Thanks to everyone attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the Senior Biotech Analysts here. In this fireside chat session, we are very pleased to have Mr. Chen Schor, President and CEO of Adicet Bio, join us today. Welcome.
Good afternoon, Kelly, and thank you for inviting us. Always a pleasure to be in this conference.
Likewise. Maybe before we talk about pipeline specific, could you give us a high-level view on why you chose to leverage gamma delta T c ells as the technology platform?
Absolutely. Happy to. So Adicet was founded by the founding CEO of Kite, which was one of the first companies focusing on alpha-beta CAR-T that was then acquired by Gilead for about $10 billion. Initially, the reason why Adicet chose gamma-delta 1 T cells is because of their key advantages fighting diseases that primarily present themselves in solid tissues, primarily solid tumors. At the highest level, the key advantages of gamma-delta 1 T cells are: one, they do not cause graft versus host disease, so they can be dosed completely off the shelf. Two, in terms of their PK, they have PK in terms of Cmax or day 28 exposure that's comparable and actually we've learned even can be higher than autologous cell therapies like Yescarta, so very good PK. Three, we've learned that they're generally safer than alpha-beta T cells.
Alpha beta T cells secrete IL-6 and cause these pretty significant rates and severity of CRS and ICANS. Gamma delta 1 T cells, upon activation, do not secrete significant levels of IL-6 and are not associated with this great incidence and severity of ICANS and CRS. And four, very importantly, these gamma delta 1 T cells travel primarily to the tissues, so they're in our skins, they're in our lungs, they're in our kidneys, and other tissues. And that's why there are significant advantages in fighting diseases, either like solid tumors or autoimmune diseases. And I'm happy to elaborate more on each of these diseases when we go there.
Great. And compared to the classic T cells, so for working with gamma delta, what particular challenges do you have to overcome?
Yeah, absolutely. So in our blood, gamma delta 1 T cells are about 1%-3%. There's much higher concentration of alpha-beta or NK cells. So the biggest barrier to entry here is manufacturing. We were founded in 2015, and for the first, I want to say, five years and now almost a decade, we really improved our ability to manufacture CAR gamma delta 1 T cells. And we're actually the first company that moved into the clinic with CAR gamma delta 1 T cells. We right now can manufacture in-house, and we have demonstrated manufacturing it to other CDMOs. We have the same release criteria, so it's quite consistent and scalable across different programs.
Okay, and for ADI-001, your leading pipeline program, you have actually accumulated clinical data from lymphoma, but made a decision actually pivot to autoimmune disease last year. Could you provide some context there and what drove this decision?
Sure, absolutely. So we have tested our approach in lymphoma, specifically in NHL. We focused on mantle cell lymphoma. We provided that we stopped enrolling for MCL. We shared an update about two months ago with the final data set. The data looked actually very good in MCL. So we enrolled 10 patients. Three out of those 10 patients were post CAR-T, i.e., they failed autologous CAR-T like Yescarta. So these were late-line patients. The overall response rate was 80%. The CR rate was 60%. And the median durability of complete response was 17 and a half months. So when you look at these data, they're actually comparable to the other autologous cell therapies in MCL. It's just that MCL is relatively a smaller market.
When we compared our data to what's required to win in autoimmune cell therapies, we decided that's a much higher market with multiple indications where our data really suggests potential for very favorable differentiation in autoimmune.
Okay, fantastic. Yeah, I understood the lymphoma is very competitive for cell therapy. And this autoimmune pursuit is a big theme for cell therapy players and also the T cell engager programs. Actually, the ACR rheumatology conference is ongoing, and we saw the new data drop. And so for ADI-001, it is a CD20 targeting cell therapy. Curious regarding the targeting strategy, how do you see it next to the very prevalent CD19 BCMA program and what kind of differentiation you see for CD20?
Sure, absolutely. So I would take, when I think about differentiation, a couple of factors: cell type and antigen. So when you think about cell type, gamma delta 1 T cells have very strong tissue tropism. I'll show in a second slide that testifies for that from patients, which means that we should be able to deplete B cells in lymph nodes very, very well. And in organs such as kidneys, when you think about lupus nephritis or lungs, when you think about systemic sclerosis. So that's a big advantage. The second advantage is better tolerability. Between CD19 and CD20, I don't think there's any significant differences. Actually, in ACR, there was one company that showed data that CD20 is much more prominently presented on naive B cells and activated B cells and ISG B cells. But I don't think there's a big difference.
I want to show you one slide that I think is really important that I don't think investors paid a lot of attention. So these are data from Schett. What we have learned from Schett is that the key to show durable responses in autoimmune patients is depletion of CD19 B cells in the lymph nodes. So here, actually, Schett compared alpha beta T cells targeting CD19 and rituximab. And look in the peripheral blood on the left side of the slide, both rituximab and CAR-T patients completely deplete CD19 B cells in the blood. Rituximab targets CD20, the autologous targets CD19. Both of them completely deplete CD19 in the blood. But look what happens in the lymph nodes. In the lymph nodes, as we know, antibodies haven't shown great efficacy and durability in autoimmune diseases.
Indeed, Schett shows that antibodies do not deplete CD19 B cells in the lymph nodes and indeed don't have this very potent efficacy. As I mentioned earlier, gamma delta 1 T cells are tissue tropic cells. Here is data from patients. We have so far dosed about 40 NHL patients. Look at the exposure. What you can see, I'll focus on the right side of the slide. If you look at the bottom right side, the best data from Axi-cel in terms of exposure of the CAR-T in the lymph nodes is about 20,000-60,000 CAR-T cells per million cells. In the top, you can see data from patients. There's nothing like data from patients. As you can see, the exposure from our own ADI-001 in terms of CAR-T per million cells is about, I don't know, let's say seven-fold higher than autologous CAR-T.
So first of all, that's fact. That's from patients. And then if you go to the next slide, we're talking about CD19 versus CD20. Here is data from biopsies. And on the left side, you can see the screening biopsy. And in green are the CD19 positive B cells in the lymph nodes. On the right side, you can see at day 10. So we have multiple lymph nodes from NHL patients. Never have we seen a single CD19 positive B cell in a biopsy. So off the shelf, well tolerated, no risk of T cell malignancy, no significant risk of CRS and ICANS, completely deplete CD19 positive B cells in the blood and in the lymph nodes. And that should transfer to favorable efficacy in patients.
Okay, fantastic. So you think this lymph node deep penetration is due to more gamma delta cell features. Is it also associated to some auto targeting strategy at all?
We don't believe it's due to the targeting. We believe it's a cell type. Gamma delta 1 T cells are tissue-tropic cells. That's the same data that we've seen from nine other publications that show that gamma delta 1 T cells go to the tissues. In every preclinical model, I'm flipping through two slides here. When we test our gamma delta 1 T cells, we see that they go to the blood, they get out of the blood, and they stay in the tissue. So that's exactly what we see.
I see. And do you expect the CD20 and the CD19 cell therapy actually could have some difference on safety front?
Not based on the antigen. I think it's more based on two key issues. One, IL-6 secretion. Alpha-beta T cells would secrete and would cause higher rate of ICANS and CRS. Gamma delta 1 T cells secrete significantly less IL-6, and that's why it causes less CRS and ICANS. That's one. And two, T cell malignancy risk, which is more of an autologous cell therapy issue.
Okay. And so ADI-001, now in the phase I trial and with lupus nephritis as the first indication to pursue, maybe tell us more on why you make this decision out of multiple autoimmune indications and what's the progress of this phase I trial?
Sure, absolutely. So we started with LN, but we're going to start to enroll five more indications starting in Q1 next year. So it's all coming together very, very nicely. We chose LN initially just because it's SLE. There's great proof of concept. Gamma delta T cells are very good tissue tropism also to the kidneys. We know that in the kidneys, there are B cell islets that are associated with this disease. And in lupus nephritis, there's very clear measurements that we can take for kidney function, eGFR, and proteinuria that show efficacy. So that's what we chose, why we chose initially LN. We're actually now expanding to SLE, to systemic sclerosis, to myositis, to ANCA-associated vasculitis, and to stiff person syndrome. So there's five more indications to follow with, I believe, at least, yeah, three of them will start enrolling in Q1 next year.
Okay. And how has been the engagement with the study sites and what kind of patient enrollment pace do you anticipate?
Sure, absolutely. So I think the key challenge, at least that we found so far engaging sites, is this close collaboration between rheumatology and oncology. Essentially, both departments need to somehow partner together in order to start enrolling patients just because the rheumatologists are less acquainted with dosing CAR-T and need this collaboration. So it's been slow to activate sites, but it's been slow for a bunch of sites. And now we have quite a few sites activated. So we're very happy with the number of sites. There are more sites coming on board. We dosed the first patient a few days ago. We just announced it yesterday. There's more patients coming into screening. So we actually see significant interest from physicians in enrolling patients, and we should have data in the first half of next year.
What is the screening success rate? What would it be?
Yeah, I think it's early, so we don't know yet. So far, it's been 100%, but it's early, doesn't mean anything. I don't expect a significant screening failure rate in this disease, yeah.
For the patient screening, inclusion and exclusion criteria, is it similar to the first pioneering IST study by Dr. Schett?
Sure. So I'm going to generalize it also to myositis and systemic sclerosis. I want to say it's overall the same type of inclusion-exclusion criteria. They need to have failed the traditional immunosuppressant therapies, have disease to treat, and then they get our therapy.
Okay. And one, could we expect the first data from this program?
Yeah, we haven't got it. There's different thoughts that we get from investors. Some say once you have just a little data, start showing it. Some say wait for more patients. So we haven't finalized, but for sure, we'll have data in the first half of next year. That's absolutely sure.
I see. And also, do you carry out those biopsy studies along the trial maybe to show the lymph node penetration of this program?
Yeah, we're trying to get some biopsies from this study, although we believe that we're in a very good place based on the biopsies that we already have because I think we've proven without doubt that we have very high concentration in the lymph nodes and complete CD19 B cell depletion in the lymph nodes. I don't think that's a significant concern in this program, unlike in other programs that have not shown that we're probably one of the companies with the best data in this field.
In terms of cell dose and the lymphodepletion regimen, do you apply the similar trial design as for the lymphoma program?
Great question. So we're starting with standard lymphodepletion compared to what Schett has used and many other companies have used. There might be an opportunity to lower the lymphodepletion primarily because we found it in our clinical studies that gamma delta 1 T cells are less susceptible to rejection by NK cells. And that might explain why our Cmax, actually, it's almost 10 times higher than Yescarta. And persistence in day 28 is actually much higher than Yescarta. So that may explain why this is the case. We might not need such a high PK in autoimmune. So I think there is an opportunity to lower the lymphodepletion. We just decided not to take that risk initially, but rather test it in the future.
Okay. And also, this first data by Dr. Schett's team actually sets a very high bar, and we have very high complete remission rate. So do you expect as the programs actually expand in this space and considering the patient baseline characteristics, probably in variety, would you expect registered clinical trials actually going to show similar type of efficacy?
Yeah, absolutely. I'm going to refer. We've done once when I was on the buy side with a big pharma, we've done a study on what % of ISTs translate to industry efficacy. We found that it's 15%. This was a couple of years ago. 50% of ISTs translate similarly in industry-sponsored studies. Those 15% were primarily infectious diseases because if you clear a virus, you clear a virus. Generally, I don't think any field will change compared to that statistics that was based on a couple of decades of data. That's true for any modality that I think we select in this therapeutic area.
Okay, very insightful. And moving to 270 program, it is CD70 targeting gamma delta T cell therapy. And curious, what is the status of progress right now and what's the plan for next year?
Sure, absolutely. So just a little bit of background. We're very, very excited about this program. It's our first solid tumor program. When we started the company, that was what Adicet was built to do. Let me just outline why we're excited. There are data with CD70 targeting alpha-beta T cells using single-chain Fv that show an overall response rate of about 25%-35% overall response rate. Our program is differentiated from those programs in many, many ways. Number one, the way we engage the tumor is using the natural receptor CD27. CD27 is much more potent, and we compared it to 300 single-chain Fvs. CD27 is a much more potent binder of CD70, and it requires significantly lower antigen density on the tumor. And it's another co-stimulatory domain. So eventually, the cells kill much better. That's point number one of differentiation.
Point number two, we know that there's going to be heterogeneity in solid tumors. Gamma delta 1 T cells have innate anti-tumor activity. So we actually show that we can kill also the tumor cells that do not express CD70. Number two. Number three, gamma delta 1 T cells have tissue tropism to the kidneys, so they should travel there and see higher concentration there. Number four, we know that there's TGF-beta in the tumor. We have a TGF-beta dominant negative receptor on ADI-270. And number five, we can allow redosing because our cells have been very well tolerated so far. We're starting from quite a high dose level, 3E8. That's actually the highest dose level that was tested by some of the alpha-beta T cell companies because they were more limited by safety. That's an issue we don't have. We just started all we enrolled.
We opened sites for enrollment recently. There's multiple patients interested in screening, so there's actually a lot of demand for this program, and we'll have data in the first half of next year as well.
Okay, fantastic. Maybe outside of these two programs, how do you think about the overall competitive landscape, especially in the autoimmune space? What are your strategies to stay competitive?
Sure, absolutely. I think at the end of the day, we should go back to what patients need. So they need something that is safe. There are many, many, many patients. They need something that we can dose also in community settings. And they need something that is efficacious. When you look at the different classes, I think in terms of safety, we have proven to be quite safe in our dosing to date. In terms of ability to dose in community settings, our safety does allow that. In terms of efficacy, I think we should see a favorable efficacy. And then the last question, I think, is durability. So some questions might ask, do I want to get one-time dose and then essentially have a durable or a very fair chance for a durable complete response using a cell therapy like ADI-270?
Or do I want to get some semi-chronic dosing of a different approach like bi specifics or antibodies that more likely than not will require some redosing? And then it's more chronic depletion of the B cells to maintain the disease, which has some implications on the long-term safety of patients. So I think there is room for everybody, but our profile so far suggests a very favorable one for patients in terms of safety and efficacy.
Okay, fantastic. Maybe can you lay down the company's plan for 2025 and 2026?
Yeah, absolutely. So 2025 will be a year of enrollment. So we expect to enroll patients both in autoimmune in multiple indications and in RCC in multiple indications. We'll have a significant data update both in the first half and in the second half for both programs. There's another program that is moving forward, two programs that are competing on the same spot for that next third clinical program. We haven't finalized what that program is, but both so far seem to be quite differentiated. And we'll make a decision on what's that third program sometime probably around mid next year.
Okay, and lastly, what is your cash runway?
We're actually very well funded. We have more than $200 million in the bank as of 9/30. And we're well funded into the second half of 2026. So multiple additional data points until we need to think about the financing.
Okay, great. We're going to wrap up here. And thanks for great discussion. And thanks for everyone for attending this session.
Thank you.