Good afternoon. Thank you for joining us. On the call today from Adicet are Chen Schor, President and CEO, Dr. Francesco Galimi, Chief Medical Officer, Nick Harvey, Chief Financial Officer, and Dr. Blake Aftab, Chief Scientific Officer. In addition, we're very pleased to have Dr. Sattva Neelapu, Professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, joining us today.
Before we begin, I'd like to remind you that various remarks that we make on this call contain forward-looking statements that are made under the safe harbor provisions of the securities laws, including, but not limited to, express or implied statements regarding the potential safety, durability, tolerability, and therapeutic effects of ADI-001, including the expected design, implementation, timing, and success of ADI-001, plans and timing for the release of additional clinical data from Adicet Bio's phase I trial of ADI-001 in relapsed and refractory NHL patients. Future progress of the GLEAN study, including ongoing patient enrolment, expectations regarding future regulatory filings for product candidates in the company's pipeline, and timing of a dose selection for the phase II trial in the H2 of 2022, and initiation of a potentially pivotal program in the H1 of 2023.
In addition to our prepared remarks, we may make forward-looking statements in response to questions including, for example, statements regarding potential future trials, our financial position, and that positive interim results from a clinical study may not necessarily be predictive of the results of future or ongoing clinical studies. Any statements made in this call that are not statements of historical fact may be deemed to be forward-looking statements. Forward-looking statements involve risks and uncertainties that could cause Adicet actual results to differ significantly from those projected, including, without limitation, the risks and uncertainties detailed in Adicet's most recent annual report on Form 10-K and subsequent filings with the SEC. This call is the property of Adicet and any replay of this conference call cannot be made without Adicet express written permission. With that, I'll turn the call over to Chen Schor, President and CEO of Adicet. Chen?
Thanks, Jen, and thank you all for joining us. It's been an exciting day for Adicet, and we're now looking forward to providing additional insight into the data. Before we begin, I'd like to thank Dr. Sattva Neelapu for graciously agreeing to join us for this call. As someone with deep insight into the clinical management of Non-Hodgkin lymphoma patients, we're pleased to have him join us today. This morning at ASCO, Sattva presented emerging data from our phase I clinical trial of ADI-001 in NHL. As you saw in his presentation and in our press release, the latest data cut was from May 31st, just six days ago. You're all seeing a fresh look at the data today. Let me walk you through the agenda for today's call. First,-
Dr. Francesco Galimi, our Chief Medical Officer, will provide a high-level summary of the ASCO data presentation, including additional preclinical data for ADI-001, three case studies, one from each Dose Level, and a preliminary outline of one of the potential pivotal studies for ADI-001. Then Dr. Neelapu will provide some commentary on a few key topics that are top of mind with investors. Finally, I'll speak to the rest of the pipeline before I open up the call for Q&A. Adicet is a pioneer in the field of gamma delta CAR T cell therapies since we were founded in 2014. We're proud of the contributions we've made to the field, which we believe has led us to become the leaders in developing gamma delta CAR T cell therapy.
ADI-001 has the important distinction of being the first off-the-shelf investigational gamma delta CAR T cell therapy to reach clinical studies and report clinical data. We believe gamma delta T cells may provide significant clinical advantages, both in terms of antitumor activity and safety, compared to other cell therapy platforms and bispecific. It's also important to note that gamma delta one T cells, which are the focus at Adicet, may provide benefits as compared to gamma delta two T cells. Over the years, we developed a robust, scalable, off-the-shelf cGMP compliant manufacturing process with a broad patent portfolio. Looking ahead, in addition to ADI-001, we have six internal preclinical programs based on our gamma delta cell therapy platform. We look forward to disclosing additional details about our internal pipeline later this year. From this growing pipeline, we plan to file new IND every 12 to 18 months.
What we're seeing today is just the beginning of the potentially robust pipeline at Adicet. Let me summarize what we have observed to date with ADI-001. We've seen encouraging efficacy data in heavily pre-treated patients with aggressive forms of Non-Hodgkin Lymphoma, including patients who have progressed following prior autologous anti-CD19 CAR T therapy. Patients with indolent lymphoma such as Follicular Lymphoma are currently not enrolled to the study. Overall, in the study, we observed a 75% overall response rate and CR rate across all Dose Levels. 80% overall response rate and CR rate at Dose Level 2 and 3 combined, which may better represent the recommended phase II dose. 100% overall response rate and CR rate in patients who relapsed following autologous anti-CD19 CAR T therapy. Let me make it clear.
We observed CRs in three consecutive patients that relapsed following autologous anti-CD19 CAR T, including in double and triple hit high-grade B-cell lymphoma patients, and including complete responses in two patients that had a prior partial response to autologous anti-CD19 CAR T therapy. Regarding durability, we're happy to report that 50% of evaluable patients with at least six month follow-up remain cancer-free. Last but not least, we continue to observe a favorable safety profile. Bottom line, we're very encouraged by all the data we have observed to date on ADI-001 potential for best-in-class overall response rate, CR rate, and durability given the antitumor activity offered by gamma delta 1 CAR T cells. Now, let me turn the call over to Francesco, who will walk us through the data in more detail. Francesco.
Thank you, Chen. Good afternoon, everyone, and thank you for joining us today to review the latest data cut from our phase I study evaluating ADI-001 in B-cell malignancies. You have heard the presentation by Dr. Neelapu this morning. We will now review the main findings, show you a few patient case studies, and share preliminary thoughts for our pivotal program. We do believe the initial results continue to be rather impressive. Our gamma delta CAR T cells are unique as they are designed to have three mechanisms for antitumor activity. First, innate antitumor activity, which targets multiple surface proteins selected by evolution to mark tumor cells for cell killing. Second, adaptive antitumor activity by an MHC unrestricted T-cell receptor. And finally, a CAR-mediated antitumor activity.
We believe the combination of these three antitumor activities in one cell therapy product may result in a more limited ability for the tumor to escape therapy. This slide summarizes important functional preclinical characteristics of ADI-001 that have been recently published. ADI-001's preclinical characterization is very thorough, and the key points are the following. First, ADI-001 has demonstrated fast targeting and elimination of lymphoma cell lines expressing a range of CD20, with kinetics that outperform that of alpha beta CAR T cells from the same donor material. Second, ADI-001 has demonstrated deep and durable inhibition of human lymphoma xenograft models. Third, ADI-001 has demonstrated favorable resilience to host elimination compared to commonly deployed genetic allogeneic approaches. This preclinical profile supports the notion that ADI-001 may represent a significant potential improvement beyond current therapies and alternative allogeneic approaches.
A quick reminder on the first-in-human study design. The dose escalation portion of the study includes three Dose Levels, starting at a rather low flat dose of 30 million CAR-positive cells and continuing to 100 and 300 million flat dose CAR-positive cells. Higher doses can also be tested under this protocol, depending on data. Each enrolled patient receives a five day lymphodepletion regimen required to deplete the endogenous T and NK compartments and to allow engraftment of the subsequent allogeneic cell infusion. We have explored two different lymphodepletion regimens shown on the slide, both based on fludarabine and cyclophosphamide. After lymphodepletion, each patient receives a single infusion of ADI-001 at the appropriate Dose Level and is then followed up for a 28-day window called the Dose Limiting Toxicity or DLT window. Safety findings emerging during the DLT window are the main drivers of dose escalation decisions.
After the DLT window is over, the patient is followed up for safety and efficacy evaluations. It is important to point out that the current focus of the trial is on aggressive forms of lymphomas, such as Large B-Cell Lymphoma and Mantle Cell Lymphoma, and that indolent lymphomas, such as Follicular, are currently not enrolled in the study and not part of our current data set. Of our eight evaluable patients so far, seven had relapsed or refractory Large B-Cell Lymphoma, including four diffuse Large B-cell, one Double hit, and one Triple hit high-grade B-cell lymphoma, and one high-grade B-cell lymphoma not otherwise specified. The eighth patient had a relapsed/refractory Mantle Cell Lymphoma. Most patients were heavily pre-treated with poor prognostic factors and relatively high tumor burden. All of the patients were stage 3 or 4.
Median number of prior therapies was four, and the median IPI prognostic score was four. More than 60% of patients were refractory to their last course of systemic therapy, and the remaining were relapsed. Three patients had previously relapsed after autologous CD19 CAR T therapy. Again, it is important to remember that our data set includes very late-stage and aggressive lymphomas. This slide shows the characteristics of each individual evaluable patient dose so far. The data set that we are discussing today includes eight patients shown on the table, three at Dose Level 1, 30 million cells, three patients at Dose Level 2, 100 million cells, and two patients at Dose Level 3, 300 million cells. As you can see, some patients receive what we call standard lymphodepletion, while others receive an enhanced lymphodepletion regimen. Our lymphodepletion regimens do not include additional agents on top of Cy/Flu.
Importantly, three Large B-Cell lymphoma patients, 38% of the evaluable patients, have received anti-CD19 CAR T-cell therapy and progressed following Axi-cel or liso-cel. This slide shows a summary of key safety findings collected so far. The only Grade 3 event was a COVID-related pneumonia two and half months after ADI-001 infusion. This patient also developed a Grade 2 CRS, probably due to the COVID infection and not related to ADI-001. The other CRS reported was a Grade 1. We had previously reported one additional Grade 1 CRS event that was retracted by the clinical site. We had one G rade 1 ICANS, which resolved within 24 hours without medical intervention. We have not seen any event of GvHD or any DLTs. Importantly, we have not seen any infections in patients receiving the ELD regimen.
Overall, in patients dosed to date, 001 appears to be very well tolerated. As shown on this table, the overall response rate and complete response rate across all cohorts was 75%. If we focus on Dose Level 2 and 3 combined, which are closer to what we expect the recommended phase II dose will be, the ORR and CR rate is 80%. Importantly, all three patients who had previously relapsed after autologous anti-CD19 CAR Ts showed a complete response to 001. Two of them had a partial response as a prior best response to axi-cel. These early findings clearly indicate the potential of 001 in this high unmet need population. Let me quickly describe individually all the patients who responded to ADI-001.
In Dose Level 1, as previously discussed in December, a 66-year-old female who had achieved a complete response developed COVID-19 related pneumonia and died of complications from it, unrelated to ADI-001 , approximately two and a half months after ADI-001 administration. The second responder in Dose Level 1 had Triple hit high-grade B-cell lymphoma. He had previously relapsed following two prior treatments with liso-cel. This patient showed a CR one month after treatment with ADI- 001 . Four months after infusion, the patient developed a local skin relapse, and local radiotherapy was administered per current standard management in these cases. The skin lesion resolved with no systemic therapy provided. The patient continues to be cancer-free seven and a half months following treatment with ADI-001 , as measured by negative PET CT scan.
Both patients in Dose Level 2 who showed a CR at day 28 have ongoing complete response. One patient beyond seven months and one patient beyond four and half months following administration of ADI-001. Both patients in Dose Level 3 have ongoing CR with follow-up beyond three months and one month following administration of ADI-001. In summary, 60% of evaluable patients with at least six months follow-up, two out of four, remain cancer-free. As expected, patients receiving lymphodepletion show a deep and prolonged lymphodepleted state. One measurable difference between the two regimens that we have used in the trial, enhanced lymphodepletion or ELD and standard lymphodepletion or SLD, is the difference in measurable levels of circulating interleukin -15. In patients receiving ELD, interleukin -15 levels are increased approximately twofold by AUC as compared to SLD.
Although we currently do not have data to prefer enhanced over standard lymphodepletion, the enhanced Interleukin-15 homeostatic response to ELD suggests it might offer a more suitable environment for ADI-001 cells to expand after infusion. Moving forward, the study will continue to use enhanced lymphodepletion, unless individual patients might require a more cautious approach, in which case standard lymphodepletion will be used. We have not observed any infection in patients dosed with enhanced lymphodepletion to date. The only infection reported was in a patient who had received standard lymphodepletion. This diagram illustrates the well-described ability of gamma delta 1 T-cells to preferentially home into a variety of solid tissues compared to peripheral blood. This is a distinctive feature that differentiates gamma delta 1s from other lymphocytes. In the peripheral blood, gamma delta 1 cells are commonly 1%-3% of circulating CD3 lymphocytes.
In other tissues, this proportion increases significantly. For example, 11-fold in GI, 8-fold in skin, et cetera. This biology has important implications for ADI-001 in our gamma delta 1 platform in general. In particular, it must be kept in mind when looking at the PK behavior of ADI-001 in the peripheral blood. This graph represents the flow cytometry PK analysis of blood samples from the study so far. A clear dose response of PK measurements can be seen in the blood, with a peak of ADI-001 expansion around day 10 and a persistence of the ADI-001 cells in the blood in Dose Level 3 measured up to 14 days. As we discussed, we believe this is likely to be only the tip of the iceberg, considering gamma delta 1 cell's tropism for tissues.
These exposures are already associated with durability beyond six months. We have chosen three case studies to illustrate the quality of the complete responses that we are seeing. The first one is a patient in Dose Level 1, a 75-year-old male with Triple hit high-grade B-cell Lymphoma. This patient had received five prior lines of therapy, including two cycles of liso-cel. In this case, the main tumor mass was in the right leg, encasing major nerves behind the knee, as shown by the red arrow. In the first assessment, the PET signal was completely gone. You can also appreciate the different position of the leg at day 28, as the tumor mass was preventing the patient from fully extending the leg at the time of the baseline scan.
The radiologist scored this response at day 28 as a complete response for Lugano criteria, and the response was confirmed as a CR at three months. As already discussed, this patient later developed a local skin relapse that was treated with local radiation. The lesion resolved without systemic therapy, and the patient remains cancer-free seven and half months after ADI-001 infusion. The second case study is a patient in Dose Level 2, a 62-year-old male with Mantle cell Lymphoma with five prior lines of therapy. He had two rather large inguinal tumor masses, shown by the red arrows in the baseline scan. At the day 28 assessment, the PET signal had disappeared for both tumor masses. The radiologist scored this patient as a complete response by Lugano criteria, and the complete response was confirmed by PET CT at month three and month six post-infusion.
This patient is still on trial and being followed per protocol. The last case we would like to show you today is a patient at Dose Level 3, 300 million cells, with Double-hit high-grade B-cell Lymphoma in four prior therapies, including axi-cel. This patient's best response to axi-cel had been partial response. The tumor lesions had completely gone by day 28 following ADI-001 infusion. This patient is still on trial and being followed per protocol. It is quite encouraging to see this depth of response to ADI-001, considering this patient's own prior experience with axi-cel. In summary, ADI-001 was well-tolerated and had an excellent safety profile in this first human study. No GvHDs or DLTs and no grade three or above CRS or ICANS were reported.
We saw compelling early efficacy data of single agent ADI-001 in heavily pre-treated aggressive Non-Hodgkin Lymphoma, including in patients who had prior CD19 CAR Ts. Again, let's remember that follicular patients are not currently enrolled in the trial. We have mentioned before the key efficacy findings, 75% ORR and 75% CR rate. 100% ORR and 100% CR rate in patients relapsed after prior autologous anti-CD19 CAR Ts. Early data suggests promising durability of responses. We can detect circulating ADI-001 in the blood by flow cytometry with clear expansion kinetics and dose-related increase of ADI-001 exposure in patients. We believe we have the potential for best-in-class overall response rate, CR rate, and durability. Dose escalation is ongoing.
Given the safety profile observed to date, the protocol has been amended to include a new Dose Level 4 at 1 billion Vδ1-positive cells and potential ADI-001 consolidation dosing at Dose Level 3 to finalize the recommended phase II dose selection. Based on this first-in-human findings, we expect a potentially comprehensive pivotal plan for ADI-001 across Non-Hodgkin Lymphoma subtypes and all lines of therapy. One option is to leverage the impressive efficacy in CAR T-relapsed patients to include a potentially accelerated path to first registration. Autologous alpha beta CD19 CAR Ts have been approved for second- and third-line diffuse large B-Cell lymphoma, and there is currently no effective therapy for patients progressing following autologous CD19 CAR Ts.
Based on our preliminary 100% overall response rate and CR rate in these patients, including two complete responses in patients who had a prior partial response to autologous CAR Ts, we expect to approach the FDA to discuss testing of 001 in a potentially pivotal single-arm clinical trial in CD19 CAR T relapsed aggressive Non-Hodgkin Lymphoma. In summary, we are extremely encouraged by this early data. There is a significant unmet need in this population, and we look forward to advancing 001 into a registrational program as soon as possible. With that, I'll now turn the call back over to Chen.
Thanks, Francesco. I'll now invite Dr. Sattva Neelapu to join us on this call to get his thoughts on a few questions that have been on top of mind for investors. Sattva, thank you for joining us today.
Thank you, Chen. It's my pleasure to be here.
Wonderful. Sattva, perhaps we can start with the first question. Based on your clinical experience, can you comment on ADI-001 durability data to date?
Sure. Although early, I think the data looks very promising to date. Of the four patients who are at least six months out from ADI-001 treatment, two remain cancer-free. This is particularly encouraging considering these patients were treated at low dose levels of 30 and 100 million CAR T cells, and the patients had aggressive lymphoma histologies, were heavily pre-treated, and had high tumor burden. In Dose Level 2, we see that both CRs are ongoing with one greater than seven months and the other greater than five months. When we look at Dose Level 1, one patient died from COVID-19, but the other one is still cancer-free. Although this patient received local radiation to a skin lesion at month four, at seven and a half months after ADI-001 infusion, the patient remains cancer-free based on a negative PET scan.
I think this is significant considering this patient had prior auto CAR T, and such patients have a median survival of only about six months. It is also important to note that following auto CAR T therapy, about 70% of patients who remain in CR at three months maintain long-term durability of their responses. In this study, so far, we have observed that all patients with a CR at day 28 remained in CR at month three, with the exception of one patient who unfortunately died from COVID complications at two and half months after ADI-001 treatment. In Dose Level 3, it is early, but seeing two complete responses in patients who only had a partial response to prior auto CAR T is very encouraging, and to me suggests that ADI-001 is likely a very potent product.
Overall, I think the observation of early CRs at day 28, the maintenance of CRs at month three, and two patients remaining cancer-free beyond six months all suggest that the efficacy and durability appear to be comparable to what has been observed with autologous CD19 CAR T therapy at this early stage.
Wonderful. Thank you, Sattva Neelapu. You know, perhaps the second question relates to persistence. Can you comment on ADI-001 persistence data to date?
Sure. First, when we look at the flow data that was shown today, the kinetics of ADI-001 expansion appears to be similar to autologous CAR T products with a very similar time to peak and a nice dose-dependent increase in ADI-001 exposure between the dose levels. The question that comes to mind is that sufficient? I think we need to consider two important factors here. First, unlike alpha/beta CAR T cells, the gamma delta T cells preferentially localize to tissues, hence what we see in the blood is likely the tip of the iceberg. Second, I think what matters clinically is durability of responses. What we have observed to date is that the expansion and persistence in the blood at low ADI-001 doses is associated with durable responses lasting beyond three to six months.
One could raise a question, can persistence of one month or less in the blood lead to durable responses? To me, the answer is yes, based on what we have learned from the auto CAR T experience. Although persistence with auto CAR T generally lasts beyond three to six months in most patients, I have certainly had patients who have had persistence as short as two to four weeks, but went on to have durable remissions lasting beyond three to five years. To give you some more context, on the ZUMA-1 study, which is a pivotal trial of axi-cel in Large B-Cell Lymphoma, a little over 15% of the patients who did not have functional persistence at three months have ongoing remissions five years later.
On the ZUMA-5 study, which is a pivotal trial of axi-cel Follicular Lymphoma, almost 40% of patients who did not have functional persistence at three months have ongoing remissions at two years. I think the expansion and persistence observed with ADI-001 to date can be sufficient to generate long-term durable responses.
Thank you, Sattva Neelapu. This is very insightful. Perhaps we can transition to the third question. The key modalities that are being explored these days in clinical trials in NHL are, for the most part, CAR alpha/beta T-cells, CAR NK cells, and bispecific. I do realize there's no head-to-head data comparing these modalities. You're in the forefront, and you have experience and you've seen data from all these modalities. Can you compare ADI-001 versus alpha/beta CAR T, CAR NK, and bispecific approaches in the field of NHL?
Sure. First, if you think about bispecifics, I think the most mature data that is available is from the pivotal phase II study of glofitamab in Diffuse Large B-Cell Lymphoma that was presented at this meeting. In this study, glofitamab showed CR rates in the 30%-40% range, with the CR rates at the lower end of that range in the post-CAR T patients. As compared to that, on the ADI-001 study, we see an overall complete response rate of 75% and a 100% CR rate in the post-CAR T patients. From a practical standpoint, bispecifics require administration of multiple cycles over several months, while ADI-001 is likely a single-dose treatment. Lastly, the safety profile of ADI-001 so far seems to be favorable compared to bispecifics with lower CRS and ICANS event.
The data to date suggests that ADI-001 may provide better efficacy with less toxicity and may be more convenient for patients compared to bispecifics. With respect to alpha beta CAR T-cells, I think there's no question that autologous alpha beta CAR T therapy has provided tremendous clinical benefit to patients. On the ADI-001 study, we observed that the efficacy in terms of CR rates is comparable or better versus autologous alpha beta CAR T-cells in patients who are as heavily pre-treated, as refractory, and have comparable median tumor burden. In addition, ADI-001 appears to be very effective in patients relapsing or those who only had a partial response after prior auto CAR T. Moreover, the safety profile of gamma delta T cells seems to be quite favorable versus autologous alpha beta CAR T cells due to reduced risk of CRS and ICANS.
With regards to CAR NK cells, I think the biggest challenge I see is that so far the data indicate that CAR NK cells don't expand or persist as well in vivo and therefore require frequent dosing compared to CAR Ts. Moreover, NK cells have both activating and inactivating receptors, and the net effect against the tumor depends on the balance of signals received through these receptors. In contrast, the ADI-001 CAR T cells proliferate and persist better, have mostly activating receptors, and as we saw in this study, can induce durable remissions with a single dose. Also, the CRs were seen with ADI-001 at doses that are approximately 1% of the doses administered in some of the recent CAR NK cells studies.
Overall, the results indicate that gamma delta CAR T cells such as ADI-001 have unique advantages over conventional alpha beta T cells, CAR NKs, as well as bispecifics.
Thank you, Sattva. With the profile of ADI-001 as we see it today, where do you see the greatest opportunity for Non-Hodgkin Lymphoma patients?
Yeah, based on the efficacy we have seen so far, I think ADI-001 has the potential to be broadly applicable to multiple NHL subtypes, including Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma, and Follicular Lymphoma. The remarkable finding of 100% CR rate in the post auto CAR T patients provides potential path for a quick single arm registration trial in this population who have a high unmet need with a median overall survival of approximately six months. Furthermore, given the excellent safety and efficacy profile, there's also a potential to investigate ADI-001 in earlier lines of therapy across different NHL histologies. As I understand, the company is thinking along similar lines as well.
Thank you, Sattva, for providing your thoughts on the call today. Let me now move to talk about next steps for the ADI-001 program before we open the call to additional Q&A. We have a number of upcoming important milestones in the near future. Regarding ADI-001, we expect to complete escalation through DL 4 to establish recommended phase II dose in the H2 of 2022. We expect to backfill enrolment to DL 3 with additional potential patients. We expect to discuss with the FDA and EMA the design of two potential pivotal studies and a potential path to BLA and MAA for ADI-001. We expect to provide at least one additional clinical update for ADI-001 in the H2 of this year. We expect to initiate at least one pivotal study with ADI-001 in the H1 of 2023.
With 75% overall response rate and CR rate in the study to date, we're very excited about the potential for ADI-001 to help many Non-Hodgkin Lymphoma patients across different lines of therapy. This makes us excited about the potential to help many other cancer patients. In addition to ADI-002, that has been recently in-licensed by Regeneron, we have a broad pipeline of six additional wholly owned internal programs in preclinical development. In all these programs, gamma delta one T-cells may offer specific advantages to patients. We currently plan to file at least one IND every 12 to 18 months, including one new IND for an internal program next year. Some of our pipeline programs target hematologic malignancies, building on our success with ADI-001. Other programs target solid tumors, and several programs may have indications both in hematologic and solid tumors.
We look forward to providing more details regarding our pipeline in the H2 of 2022, so stay tuned. Finally, we remain well funded with approximately $280 million in cash and cash equivalents at the end of the H1 of 2022, and are well capitalized into the H2 of 2024 to achieve the near-term milestones we discussed today, and potentially more. With that, I'll turn it over to the operator to open it up for Q&A. Operator?
Thank you. To ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Again, that's star one on your touchtone telephone to ask a question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Michael Schmidt of Guggenheim. Your line is open.
Hey, Michael.
Hey. Thank you for taking my question. Congrats. Great to be here today. Just perhaps a couple follow-up questions. There were two non-responders overall among the eight patients treated, and I was wondering if you have any insights into the PK and cell expansion dynamics in those two patients, which may perhaps explain why they did not respond.
Absolutely. Hey, Michael, always good to hear from you. Francesco, why don't you help address this one?
Sure. You are correct. We had the very first two patients in Dose Level 1 who progressed before they completed the DLT window, so they had to be replaced per protocol. Let me remind you, they were one primary refractory Burkitt Lymphoma and one Diffuse Large B-Cell Lymphoma with a massive tumor burden. To answer your question, we don't have any clear PK-related explanation as to why these two patients progressed so early. Our current interpretation is that they were too far advanced in the history of their disease. We don't have any clear correlated points that are culprits in terms of failure of the therapy to help these two patients.
Michael.
Okay.
Was that addressed? Did that address your question, or do you have any follow-ups?
Yeah, I was actually more referring to the two with progressive.
Yeah
I think it was one in Dose Level 1 and one in Dose Level 2, and whether that's correlated with poor expansion kinetics, for example.
Okay.
Yeah.
Sorry for-
Yeah
getting the wrong 2 patients.
Yeah.
Yeah.
Yeah. I would just say, you know, consistent with what Francesco said, regardless of the patient experience, we don't see any correlation with expansion. At the end of the day, in the progressive disease patients, we can still see evidence of detectable CAR T by flow in a similar expansion profile. You know, look, we're dealing with small numbers. Correlative science, I think, is a little bit out of touch at this point, right? We've not yet in our grasp. Probably have to wait till the expansion cohorts to get to the numbers we need to really start understanding the trends and means and all that. At this point, drug was detectable in those patients, again, with a similar profile. That's what's seen with our complete responders.
Yeah, that makes sense. You know, the safety profile obviously looks very, surprisingly, compelling, actually, compared to other CAR T therapy studies. Any particular explanation perhaps around the low rate of CRS and even infections were really low?
Yeah. You know, This is Blake. You know, I would say consistent with the preclinical data sets that have, you know, been presented many times over and are still existing in our corporate deck. You know, the cytokine profile, the activation cytokine profile for our drug and really the platform, you know, lacks key cytokines are associated with the CRS events, specifically IL-6 and a few others. So I'll just say, you know, in the patient population here, very similar to what we reported in December, we're still not seeing those increases in IL-6 systemically. Again, that dovetails quite nicely with what Francesco has reported with the benign CRS profile.
I guess regarding the infections, note that we're using the ELD and the only infection we've seen was a standard lymphodepletion. Keep in mind that gamma delta T cells play a key role fighting viral and bacterial infections. Perhaps that's why we haven't seen any infections so far in enhanced lymphodepletion.
Okay. That's quite interesting. You know, last question, you know, as you sort of move towards one, it sounds like perhaps two pivotal studies next year, you know, where do you stand with manufacturing scale? Do you have enough capacity to support one or two pivotal studies in the near term?
Sure. Absolutely. So far we've used one CDMO w e're now qualifying. A second CDMO, w e already started working on the manufacturing towards the pivotal studies. We continue to manufacture on an ongoing basis. I think we're in quite a good place in terms of manufacturing. We don't expect any issues at this point.
Okay, great. Thank you so much.
Thank you.
Thank you for asking, Michael.
Thank you. Our next question comes from Kelly Shi of Jefferies. Please go ahead.
Congrats on a very great progress. My first question is regarding the one case of ICANS. Could you actually share more details about the patient and regarding the tumor burden? Do you plan to implement any risk mitigation to prevent-
To prevent
-ICANS from happening, for the later enrolled patients on the trial?
Yeah. That was a Grade 1 ICANS event. It was a very minor event which resolved spontaneously without any particular treatment. Essentially, the patient had a syncope on their way around the hospital during a visit. It was really a minor event. To answer your question, we are obviously very vigilant, and we have all the infrastructure in place to monitor and treat those events. That particular occurrence doesn't trigger any particular change in the trial design because it was, as I said, a minor event. In terms of tumor burden, I think you were asking, that patient was in the range of other patients. There was nothing particularly notable that I can recall about that patient to explain the ICANS.
Okay. Great. Thanks. I also have a follow-up on CRS. You have a pretty low rate of CRS onset b ut I'm just curious, any particular reason that you only observe that at a Dose Level 1 but not at higher doses?
Yeah.
Well, I don't have an explanation. It could be just a consequence of very rare set of events. They happen at low grade here and there.
Yeah.
It's a good point. I don't have an answer.
Kelly, we actually had two cases of CRS. One of them, Grade 2, was for the patient with COVID pneumonia at month two and half. Probably not related to ADI-001. The other one was Grade 1 CRS, which is really minor and, you know, resolves quickly, no therapy. It's quite a clean profile. I would say we had only one grade, one CRS that, you know, may be associated during the period of expansion of the cells and, you know, that's quite nice to see it's only in those overall.
Great. One last question, if I may. For those three patients achieved the CR who actually experienced autologous CD19 CAR T treatment previously, are all three of them achieved the PR from the CD19 CAR, or am I actually mistaken? Also, are you going to enrol more patients who actually failed to respond to auto CD19 CAR T? Thank you.
There were three patients with prior exposure to autologous CD19 CAR T, and they all three responded as a complete response to ADI-001 . The first one of those three patients had a prior exposure to two cycles of liso-cel, and that patient showed a complete response both times to liso-cel and obviously relapsed both times before coming to our trial. The second and the third patient with prior autologous CD19 CAR T had received axi-cel as part of their prior lines, and both patients had shown a best response of partial response to axi-cel before getting ADI-001 and showing a complete response. That is the situation. Regarding moving forward, we will continue, of course, enrolling patients with prior exposure to autologous CD19 CAR T.
We don't select the prior response as a criterion, so one can expect a pretty representative sample of prior autologous CAR T relapses.
Yeah. The only thing that I would add is the note and, you know, when you compare it to other companies is that these complete responses are in DLBCL and then in Double hit and Triple hit high-grade Lymphomas. So these are tough patients and very few companies were able to show CRs in these patients. So we're very, very happy about this data.
Thank you very much. Congrats again.
Thanks. Good. Always good questions from you. Thank you, Kelly Shi.
Thank you. Our next question comes from Asthika Goonewardene of Truist Securities. Your line is open.
Hi, guys. Thanks for taking my questions. Our congratulations as well for this very elegant data. I was wondering if Dr. Neelapu, who is also on the line, maybe could give us a little bit of color in your practice, what proportion of these relapses in the clinic present as skin lesions? Then for the patient who did get that skin, that cutaneous relapse, how do you compare that to a more traditional relapse that you see in the clinic?
Sure. Dr. Neelapu is right here.
Yeah, sure. No. If you think about extranodal presentation for Large Cell Lymphoma in general, that occurs in about 20% of the patients. So it's a bit slightly less common compared to typical nodal presentation, but it's not unusual. This patient had a localized skin relapse and was treated with local radiation therapy, you know, and no systemic therapy at the time and maintained a complete remission at seven and a half months, suggesting that he's probably had good systemic control of the disease, likely from ADI-001. And that's particularly significant considering this patient relapsed after prior liso-cel, two infusions of liso-cel, and these patients typically have a median survival of only about six months or so.
Got it. Dr. Neelapu, did you biopsy that lesion, and are you checking for the presence of gamma delta T cells in the tissue?
Yeah. The biopsy, yes, was performed, but we didn't have a chance to check for the presence of ADI-001 cells, so I don't have that information.
Okay. Francesco, will you be updating us on that at a later point?
Yeah. We'll provide at least one update later this year in the H2 . Not sure if it's gonna be one or two updates. You know, if we have the data, then we're happy to provide additional details. Absolutely.
Got it. Just wanna ask, you mentioned that you're gonna explore a Dose Level 3 consolidation regimen. Can you maybe talk to us a little about what that will look like? Just because there may be a couple of different definitions from other cell therapy companies and what they call consolidation.
Sure. You are correct. We are considering under the current protocol the option to test the consolidation setting. Our definition of consolidation is a pretty standard one, which means a patient who essentially received the lymph depletion and the first dosing of ADI-001 , and at a certain time point after that, receives another round of the lymph depletion plus ADI-001 for the purpose of pushing the response further down, essentially improving the depth of the response. It would be a repetition of the entire cycle. More than likely, we will use the standard lymph depletion for the second time around. It's important to, you know, not to push too hard with the lymph depletion.
For patients who might be considered for that consolidation test, essentially, they would be receiving enhanced lymph depletion the first time around.
Standard lymphodepletion the second time around with ADI-001 at the same dose level both times, Dose Level 3. It's not something we feel is needed, quite frankly, but we feel the, you know, the importance of testing with just a few patients for that paradigm.
Yeah, I think Francesco gave you the answer about second lympho depletion, likely standard lympho depletion. That's without reading your second note today. You just answered the question that you had. I guess one point to add here, every time we're talking about a small n, but every time we've looked at the data so far, it got better. Initially 50% CR, then in the abstract, 67% CR. Now 75% CR. You know, the efficacy data looks quite compelling. Essentially our journey for the next, you know, six months is to select the recommended phase II dose, and this is likely to be either DL 4 or DL 3, or if we see very compelling data from a consolidation data DL 3, that might be also the recommended phase II dose.
We're doing the right exercise to enable us to select the right dose for the pivotal program.
Great. Guys, thanks for all the color. I really appreciate it, and congrats again.
Thanks for asking. Always great questions.
Thank you. Our next question comes from John Newman of Canaccord. Your line is open.
Hi, guys. Thanks very much for taking my question. The first question I had was for Dr. Sattva Neelapu. I'm curious if you have any thoughts on the stability of the CD19 target, CD19, excuse me, target, versus CD20. If in addition to the unique properties of ADI-001 that could be playing into potentially a better response.
Yeah. First, if you look at our transcript levels from the TCGA data, the CD20 expression level is much higher than CD19. Then if you look at protein expression, as we shared today, you know, at diagnosis, 98% of all B-cell lymphomas are CD20 positive, and this CD20 expression seems to be quite stable even after multiple treatments with anti-CD20 antibodies. Post CD19 CAR T cell therapy also, we've reported that 95% of them are still CD20 positive. Its expression seems to be quite stable, and in fact, at this meeting there were three abstracts, you know, looking at the rate of CD20 loss from multiple centers. That seems to be about 5% even after in relapsed refractory cases, including patients who relapsed off bispecific CD20 antibodies.
Now with CD19, post CD19 CAR T, we see about a third of the patients have CD19 loss. So that's the data that's been reproducible from multiple centers as well in multiple different studies.
I had one additional question for you, Dr. Sattva Neelapu. We've heard a lot of discussion here at ASCO in Chicago this weekend about the difficulties in obtaining CAR-T therapy, more so for BCMA, but we've also heard some commentary about the CD19 targeted therapies. Given that this is an off-the-shelf allogeneic treatment, how do you think that could potentially change the way that these therapies are viewed, even at a large center, such as your own? Thanks.
Yeah, definitely because these patients have aggressive B-cell lymphomas, they need treatment right away majority of the time. Having a therapy that's readily available off the shelf is, you know, much more appealing, both for patients and also from a practical standpoint and from a medical standpoint, because they need to be treated, quickly. If I have a choice between two CAR T products that are, one is autologous, one is allogeneic, and the turnaround time for autologous is three to five weeks or longer, and they have comparable efficacy or, you know, and similar toxicity, I would definitely go for allogeneic in that setting. Now in this study so far we are seeing the efficacy is probably comparable or better, and the efficacy is also seems to be much more.
Sorry, toxicity seems to be much lower, compared to auto CAR-T that are currently FDA approved.
Okay. Thank you.
Thanks, John. Great questions.
Thank you. Our next question comes from Reni Benjamin of JMP Securities. Please go ahead.
Good afternoon, guys. Thanks for taking the question, and congratulations on the data. I'm just curious regarding the dose expansion, the cell expansion that's occurring. A s I look at the flow, it seems like by day 28, those cells are no longer there. Yet you're having a long-lasting impact. Do you have any sense as to if there's any crosstalk between, you know, the gamma delta cells and alpha betas? W hat's happening with the memory cells from the T-cell components? And ultimately, whether or not, you know, retreatment as a maintenance might be considered going forward?
Yeah. You know, maybe I'll take the first part of that. You know, with respect to how the gamma deltas are influencing, you know, endogenous milieu, upon recovery. Just say we don't have any information about that from our translational endpoints. I think the PK data currently, you know, stand on their own. It's good to see it by flow cytometry. It's good to see the expansion profile very much mirroring that which has been demonstrated by alpha beta CAR Ts. I would just say, you know, it's gonna take a lot more time for us to, you know, further evaluate what may be occurring upon repopulation a nd definitely, of course, you know, in consolidation regimens of, you know, when we get there. I'll defer to Francesco on the second part of the question.
Yeah, for the maintenance concept, I think it's a little too early to commit and consider very creative, you know, regimens. The protocol does allow the exploration of certain settings. The one that is on top of our priority, as we already discussed, is consolidation concept. It's a little, like, in my opinion, too early to discuss about possible maintenance scenarios. I'm not saying that they have no merit. I'm just saying that we don't know enough about the regimen as it is. It appears to be pretty safe and tolerated and efficacious already in single dose.
Yeah. I guess, Reni, two comments that might be worth noting. When you look at products like Yescarta or even if you look at Legend as an example, so you'll find out that the functional persistence can translate to excellent durability measured in years, and again, functional persistence be below 30 days and translates to years of durability. We're very happy with the data that we have from the durability. You can see, you know, durable responses starting from Dose Level 1, definitely in Dose Level 2, and it's even increasing the Dose Level 3. We're in a good spot and keep in mind we're only seeing what's in the blood. Most of it is in the tissues that's represented in the slide today when it comes to gamma delta 1.
Got it.
You make a good nuance between functional durability. I'm trying to remember, maybe you can remind me, how long have we seen the persistence of, you know, call it the first generation CAR T products, you know, in these patients?
Yeah. Maybe Dr. Sattva Neelapu can comment on it. Obviously, only data in the public domain.
Yeah.
Yeah.
Yeah. With autologous CAR T, you know, persistence has been reported in years, especially the 4-1BB-based CARs. There's a recent publication from the UPenn group showing persistence at 10 years even b ut if you look at the axi-cel data from the ZUMA-1 that we reported after three years, there was really no functional persistence. None of the patients had functional persistence. All of them had recovery of normal B cells. Even though we can detect the CAR transgene by PCR, but they don't seem to be functional at that stage.
Right. One final-
As I mentioned earlier, you know, some of the patients lose functional persistence as early as two to four weeks or even three months and go on to maintain their clinical remission for years.
Got it. One final question from me, again, just thinking about next steps. You know, a lot of the first generation of CAR Ts were being evaluated in combination with, you know, either checkpoints or other types of therapies. Any thoughts as to, you know, next steps in regards to combinations?
Right now we're keeping it simple. Single dose provides 75% CR rate and that's pretty good. I'm not sure if we need to combine at this point. Right now that's the plan and if anything changes of course we'll update, but seems to work reasonably well as a single agent.
Great. Thanks for taking the questions.
Absolutely. Thanks, Reni.
Thank you. Our next question comes from David Dai of SMBC. Your line is open.
Great. Thanks for taking my questions and, congrats on the data. I just wanna follow up on the, on the combination strategies, that was alluded to earlier. So we know that it seems like the safety profile being extremely good. So, I just want to understand, you know, what are potential combination, partners that you're thinking about potentially to move this one into early line therapies as soon as possible?
Yeah. We're now working on the design of two studies. One of them, as Francesco mentioned, is likely to be patients that progressed on autologous CD19 CAR T. The second study, we haven't finalized the design, but you know, an earlier line of therapy is not an unlikely question regarding the specific design. I think we're working on the design and at the right point in time, we'll share the full details. I'm sorry it's not a full answer, but that is the honest answer. We're working with the best of the KOLs in the world, obviously led by Professor Sattva Neelapu, to design the study. Once we have the data, we'll share them.
That is very helpful. Thank you so much for taking my questions.
Absolutely. Thanks, David. Great question.
Thank you. Our next question comes from Soumit Roy of Jones Research. Your line is open.
Hi, everyone. Thanks for taking the question and congratulations again on the data. One question on the consolidation strategy. Could you tell us why you're thinking that way, since most of them are in CR? Usually we see companies doing it when they see a lot of partial responders. Any comments would be.
Yeah. You know, it's a great question. We're actually starting from a great place, right? We have seen only CRs so far, so we're not sure if consolidation dosing will be beneficial. You know, we take it with high responsibility to select a recommended phase II dose, and that's why we decided both to go into a DL 4 and to consolidate the DL 3 and look at the totality of the data and use good clinical judgment in making recommendations for the recommended phase 2 dose. I would agree that on its face, you know, we're starting from a great place and choosing between very, very good and excellent sometimes is more challenging than what we wish. Hopefully we'll make that decision later this year.
Got it. Curious if you're seeing any expansion of endogenous alpha beta CD8s if gamma deltas are acting as the APC cells?
Yeah, if we hear the question. We showed the data in the deck regarding the alpha, beta, and NK, but Blake Aftab has much better point here.
Yeah. I mean, I would say that the profile, again, the interaction and how gamma deltas may be influencing the recovery of the endogenous CD8 repertoire, unknown at this point. In the deck on the IL-15, AUC data between SLD and ELD, that's overlaid on top of the CD8 and NK populations and showing their recovery. Ultimately, we do see CD8 T cells coming up later on in the one-month cycle, depending on the lymphodepletion regimen. You know, the T cells are recovering late in the cycle. I think that's all we can say. As far as interactions between the two populations, unknown at this point.
Got it. One last question, since we have Dr. Sattva Neelapu here. If the pivotal trial turns out to be a single-arm, what efficacy benefits you expect that would allow for a single-arm trial at this point where autologous is already in the market?
Currently here, the pivotal trial that we have in mind is to do something in the post-CD19 CAR T failures. This is a group that has a significant unmet need. There's currently no FDA-approved therapy for these patients, and the median survival is only six months. I think the bar is pretty low for those patients. A durability of responses in about 30%-40% of the patients lasting six months is a potential path for approval, in my view.
Yeah. Yeah. Keep in mind, these patients have a median overall survival of about six months. That patient that we have, that third patient in DL 1, the six month scan was actually done at the seventh month because the patients was pretty much on vacation, and it was tough to get him back to the site to get the scan. He was cancer-free and on vacation at month seven.
Great. Thank you so much for taking all the questions, and congratulations again for a robust data.
Thanks for asking.
Thank you, ladies and gentlemen. This does conclude today's conference call. Thank you for participating. You may now disconnect.