I believe the core, if you see CD19 positive B-cell depletion in the blood, and if you see most of the antibodies going down, and you see the disease scores are improving, you know, patients are probably getting significant benefit.
Sure, sure. Transitioning here to oncology, can you talk about the potential advantages of gamma delta T cells, specifically for solid tumors, which has been more challenging than the heme malignancies for CAR Ts, and obviously represents a large unmet need. How might gamma delta T cells have an advantage potentially in solid tumors?
Sure, absolutely. We're very excited about the potential of gamma delta one T cells in solid tumors. In fact, that's one of the reasons the company was started. And I'm happy to speak about our first program, ADI-270, in more details. The reason I'm excited is gamma delta one T cells inherently approach some of the biggest challenges that we have in solid tumors. Number one, we need the cell to get to the tissues. Well, gamma delta one T cells are tissue tropic cells, so they have the highest likelihood to get into the tumor and show their activity, number one. Number two, gamma delta one T cells have innate anti-tumor activity.
We know that in solid tumors, we're gonna see some heterogeneity in the tumor, so having innate anti-tumor activity is very important because you can, you can kill multiple type of tumor cells, different populations in the tumor. And in fact, it's not our data. There was a study, I believe it was in 2015, by Gentles et al., where they took about 6,000 biopsies across 25 different tumors and tried to correlate the presence of which cell correlates best with overall survival. And guess what? It's gamma delta T cells. They go there, they have innate anti-tumor activity, and they can show potential efficacy. So we're excited, and 270 is our first program going into solid tumors.
Great, and just a follow-up on ADI-270. This is your CD70 targeted off-the-shelf gamma delta one CAR T, which I believe you're testing in renal cell carcinoma. It's exciting. It's the first program in solid tumors. It seems like you've also added some bolt-on technologies to ADI-270. I wondered if you could talk about those.
Absolutely. Happy to talk about it. So I'll actually use a slide for this, because if we've seen data with CD70 targeting cell therapy approaches, everything about ADI-270 is differentiated. Let's start with how we engage CD70. We compared the natural ligand for CD70, which is CD27, versus about 300 different single-chain Fvs. And we found that nature did the best job, and CD27 is a very potent binder, the most potent versus CD70. In fact, it's not only our conclusion. A couple of other academic institutions, like MD Anderson and a few others, reached to the same conclusion. So the benefit of CD27 is that it can engage tumors with significant lower density of CD70.
If you look at data with alpha beta approaches, targeting with a single chain Fv targeting CD70, they show efficacy, but it requires very high CD70 density. With CD27, we can show better, better efficacy at lower CD70 density, so better way to engage the tumor by CD27. Second advantage of CD27, it's another costimulatory moiety. So essentially, you have three costimulatory mechanism: the CD27, 4-1BB, and CD3 zeta. And the third advantage of CD27 is that it is expected to be associated with higher Cmax and higher persistence, given that it can fight back the alloreactive T cells that are trying to reject, essentially, the graft. So that's one differentiation. The second one, very important, and for every point of differentiation, we actually compared head-to-head for ourselves, ADI-270 versus alpha beta with the CD70.
I'm gonna cover two slides for this. The second advantage is innate anti-tumor activity. We know we're gonna see heterogeneity, and we know that gamma delta T cells can address potentially that heterogeneity using their innate anti-tumor activity, and that's another significant advantage. The third advantage, we have the TGF-beta dominant negative receptor, which can address the immunosuppressive environment in the tumor. There is a couple of slides that walk through this in our corporate deck. I chose two. One is the differentiation once you see low CD70 levels in the tumor, which is the panel in the middle. So in green and in red are alpha beta T cells with a CD70 CAR on them, just like the alpha beta CAR T targeting CD70 that has been tested in the clinic, and in blue is ADI-270.
You can see that essentially at low CD70 environment, a CD70 alpha beta CAR T shows very little efficacy. You can see that ADI-270 shows much better efficacy in low CD70 density. If you like—if you take kind of a more artificial cell line with very high CD70, they'll all perform in the same way, but life is not perfect, so the low is probably closer to reality in some patients. So that's advantage number one. Let's see this. That's the second slide. If you take a CD70 tumor and you knock out the CD70, and you compare alpha beta T cells to gamma delta T cells, so you can see CD70 targeting alpha beta T cells, essentially 20% is a barrier.
It's not associated with efficacy, and you can see that in blue, ADI-270 shows nice cytotoxicity versus tumor cells that are CD70 negative. So when you think about it, gamma delta T cells engage the tumor, they penetrate, they can... We have the TGF-beta dominant negative receptor, and we can show efficacy using the innate anti-tumor activity in addition to the anti-CD70 moiety.
Hey, perfect. Well, it looks like we are out of time. So I wanted to thank Chen.