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. 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, express or implied statements regarding the potential safety, durability, tolerability, and efficacy of ADI-001.
Future progress of Adicet's phase I 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 II 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 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'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. 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 I clinical study of ADI-001 in patients with aggressive non-Hodgkin's lymphoma or NHL. Like me, I know you all like your data cuts fresh, 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 I data as of the December fifth data cut date. Dr. Neelapu will provide his perspective on the data. 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. Why don't we start with slide five?
Since our founding in 2014, we have led the field of discovering and developing off-the-shelf engineered gamma delta T-cell therapies 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 three 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 gratifying 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 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 first 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 six 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 four 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 12-18 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 2022, and are well capitalized into the first half of 2025. Let's move to slide six. Let me summarize what we have observed with ADI-001 as of our December fifth cut-off date. We continue to see encouraging early efficacy in heavily pre-treated 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 five out of five large B-cell lymphoma or LBCL patients relapsing after prior autologous anti-CD19 CAR T therapy. An 86% CR rate in LBCL patients across DL 3 and above. The CR rate in LBCL across all dose levels is 75%. In both DL 2 and DL 3, we saw a 33% 6-month CR rate. We continue to follow- up on patients in DL 4 to assess the six-month durability. In DL 4, 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. We also plan to evaluate the potential for a second pivotal study in earlier line LBCL patients. Stay tuned for more details on this second potential pivotal study next year. Why don't we move to slide seven? We're very encouraged by the clinical data and excited to see what we believe is the underlying biology of gamma delta T- cells through its three 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 I 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 me give you a quick reminder of the first human study design on slide nine. As you can see, the dose escalation portion of the study includes four dose levels, starting at a rather low flat dose of 30 million CAR-positive cells and continuing on to 100 million, 300 million, and 1 billion flat dose of CAR-positive cells. 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 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 dose escalation decisions. One exploratory section of the protocol, which we call part 1b, includes patients receiving a single lymphodepletion and two infusions of DL 3 at 300 million CAR positive cells on day one and seven, 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 one 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 characteristic table on slide 10. Of our 16 evaluable patients so far, 12 had relapsed or refractory large B-cell lymphoma, including one double-hit and one triple-hit high-grade B-cell lymphoma. Three patients had re-relapsed refractory mantle cell lymphoma and one follicular lymphoma. All patients were heavily pretreated with poor prognostic factors and relatively high tumor burden. Most patients were stage three or four.
The median number of prior therapies was four, and the median IPI prognostic score was three 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. Six patients, five large B-cell lymphomas and one mantle cell lymphoma, had previously relapsed after autologous CD19 CAR T therapy. Again, it's important to point out that our data set includes 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 three or above. The reported CRS were all grade one, apart from one grade two in a patient with COVID, which we reported previously. We had one grade one ICANS, which resolved 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 enhanced 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%. The 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 those level three and above, six complete responses out of seven evaluable patients. Across all those levels, the CR rate in large B-cell lymphoma was 75%, nine out of 12.
All five 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 three mantle cell lymphoma patients, one in dose level two and two in dose level four. 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 showed a radiological partial response at day 28. This last patient is actually MRD negative per local assessment. At the option of the investigator, the patient is in clinical complete remission at this time.
We are 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 one 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 four. 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 two patients in dose level three, while in MRD negative CR, received a second infusion of ADI-001 at 300 million cells in dose level three after a second round of standard lymphodepletion, three and two months after the first infusion, respectively. Out of these two patients, Sorry, one of these two patients is still in complete response and doing well. The other patient developed a viremia that led to death five months after the first infusion, unrelated to ADI-001. The patient had progressed after four lines of therapy and received a total of three lymphodepletions, one for the autologous and two 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 lymphodepletions in the ADI-001 program. We have also started to dose a cohort of patients that is shown on the slide as dose level three, day one and seven. We call it part 1b in the protocol. These patients received two doses of 300 million CAR positive cells one week apart after one single round of lymphodepletion. This is a regimen that we are evaluating for possible recommended phase II dose together with dose level four. As you can see on the diagram, the first evaluable patient in this cohort shows a complete response currently ongoing almost three months after the beginning of treatment with 001. In part 1b and in dose level four, the new large B-cell lymphoma patients show three complete responses out of four evaluable patients.
The only non-responder 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 four, 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 a radiological CR. We'll keep you updated. Regarding durability, both dose level two and dose level three demonstrate a 33% six-month complete response rate, which is comparable to durability of approved autologous CAR T's for late-line aggressive non-Hodgkin lymphoma. Patient follow-up continues in dose level four to assess six months durability.
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. These patients are very high unmet need in non-Hodgkin lymphoma. Let's move on to slide 13. This diagram illustrates the well-described 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 1 from other lymphocytes. In the peripheral blood, gamma delta 1 cells are commonly 1%-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 robust expansion of ADI-001 as measured in the peripheral blood at the higher dose levels, with peak results occurring between day seven and 10, and persistence for dose level four visible through day 28 as measured by flow cytometry.
We're also starting to explore the PK profile in patients receiving the two separate dose level three doses one week apart, the part 1b of the protocol that I mentioned. 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 cell's tropism for tissues. It should also be noted that exposures starting at dose level two are already associated with durability beyond six 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 human study with no GvHD, no DLTs, and no grade three 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. I've 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 five out of five 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 three and above, with a 75% CR rate in large B-cell lymphoma across all dose levels. Both dose levels two and dose level three demonstrate a 33% six-month CR rate, and we're continuing to follow patients in dose level four to assess six-month durability.
Finally, as I just discussed, we have observed circulating ADI-001 cells visible through day 28 in peripheral blood at dose level four. In light of these data, we see a potential for best-in-class ORR, CR, 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 II dose. Our current assumption for the recommended phase II dose is one of the higher dose in cohorts, dose level four or dose level three at day one and seven. 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 progress at 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 two CRs in patients who had a prior PR to autologous CAR T, we expect to approach the FDA to discuss testing 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 these 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 a second pivotal study in earlier line large B-cell lymphoma.
With that, I'll 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.
Why don't we go with slide to slide 18. We're gonna 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?
Yeah, sure. to my knowledge, the CR rate observed in the study is the highest reported in phase I 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. In both dose level two and in dose level three, we are seeing durability at six months of about 33%. In dose level four, there is not yet sufficient follow-up time. The six-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. Each dose cohort has a very small N, so it is important to look at the CR rate in totality. You know, at dose level one and dose level two out of the three patients responded for a CR rate of 67%. At dose level three of three patients had a, you know, responded for a 100% CR rate, so I think this is probably an outlier on the high side. At dose level four, three of six patients had a CR for a 50% CR rate. This is probably an outlier on the low side. It's also important to note that at dose level four, as Francesco mentioned, had one, radiological PR as per central read, but as for the investigator, this patient had a MRD negative status and was assessed as a complete remission.
An investigator CR rate in dose level four 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 one, it was 67%. Dose level two, it was 50%. At dose level three, it was 100%. At dose level four, it 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?
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 six months. In clinical practice, the observed response rates are in the 20%-40% range with various therapies in these post-CAR T patients, with a median PFS of only about two months. 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, most of the patients unfortunately progress. I think ADI-001 may offer an attractive treatment option for these patients.
Thank you, Sattva. 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 this study is the highest reported in a phase I study in relapsed/refractory large B-cell lymphoma patients. Preliminarily, it has a very favorable safety profile. It is expected to be well-tolerated by most patients. It is off the shelf. Readily available to patients without any need for delay or bridging therapy. 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, you know, 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.
Let us move to talk about the next step for the ADI-001 program on slide 23. Looking ahead, we expect to continue enrolling patients in the phase I study and obtain additional durability data to further support the recommended phase II 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 in 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 II 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 therapies, 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.
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. As Dr. Neelapu mentioned, autologous CAR T therapies are now approved both in third line and in second line LBCL. Let's talk about numbers. According to a recent publication in Leukemia & 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. Unfortunately, 70% of these patients experience disease progression. Moving to second-line DLBCL where autologous CAR T were approved earlier this year in the U.S., it is estimated 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 therapies per their approved label. Unfortunately, 60% of these patients experience disease progression in the second-line setting. 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 six months, and this is a growing patient population. What therapy will these patients take? We're very excited about the 100% CR rate 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 needs. 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. Starting with the number of patients, as we mentioned, 70% of third-line and 60% of second-line LBCL patients that receive autologous CAR T will experience a disease progression.
The overall survival in this patient population is at six months. As I mentioned, ADI demonstrated a 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 that drug of choice if approved. Regarding our potential second pivotal study in earlier line LBCL, we expect to provide additional guidance next year. Why don't we move to slide 27. As we discussed during our virtual R&D event last month, we've 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 one IND every 12-18 months, starting with IND for ADI-925 in the second half of 2023. 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 one PR in dose four 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 is specific in advanced setting of aggressive lymphoma. Durability.
In the dose levels where we can measure six-month CR rates, namely dose two and dose three, ADI-001 demonstrated a 33% six-month CR rate. Generally, as mentioned by Dr. Neelapu, comparable to autologous CAR T in third line advanced settings of aggressive NHL. Persistence. We see it increasing to 28 days by flow cytometry in dose four. Safety. No DLTs, no GvHD, no grade three CRS, no grade three ICANS, and grade three infection rate generally more favorable to the one reported with autologous CAR T in third line settings. Path to approval. A 100% CR rate in post-CAR T LBCL patients who currently do not have an effective therapy and have a median overall survival of six months. We believe this will provide a potential clear path to BLA and MAA for a first-planned pivotal study.
These data are very exciting and demonstrate 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 equivalent 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 in 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?
We will now begin the Q&A session. Please note that this call is being recorded. If you have joined via the audio line, please press star nine. Questions will be answered in the order they are received. We will now pause a moment to assemble the queue. Our first question comes from Michael Schmidt from Guggenheim. Michael, please go ahead.
Hey, guys. Thanks for taking my question.
Hey, Michael.
Super interesting data. Super interesting data. Can you maybe comment a bit more about your thoughts on your recommended phase II dose? Obviously, we haven't seen a lot of follow-up yet on dose level four patients. You know, any thoughts you have here would be greatly appreciated. How confident are you that you will not need a retreatment given obviously that one of the two long responders was indeed retreated at dose level three?
Sure. I'll take that question. As I mentioned during my presentation, we currently have two regimens under consideration for recommended phase II dose. One is dose level four, which is 1 billion cells in single administration, and one is the part 1b, like we call it, which is dose level three, given one week apart under one lymphodepletion. We are characterizing both regimens, and our prediction is that the final decision will be between one of the two. We will have sufficient response rates, safety information, of course, and also durability data to refine our thinking in time for the execution of the study. 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 would be necessary.
As you have seen in our data set from... actually from the very early days of the study, including relatively low dose levels, we have very deep and rather prolonged, we now know, rather prolonged durable responses. We don't expect the second dosing to be necessary. Remember that we dosed those two patients with another round of lymphodepletion in dose level three on an exploratory basis. Those two patients were in MRD negative CR when they were redosed. It was an exploratory activity that we thought we wanted to execute during dose level three on our way to dose level four. We are not planning to move forward with a double lymphodepletion regimen because it's not necessary and it's certainly heavy on the patients.
Yeah, Michael, just one thing to add here. Unlike many other companies that you may know that go with some kind of a consolidation dosing to essentially maintain a response or deepen a 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. 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, you know, PK or AUC in terms of the cells in circulation?
That is obviously a very important question. Our N 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 of response, predictor of durability. Our current dataset 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.
Yeah. Michael, to remind you, in dose level one, 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 bleak of a PK in the blood. You know, keep in mind, a lot of these cells are in the periphery.
Great. Thank you.
Thank you.
Our next question comes from Asthika Goonewardene from Truist. Go ahead, Asthika.
Hey, guys. Good morning. Thanks for taking my questions, Chen and Francesco, on some very interesting data here. Maybe I have got a couple of questions. Hi. Morning. I got 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? What kind of data would make you really excited?
Yeah. I think in the post-CAR T setting, as I mentioned, there's currently no effective therapeutic options. With existing, you know, regimens, we are seeing median PFS of only about two months. I think if we see a durability of about 30% at six months, that would be, 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. Now, I'm sorry, what your second question was?
The second question that I have is, have you got any post-treatment biopsies, maybe from lymph nodes, et cetera, that might give you some clinical anecdotes on how well ADI-001 infiltrated? I'm also wondering, the skin lesion in that patient that occurred on dose one, Were you able to confirm the presence of gamma delta T- cells in that lesion after it was treated?
Yeah. Yeah. I think I'm gonna have Francesco answer this one because he knows this patient, much better, than perhaps.
Yeah. Regarding the biopsy, we do have a per protocol biopsy scheduled on day 10, and we try to collect as many samples as possible. The problem is that in most cases, by day 10, there's nothing to biopsy because the responses are typically occurring early on after the dosing. By day 10, more often than not, there's really not much to biopsy. We're collecting the data, and we'll keep you posted once we have enough. Regarding the skin lesion, we know that it was histologically confirmed to be tumor tissue. It was CD20 positive. We are not able to...
I mean, that particular biopsy was not assessed for the presence of gamma delta cells because logistically, the biopsy occurred not at the site where the patient was being followed, but the patient was remote at that time. We don't have access to the actual tissue block. We know it was tumor, we know it was CD20 positive. I don't have the answer to your very good question on the presence of gamma delta cells.
Okay. Just a quick one, guys, Chen and Francesco. You filled at dose level four. You have one patient in the modified dose level three. How many more patients will you aim to enroll into this modified dose level three, and how many would you like to backfill into dose level four? I guess related to that, beyond the efficacy evaluable patient presented in the slide today, have you dosed any other patients in the subsequent dose levels?
Yeah. We don't have specific numbers, other than saying that for the part 1b, the modified dose level three, we'll have a minimum of three patients in that. We could be more. We don't know exactly, but that's the protocol is written as a dose escalation for that component. We'll have a minimum of three patients for that cohort.
Great. Thanks so much for taking my questions, guys.
Thank you.
Our next question comes from John Newman from Canaccord. John, go ahead.
Hi, guys. Thanks for taking my question. really nice data update here. I had a question for Dr. Neelapu, perhaps as well as for the Adicet team. I just wondered if you could comment on your thoughts regarding the CD20 target itself in lymphoma versus CD19. You know, we've always thought that the stability of CD20, among other things, could be advantageous. Given the data we've seen over the years with CD19, just curious if you could give us your thoughts on the approach here where you're going after CD20 versus some of the earlier work for CD19. Thanks.
I think if you look at expression-wise, in fact, the CD20 expression, both the transcript and protein levels, antigen density tends to be higher in lymphomas in general, including large B-cell lymphoma. When we looked at patients relapsing after prior CD19 CAR, we see about 95% of these patients have, still have CD20 expressed on the cell surface. Following anti-CD20 antibody-based therapies, we still see persistence of the CD20, you know, in these patients, more than 95%-98% of the time. I think both from an antigen density perspective and given the broad expression, across different B-cell lymphomas in general, I think CD20 remains a very good target, both for antibody approaches as well as the CAR approach.
Why was CD19 dollar for CAR? I think that's an open question. I think, one of the initial thinking was that CD19 is also expressed in precursor B cells, but not in, but not so for CD20. It's applicable for both ALL and B-cell malignancies, whereas CD20 would be applicable mostly for B-cell lymphomas.
Okay. Thank you. Okay. Thank you.
A reminder, if you have a question, you may dial star nine to activate the raise hand. Our next question comes from Reni Benjamin from JMP. Reni, please go ahead.
Hey, good morning, guys. Thanks for taking the questions. I'd love to just kind of probe a little bit. What are your thoughts on why the patients are relapsing, you know, in these cases? Are there any additional parameters that you're looking at that could be modified to improve persistence? I have a follow-up.
Yeah, we are characterizing these relapses, and we currently don't have any real data, as I mentioned earlier in another context. The N is so small that we're starting to collect the data, and we are monitoring the relapses and, you know, we'll collect the data and try to find correlates. For now, we just don't know. It's not surprising that at some point some patients might relapse, but we just don't know. Regarding modifications or things that we could implement to improve durability, right now we are, you know, we go stepwise, the single-dose response rate and durability seems to be pretty good already.
I can't exclude that in the future we might play around with the regimen further, but I think we have very solid grounds to establish a pivotal path, at least for our initial pivotal trials. We are currently, as I mentioned, considering, and I'm really transparent here, we are considering. We don't know the answer. We are considering the part 1b regimen as a potential way to maybe improve on the PK. We don't know if that is actually true yet because we only have one patient, as you have seen on the plot. That is under consideration exactly for the reason you said, trying to adapt the regimen to maximize PK coverage, to maximize maybe response rate and durability.
I think just want to add on this. I mean, most likely, almost 100% of the tumor killing is done in the first few weeks. If you provide a hefty dose of DL 4 single dose or two doses of DL 3, you know, one week apart, most likely by day 28, there is a fair chance, as you know, that you'll turn into a CR, and most of the patients are CR and potentially a durable CR as we've seen in DL 2 and DL 3 with 33% of the patients.
Got it. My other question is just in regards to the patient journey. You know, are patients being hospitalized after infusion or because there are no ICANS, no GvHD and the like, this is largely outpatients. Are patients being treated prophylactically with tocilizumab? I guess for Dr. Neelapu, you know, what is the OS of CAR T patients who have a response less than six months versus those that have, you know, a CR greater than six months?
Let's start with the first part.
Yeah. I'll take the first part, and then Sattva, you can address the second part. First of all, the patients are not pre-treated. Obviously, we do have in the protocol provisions to allow the physicians to use the normal approach should CRS of some severity occur, including the use, if necessary, of toci. That has never happened on the study, with the only exception of one patient who had toci as part of the management of COVID syndrome. The unfortunate patient that you might recall in dose level one who had a rather spectacular response, but unfortunately later succumbed to COVID. That patient received toci, but the IL-6 peak that we saw in that patient was related to the COVID syndrome.
The overall quality of the experience, shall we say, we are told in these early days of the trial, is rather good for the patients. There are minimal to absent findings safety-wise and tolerability-wise. You are correct, the patients are admitted to the hospital for now. With this safety profile, we plan to release that type of provision very soon because I think we have a very compelling safety profile. In the grand scheme of things, I think this is a drug that if it continues like this, will be very easily positioned in the community centers, where you don't need a particularly complicated setup. If the safety profile on larger N confirms to be benign as we have seen so far. I'll pass it on to Sattva for the other part of the question.
With regards to, you know, the OS at six months, I'm not aware of any data, but in general, majority of the relapses of the auto CAR tend to occur within the first three months. And the median survival, you know, as we shared with you in the publications, is about six months in post-CAR T relapses. If the relapse, what's been looked at in terms of survival is that if there is a progression event within the first 12 months, then only 5% of those patients survive it or alive at five years. Whereas if they do not have a progression event in the first 12 months, 95% of them are still alive at five years.
I think, you know, the progression within the first year, it indicates a major unmet need, because most of those patients die of progression of disease.
Great. Thank you for taking the question.
Thank- thank-
Our next question comes from Kelly Shi from Jefferies. Kelly, please go ahead.
Thank you for taking my questions. My first question is, I wonder if you could share more color on the potential pivotal trial design. Regarding the post-CD19 CAR patients, do you refer to the respon-- I mean, the patients who responded to the previous CD19 CAR T with the PR/CR are also, would you also include also the patients who actually had only insufficient response like stable disease to the previous CD19 CAR T? The relevant question to this is for the five post CD19 CAR T you enrolled on the ADI-001 trial, what has been their responses to the previous CD19 CAR T? How many PR and how many CR? Also, just one more for the pivotal trial design.
Would you exclude the prior CD20 engaged or treated patients? Thank you.
Okay. Many questions. I hope I can remember them all. First of all, for the first. Correct me if I miss something. First, for the first pivotal design, the current thinking is to have a relatively straightforward, I must say, single-cohort pivotal intent study with a sample size that in our prediction should be in the double digits, so less than 100 patients. That's the general expectation. We expect the endpoint to be overall response rate. Of course, the FDA will have to chime in here, but that's our expectation. The bar is relatively low for the reasons that Sattva just discussed. In pivotal territory, it's a relatively straightforward design without any need of a control arm and without any particularly large or long enrollment need.
That's our current thinking, we are on our way to engage the FDA on those fronts. Your second question was regarding the prior therapy, sorry, the prior responses that our post-CAR T patients experienced when they received autologous. These are CAR T relapse patients, so by definition they had some form of response to their autologous. In particular, as I alluded to, there were two PRs. Two patients in the five had a best response to autologous, experienced a partial response. Three had experienced a CR, a complete response. All of the five responded as a CR to our treatment, which I think bodes very well for the future of that particular initiative. Your next question, I apologize, I forgot.
I think it was the CD20, CD3. Kelly, you might have seen in the ASCO there were two publications regarding the CD20 expression in patients that progressed from CD20, CD3 with.
Oh, yeah.
Tenets very similar to initial diagnosis in the 93%-95% from both publications at the most recent ASCO. I think one last question, Kelly, if you have one, and then I think we're after the top of the hour, so we'll conclude. Do you have a follow-up question, Kelly?
No, that's all. Thank you.
Okay. Thank you.
Perfect. Thank you.
Great. Well, thank you all for joining us today, and we look to provide you with future updates.
Thank you.
Have a good rest of your day.
Bye-bye.
Bye-bye. Thank you.
That is the end of today's call. Thank you all for joining. Goodbye.