Adicet Bio, Inc. (ACET) Earnings Call Transcript & Summary

Welcome to Adicet's specially scheduled Conference Call. This call is being recorded. At the end of the company's prepared remarks, we'll open the call for questions, and we'll provide specific instructions at that point. I would now like to turn the call over to Anne Bowdidge. Please go ahead.

Good morning. 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 pleased to have Dr. Sattva Neelapu, Professor in the Department of Lymphoma/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, expressed or implied statements regarding the potential safety, durability, tolerability and efficacy of ADI-001, future progress of Adicet's Phase 1 trial of ADI-001 in relapsed refractory NHL patients, including ongoing patient enrollment, timing for the release of additional clinical data from the trial, selection of a recommended Phase 2 dose, expectations regarding future discussions with regulators and regulatory filings for product candidates in the company's pipeline and timing for transition to pivotal programs, including the initiation of a potentially pivotal study in CAR-T relapse patients in the second quarter of 2023 and an additional potential pivotal study in [ LBCL ] patients. 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 or 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's 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's expressed written permission. With that, I'll turn the call over to Chen Schor, President and CEO of Adicet. Chen?

Thanks, Anne, and thank you all for joining us today. We're conducting this call live this morning from New Orleans, where we're all here for ASH. We're happy to be joined by Dr. Sattva Neelapu from the University of Texas MD Anderson Cancer Center. We're grateful to have Sattva join us today given his experience with ADI-001, and deep insight into the clinical management of NHL patients. As you saw from our press release yesterday, we announced an updated data cut from our Phase 1 clinical study of ADI-001 in patients with aggressive non-Hodgkin's lymphoma or NHL. Like me, I know you all like your data cut stretch, so you'll be pleased to see that the latest data cut happened on Monday, less than a week ago. I'd like to thank the entire Adicet team for making this happen so we can give you the latest view of the data today. Let me walk you through the agenda for today's call. After I provide a few remarks, I'll pass it over to Dr. Francesco Galimi, our Chief Medical Officer, to provide a high-level update of the Phase 1 data as of the December 5 data cut date. Then, Dr. Neelapu will provide his perspective on the data. And finally, I'll close with some milestones that you can expect for 2023 before I open the call for Q&A with the rest of the Adicet team who is with us here today. So why don't we start with Slide 5. Since our founding in 2014, we have led the field of discovering and developing off-the-shelf engineered gamma delta T cell therapy for patients fighting cancer. Over the years, we developed significant expertise in gamma delta T-cell biology in engineering gamma delta T cells to enhance their potency and in harnessing the 3 antitumor mechanisms inherent in gamma delta 1 CAR T cells. At the same time, we developed a robust, scalable and reproducible off-the-shelf cGMP compliant manufacturing process and built a broad patent portfolio. In March last year, we were the first company in the clinic with a gamma delta CAR T cell therapy product candidate and it's credifying to see that the underlying biology of gamma delta T cells has translated to significant and meaningful clinical activity in patients. The clinical data with ADI-001, a first-in-class allogeneic investigational gamma delta CAR-T cell therapy indicate that the gamma delta T cells may provide significant advantages, both in terms of antitumor activity and safety compared to other cell therapy platforms and bispecifics. Based on the data presented today, we expect to transition ADI-001 to a pivotal program with potentially best-in-class overall response rates, CR rate and durability profile in the second quarter of 2023. We will provide additional clarity on the third pivotal study for the program as well as the addressable patient population during the call today. More details regarding the potential second pivotal study are expected to be provided next year. In addition to ADI-001, we have 6 internal gamma delta-1 T cell therapy preclinical and discovery programs in development. At our R&D event last month, we provided additional data on 4 highly differentiated gamma delta T cell therapy preclinical programs, all building on years of expertise, IP and know-how in gamma delta T cell biology. As we said previously, we plan to file one new IND every 12 to 18 months, starting with IND for ADI-925 in the second half of next year. We're also extremely well financed with $282 million in cash as of the end of the third quarter of '22 and are well capitalized into the first half of 2025. Let's move to Slide 6. Let me summarize what we have observed with ADI-001 as of our December phase cutoff date. We continue to see encouraging early efficacy in heavily pretreated patients with aggressive forms of NHL, including in patients who had progressed following prior autologous anti-CD19 CAR-T therapy. Overall, in the study, we observed a 75% overall response rate and 69% CR rate across all dose levels with a favorable safety and tolerability profile. A 100% overall response rate and CR rate in 5 out of 5 large B-cell lymphoma or LBCL patients relapsing after prior autologous anti-CD19 CAR-T therapy, an 86% CR rate in LBCL patients across DL3 and above, the CR rate in LBCL across all those levels is 75%. In both DL2 and DL3, we saw a 33% 6-month CR rate. We continue to follow up on patients in DL4 to assess the 6-month durability. In DL4, circulating ADI-001 cells are visible through day 28 in peripheral blood. Overall, the data suggests that ADI-001 may provide potential best-in-class overall response rate, CR rate and durability given the antitumor activity offered by gamma delta 1 CAR T cell. In terms of next steps, we plan to initiate our first potential pivotal study in post CAR-T LBCL patients in the second quarter of next year. And we also plan to evaluate the potential for a second pivotal study in earlier line LBCL patients. Stay tuned for more details on the second potential pivotal study next year. Why don't we move to Slide 7? We're very encouraged by the clinical data and excited to see what we believe is the underlying biology of gamma delta 1 T cells through its 3 mechanisms of antitumor activity and favorable safety profile translating to significant and meaningful clinical activity in NHL patients. As a company, we're committed to developing more effective therapies for cancer patients and are extremely gratified to see these early durable, complete responses in this very sick patient population with limited options. I'll now turn the call over to Francesco, who will walk us through the data in more detail. Francesco?

Thank you, Chen. Good morning, everyone. Thank you for joining us today to review the latest data cut from our Phase 1 study evaluating ADI-001 in B-cell malignancies. I will now review the main findings, which we believe continue to be very encouraging and share preliminary thoughts for our future pivotal program. Let's first give you a quick reminder of the first-in-human study design on Slide 9. As you can see, the dose escalation portion of the study includes 4 dose levels starting at a rather low flat dose of 30 million CAR-positive cells and continuing on to 100 million, 300 and 1 billion flat dose of CAR-positive cells. Each enrolled patient received a 5-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 2 different lymphodepletion regimens shown on the slide, both based on fludarabine and cyclophosphamide. After lymphodepletion, each patient received a single infusion of ADI-001 at the appropriate dose level and is then followed up for a 20-day window called the dose-limiting toxicity window or DLT window. Safety findings emerging during the DLT window are obviously the main drivers of those escalation decisions. One exploratory section of the protocol, which we call Part 1b, includes patients receiving a single lymphodepletion and 2 infusions of DL3 300 million CAR-positive cells on day 1 and 7 for a total dose of 600 million CAR-positive cells. After the DLT window is over, the patient is followed up for safety and efficacy evaluation. It is important to point out that the current focus of the trial is on aggressive forms of lymphoma such as large B-cell lymphomas and mantle cell lymphomas. To date, we have enrolled only 1 follicular lymphoma patient in the group of 16 efficacy-evaluable patients. Additional follicular lymphoma patients may be enrolled on the potential future cohorts of this study. Let's move to patient characteristics table on Slide 10. Of our 16 evaluable patients so far, 12 had relapsed or refractory large B-cell lymphoma, including 1 double hit and 1 triple-hit high-grade B-cell lymphoma. 3 patients had relapsed/refractory mantle cell lymphoma and 1 follicular lymphoma. All patients were heavily pretreated with poor prognostic factors and relatively high tumor burden. Most patients were stage 3 or 4. The median number of prior therapies was 4 and the median IPI prognostic score was 3 for the large B-cell lymphoma group. 69% of the patients were refractory to their last course of systemic therapy and the remaining were relapsed. 6 patients, 5 large B-cell lymphomas and 1 mantle cell lymphoma had previously relapsed after autologous CD19 CAR-T therapy. Again, it's important to point out that our data set includes a very late stage and aggressive lymphoma. Let's move to Slide 11. This slide shows a summary of the key safety findings collected so far. There were no CRS or ICANS events reported grade 3 or above. The reported CRS were all grade 1, apart from 1 grade 2 in a patient with COVID, which we reported previously. We had 1 Grade 1 ICANS, which result within 24 hours without medical intervention. We have not seen any event of GvHD or any DLT. The occurrence of infection in our cohort so far appears to be rather low in spite of the use of advanced lymphodepletion. Overall, in patient dose to date, ADI-001 appears to be very generally well tolerated. Let's go to Slide 12 and talk about efficacy. This slide shows our response data on a swim lane plot. The overall response rate across all cohorts was 75%, 12 patients responding out of 16 evaluable and the CR rate was 69%, 11 CRs out of 16 evaluable. If we focus on the large B-cell lymphoma patients, the complete response rate was 86% in dose level 3 and above, 6 complete responses out of 7 evaluable patients. Across all those levels, the CR rate in large B-cell lymphoma was 75%, 9 out of 12. All 5 large B-cell lymphoma patients who had relapsed after prior autologous CD19 CAR-T showed a complete response to ADI-001. These patients are indicated by the yellow mark to the left of their tumor type on the slide. The CR rate in that population is currently 100%, which we believe is obviously very promising. We also had 3 mantle cell lymphoma patients, 1 in dose level 2 and 2 in dose level 4. The first MCL is still in CR, complete response, 11 months after infusion. The second mantle cell showed a complete response at day 28. And the third that showed a radiological partial response at day 28. This last patient is actually MRD negative per local assessment. And in the option of the investigator, the patient is in clinical complete remission at this time. We're currently reporting a partial response on the Lugano criteria, and we'll obviously provide updates in the future about the evolution of this patient. The very first patient on the graph in dose level 1 is a patient that we discussed before. While in complete response, he had a skin relapse that made him progress on the Lugano criteria. So his complete response technically lasted up to month 4. However, the skin lesion was irradiated as per normal clinical practice and the patient is still doing well and free of disease without any systemic anticancer therapy, more than 14 months after infusion. On an exploratory basis, mainly to understand the safety and PK of a second lymphodepletion and a second dose of ADI-001, the first 2 patients in dose level 3 while in MRD-negative CR received a second infusion of ADI-001 at 300 million cells in dose level 3 after a second round of standard lymphodepletion, 3 and 2 months after the first infusion, respectively. One of these 2 patients is still in complete response and doing well. The other patient developed a viremia that led to death 5 months after the first infusion unrelated to ADI-001. The patient had progressed up to 4 lines of therapy and received a total of 3 lymphodepletions, 1 for the autologous and 2 for the ADI-001 infusions. This patient did not experience any disease progression following the MRD-negative complete response to ADI-001 on day 28. We currently do not plan to pursue consolidation dosing with multiple lymphodepletion in the ADI-001 program. We have also started to dose a cohort of patients that is shown on the slide at dose level 3 day 1 and 7. We call it Part 1b in the protocol. These patients received 2 doses of 300 million CAR-positive cells, 1 week apart after 1 single round of lymphodepletion. This is a regimen that we are evaluating for possible recommended Phase 2 dose together with dose level 4. As you can see on the diagram, the first evaluable patient in this cohort shows a complete response, currently ongoing almost 3 months after the beginning of treatment with ADI-001. In Part 1b and in dose level 4, the new large B-cell lymphoma patients show 3 complete responses out of 4 evaluable patients. The only nonresponder was a stable disease who decided to withdraw consent and left the study. As I already mentioned, the post-CAR-T mantle cell lymphoma in dose level 4, shown as a radiological PR on the plot, was assessed by the PI as MRD-negative CR. The case is under review and may convert into radiological CR. We'll keep you updated. Regarding durability, both the dose level 2 and dose level 3 demonstrate a 33% 6-month complete response rate, which is comparable to the durability of approved autologous CAR-Ts for late-line aggressive non-Hodgkin lymphoma. Patient follow-up continues in dose level 4 to assess 6 months durability. Overall, the preliminary efficacy data in this trial to date has shown very high response rates comparable to the clinical experience with approved CAR-Ts and in particular, a very striking 100% CR rate in post-CAR-T relapsed large B-cell lymphoma patients. As we know, these patients are very high unmet need in non-Hodgkin lymphoma. Let's move on to Slide 13. This diagram illustrates the well-described in preferential homing of gamma delta 1 T cells to 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% to 3% of circulating CD3-positive 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, and for 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. Let's move to Slide 14 to talk about PK. This graph represents the flow cytometry PK analysis of blood samples from the study so far. It should be noted that the sample size is still small and is affected by a lot of variability in flow cytometry measurements. That said, we continue to see a robust expansion of ADI-001, as measured in the peripheral blood at the higher dose levels, with peak results occurring between day 7 and 10 and persistence for dose level 4 visible through day 28 as measured by flow cytometry. We're also starting to explore the PK profile in patients receiving the 2 separate dose level 3 doses, 1 week apart, the Part 1b of the protocol that I mentioned. But we have too few samples for now to draw any conclusion. As we discussed, we believe the PK measured in the peripheral blood is likely to be only the tip of the iceberg considering gamma delta 1 cells tropism for tissues. It should also be noted that exposure starting at dose level 2 are already associated with durability beyond 6 months. To summarize, let's move to Slide 15. As you saw in the data presented today, ADI-001 was generally well tolerated and had an excellent safety profile in the first-in-human study with no GvHD, no DLTs and no grade 3 and above CRS or ICANS reported. We saw compelling early efficacy data of single-agent ADI-001 in heavily pretreated aggressive non-Hodgkin lymphoma, including in patients who had prior CD19 CAR-T. As mentioned before, the key efficacy data, 75% overall response rate and 69% CR rate across all dose levels, a 100% ORR and CR rate in 5 out of 5 large B-cell lymphoma patients relapsing after prior autologous anti-CD19 CAR-T therapy, an 86% CR rate in large B-cell lymphoma patients across dose level 3 and above, with a 75 CR rate in large B-cell lymphoma across all dose levels. Both dose level 2 and dose level 3 demonstrate that 33% 6-month CR rate and we are continuing to follow patients in dose level 4 to assess 6 months durability. And finally, as I just discussed, we have observed circulating ADI-001 cells visible through day 28 in peripheral blood at dose level 4. In light of these data, we see a potential for best-in-class overall response rate, CR rate and durability given the antitumor activity offered by gamma delta 1 CAR T cells. Enrollment is currently ongoing to provide additional durability data and further support the recommended Phase 2 dose. Our current assumption for the recommended Phase 2 dose is one of the higher dosing cohorts, dose Level 4 or dose level 3 at day 1 and 7. But we expect to confirm the durability data prior to initiating the first pivotal study, which is currently planned for the second quarter of 2023. Let me conclude by talking briefly about the pivotal plan on Slide 16. Based on these FIH findings, we expect a potentially comprehensive pivotal plan for ADI-001, across NHL subtypes and lines of therapy. We believe there is a significant unmet need for an effective therapeutic option for patients who progressed following autologous CAR T therapy. To address that population, we expect to start our first potential pivotal study, leveraging ADI-001's impressive efficacy data in these patients post autologous CAR-T. These patients have no effective therapeutic option and potentially provide an accelerated path to first registration. Based on our preliminary 100% ORR and CR rate in these patients, including 2 CRs in patients with a prior PR to autologous CAR T, we expect to approach the FDA to discuss testing ADI-001 in a potentially pivotal single-arm clinical trial in post CAR T large B-cell patients. We currently expect the primary endpoint to be ORR and the number of patients to be enrolled into the study in the double-digit range. Of course, the FDA will review the available durability data at the time of BLA submission. In summary, we are extremely encouraged by this early data. There is a significant unmet need into the post CAR T large B-cell population and we look forward to advancing ADI-001 into a pivotal study in this indication as well as potentially in the second pivotal study in earlier line large B-cell lymphoma. With that, I will now turn the call back over to Chen and move to Slide 17.

Thank you, Francesco. Sattva, thank you for joining us today. We look forward to hearing your thoughts on a few questions that have been on top of mind for investors.

Thank you, Chen.

So why don't we go to Slide 18, and we're going to start with the first question. The first question we'd like to address is regarding durability. I realize this is early in the study. But based on your experience, can you comment on ADI-001 durability data to date?

Yes, sure. So to my knowledge, the CR rate observed in the study is the highest reported in Phase 1 study in large B-cell lymphoma patients. The CRs have been observed at all dose levels starting from a rather low dose of 30 million CAR-positive cells. Both dose level 2 and in dose level 3, we are seeing durability at 6 months of about 33%. In dose level 4, there is not yet sufficient follow-up time. The 6-month durability of 33% that we are observing is comparable to the durability reported for approved autologous CD19 CARs. I think it is especially promising to see CRs in patients relapsing after autologous CARs as there are currently no established therapeutic options in these patients.

Thank you, Sattva. Why don't we move to our second question on Slide 19. Perhaps you can comment on the response rate across all dose levels in the study to date.

Yes. So each dose cohort has a very small N. So it is important to look at the CR rate in totality. At dose level 1 and dose level 2, 2 out of the 3 patients responded for a CR rate of 67%. At dose level 3, 3 of 3 patients had responded for a 100% CR rate. So I think this is probably an outlier on the high side. At dose level 4, 3 of 6 patients had a CR for a 50% CR rate. This is probably an outlier on the low side. But it's also important to note that at dose Level 4, as Francesco mentioned, had 1 radiological PR as per central read, but as per the investigator, this patient had an MRD-negative status and was assessed as a complete remission. So an investigator CR rate in dose level 4 is about 67% at this point. In totality, we see 11 of 16 patients had a CR for a 69% CR rate across all patients on the study to date, which compares favorably to autologous CARs. If you look at the LBCL, large B-cell lymphoma cohort, which included 12 of 16 patients on the study to date, the CR rate is overall consistent across all cohorts. At dose level 1, it was 67%; dose level 2, it was 50%, and dose level, it was 100%, and at dose level 4 was 67% for an overall CR rate of 75%.

Thank you, Sattva. This leads me to the next question on Slide 20. Can you comment on the unmet medical need for patients progressing following the currently approved autologous CAR-T therapy?

The patients with large B-cell lymphoma relapsing after autologous CD19 CARs have a significant unmet need. There are currently no effective therapies for these patients who have a median overall survival of approximately 6 months. In clinical practice, the observed response rates are in the 20% to 40% range with various therapies in this post CAR-T patients with a median PFS of only about 2 months. So current therapies do not really seem to offer significant benefits in terms of survival in these patients. It is very encouraging to see a 100% CR rate with ADI-001 in post CAR-T patients in large B-cell lymphoma. Autologous CD19 CARs are now approved in third-line and second-line non-Hodgkin lymphoma settings, but most of the patients unfortunately progress. I think ADI-001 may offer an attractive treatment option for these patients.

Thank you, Sattva. So let's go to our final question on Slide 21. Can you comment on the potential opportunity for ADI-001, in earlier-line LBCL patients.

I think there is significant potential for ADI-001 in earlier lines of therapy. And it derives from some of the key features we have observed to date. As I mentioned, the CR rate in the study is the highest reported in a Phase 1 study in relapsed/refractory large B-cell lymphoma patients. And preliminarily, it has a very favorable safety profile. So it is expected to be well tolerated by most patients. It is off the shelf, so readily available to patients without any need for delay or bridging therapy, and this is critical for patients with aggressive disease. It is fully allogeneic, therefore, not directly impacted by prior chemotherapies or the immune function of the patient. It could, in principle, be provided in second-line setting or in first-line patients that are high risk. The company is working on the specific designs of the studies.

Sattva, thank you for joining us today and for providing your thoughts on the call this morning.

Thank you, Chen.

So let us move to talk about the next steps for the ADI-001 program on Slide 23. Looking ahead, we expect to continue enrolling patients in the Phase 1 study and obtain additional durability data to further support the recommended Phase 2 dose. We plan to provide at least one clinical update for ADI-001 in the first half of 2023. We also plan to meet with the FDA and EMA to discuss the pivotal program and potential path to BLA and MAA for ADI-001, in particular, we expect that our first potential pivotal study will be post-CAR-T LBCL patients. We currently plan to begin this study in the second quarter of 2023. We also look to evaluate a potential second pivotal study in earlier line LBCL patients, which may start with a Phase 2 running. Stay tuned for more information in the coming year. Given the clinical activity demonstrated with ADI-001, we plan to look for opportunities for future expansion in additional NHL subtypes. We're extremely excited about the potential for ADI-001 to help many more NHL patients across different lines of therapy. And we believe there is significant market opportunity for ADI-001, as you can see in the next few slides. Let's go to Slide 24 and discuss the potential in post-CAR-T LBCL. So given the 100% CR rate that we mentioned was demonstrated in LBCL patients that progressed following autologous CAR-T, it is time to turn our attention to fully understand the unmet medical need in this patient population and the impact and market opportunity that ADI-001 can have in this patient population. Let's start with the number of patients. So as Dr. Neelapu mentioned, autologous CAR-T therapies are now approved both in third line and in second line LBCL. So let's talk about numbers. According to a recent publication in leukemia and lymphoma, which forecasted the incidence of DLBCL, we expect 5,700 treatment-eligible third-line DLBCL patients in the U.S. in 2025. In Western Europe, the corresponding number is 5,300 patients. Autologous cell therapies are approved for these patients, but unfortunately, 70% of these patients experience disease progression. Moving to second Ideal BCL, where autologous CAR-T were approved earlier this year in the U.S., it is estimated that there will be 13,400 treatment eligible second-line DLBCL patients in the U.S. in 2025. In Western Europe, the corresponding number is 11,900 patients. Some of these patients may benefit from autologous CAR T therapy per their approved label. But unfortunately, 60% of these patients experience disease progression in the second-line study. So let's describe the unmet medical need in this patient population, moving to Slide 25. Unfortunately, there is no effective therapy for patients who progress on autologous CD19 CAR-T. The median overall survival for these patients is approximately 6 months. And this is a growing patient population, what therapy will these patients take? We're very excited about the 100% CR rates demonstrated by ADI-001 in LBCL patients that progressed on autologous CAR-T. We are fully committed to rapidly progressing to a pivotal study and potentially to BLA and MAA to address these very significant unmet medical need. Let's move to Slide 26. The first pivotal study is expected to be in LBCL patients that progressed on autologous CAR-T, as we mentioned, let's talk about the potential market opportunity here. So starting with the number of patients, as we mentioned, 70% of third line and 60% of second-line LBCL patients that received autologous CAR-T will experience a disease progression. The overall survival in this patient population is at 6 months. And as I mentioned, ADI demonstrated 100% CR rate in this patient population. We believe there is significant and growing market opportunity here where ADI-001 has the opportunity to become the drug of choice, if approved. Regarding our potential second pivotal study in earlier line LBCL, we expect to provide additional guidance next year. So why don't we move to Slide 27. As we discussed during our virtual R&D event last month, we have built a broad pipeline of CAR and Cad gamma delta T cell product candidates, including ADI-925, our first-in-class Cad gamma delta T cell program for multiple hematological and solid tumors. We're very excited about our preclinical programs and look forward to providing you with more information in the year ahead. As we've said in the past, we currently plan and are on track to file at least 1 IND every 12 to 18 months, starting with IND for ADI-925 in the second half of 2023. So to summarize, let's move to Slide 28. Let's focus on the big picture of what we've learned today for ADI-001. Overall response rate, 75%; CR rate, 69% across all cohorts. The difference is 1 PR in DL4 by central radiological assessment. And as mentioned earlier, this response was reported by the investigator as MRD-negative CR. This CR rate is among the highest rates in autologous and allogeneic CAR-Ts and bispecifics in advanced setting of aggressive lymphomas. Durability, in the dose levels where we can measure, 6-month CR, namely DL2 and DL3, ADI-001 demonstrated a 33% 6-month CR rate, generally, as mentioned by Dr. Neelapu comparable to autologous CAR-T in third-line advanced setting of aggressive NHL. Persistence, we see it increasing to 28 days by flow cytometry in DL4. Safety, no DLTs, no GvHD, no grade 3 CRS, no grade 3 ICANS, and grade 3 infection rate generally more favorable to the one reported with autologous CAR-T in third-line settings. As to approval, 100% CR rate in post CAR-T LBCL patients who currently do not have an effective therapy and have a median overall survival of 6 months. We believe this will provide a potential clear path to BLA and MAA for our first planned pivotal study. These data are very exciting and demonstrates that ADI-001 has the potential to generate meaningful responses in patients where other therapies have failed. We're also well-funded with approximately $282 million in cash and cash equivalents as of the end of the third quarter of 2022 and are well capitalized into the first half of 2025. We look forward to updating you on our progress as we work to make a difference in the lives of cancer patients advancing ADI-001 and our pipeline of engineered gamma delta T cells. With that, I'll turn it back to the operator to open it up to Q&A. Operator?

Please note that this call is being recorded. [Operator Instructions] Our first question comes from Michael Schmidt from Guggenheim.

Super interesting data. And can you maybe comment a bit more about your thoughts on the recommended Phase 2 dose? Obviously, you haven't seen a lot of follow-up yet on dose level 4 patients. Any thoughts you have here would be greatly appreciated. And how confident are you that you will not need retreatment given, obviously, that 1 of the 2 long responders was indeed retreated at dose Level 3?

Sure. I'll take that question. As I mentioned during my presentation, we currently have 2 regimens under consideration for recommended Phase 2 dose. One is dose level 4, which is 1 billion cells in single administration and one is the Part 1b, that we call it, which is dose level 3 given 1 week apart under 1 lymphodepletion. We are characterizing both regimens. And our prediction is that the final decision will be between 1 of the 2. We will have a sufficient response rate, safety information, of course, and also durability data to refine our thinking in time for the execution of the study. So we are collecting the data, and we will keep you posted. Regarding your other question of the need or potential need of a redosing, we really don't expect that they would be necessary. As you have seen in our data set actually from the very early days of the study, including relatively low dose levels, we are very deep and rather prolonged, we now know rather prolonged durable responses. So we don't expect the second dosing to be necessary. Remember that we dosed those 2 patients with another round of lymphodepletion in dose level 3 on an exploratory basis, those 2 patients who are in MRD-negative CR when they were redosed. It was an exploratory activity that we thought we wanted to execute during dose level 3 on our way to dose level 4. So we are not planning to move forward with a double lymphodepletion regimen because it's not necessary and it's certainly heavy on the patient.

Yes, Michael, just one thing to add here. Unlike many other companies that you may know that go with some kind of consolidation dosing to essentially maintain response or deepen response that patient that you referred to was provided a second dose of ADI-001, while in an ongoing MRD-negative complete response, there was no cancer in that patient, it was purely to understand PK and safety.

Okay. And then maybe just a follow-up. When you look at those patients with long-duration CRs versus the ones that progressed earlier. Is there any correlation of PK or AUC in terms of the cells in circulation?

Yes. That is obviously a very important question. Our aim is too small to identify any correlation of any kind. But we're obviously collecting all the data that we can and when the N increases to a certain level, we might be able to identify some predictor or response predictor durability. But our current data set is too small to make that search possible for now. Of course, the moment we can we'll obviously start looking for correlations with PK, with clinical features, et cetera.

Yes. Michael, to remind you, in dose level 1, one of the first patients that we treated had very significant tumor burden and is still cancer-free 14 months after the study and had barely a blip of a PK in the blood. So keep in mind, a lot of these cells are in the periphery.

Our next question comes from Asthika Goonewardene from Truist.

Some very interesting data here. Maybe I had a couple of questions. I had a couple of questions for Dr. Neelapu and then one for you Chen and Francesco. Dr,. Neelapu, I was wondering if the post-CAR T setting, what is the minimum bar for what you would like to see and in terms of efficacy? And what kind of data would make you really excited?

Yes. So I think in the post CAR T setting, as I mentioned, currently, it means no effect to therapeutic options. So with the existing regimens, we are seeing median PFS of only about 2 months. So I think if we see a durability of about 30% at 6 months, to me, that would be a home run. Obviously, all of us would like to see much higher, but I think that would make a significant different impact for these patients. I'm sorry, what your second question was...