Allogene Therapeutics, Inc. (ALLO) Earnings Call Transcript & Summary

Hello, and welcome to the Allogene Therapeutics CD19 Forum. My name is Christine Cassiano, and I'm the Chief Communications Officer at Allogene. As this forum and the upcoming ASCO 2021 Annual Meeting are being held virtually by necessity, I'd like to take a few moments to talk about what we have in store for today. First, we'll be making certain forward-looking statements during this program. These may include statements regarding the success and timing of our ongoing and planned clinical trials, data presentations, regulatory filings and future research and development efforts, among other things. These forward-looking statements are based on current information and assumptions and expectations that are subject to change. Please also review our forward-looking statement in the slide deck, which will be accessible on our website in the Investor Relations section at the conclusion of this presentation and a full description of potential risk factors found in our latest SEC filings. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. Shortly after the conclusion of our CD19 Forum, you will also be able to find content from today's presentation as well as a video replay on our website. Our lead program targeting CD19 is perhaps the most advanced allogeneic CAR T program in the field. Today's forum will highlight the latest results from our ongoing Phase I trials of ALLO-501 and ALLO-501A and ALLO-647. These data sets will also be poster presentations at the American Society of Clinical Oncology Annual Meeting in June. I'd like to walk you briefly through our agenda and introduce our speakers. We will start our prerecorded sessions with Dr. David Chang, our CEO, President and co-Founder, who will discuss the strategy we are pursuing and our vision for what's possible as we begin to demonstrate the unique benefits of allogeneic cell therapy. Next, Our Executive Vice President of Research and Development and Chief Medical Officer, Dr. Rafael Amado, will set the stage for what will be presented from our ALPHA and ALPHA2 studies on ALLO-501 and ALLO-501A, respectively. We'll then welcome Dr. Frederick Locke, the co-leader of the Moffitt Immuno-Oncology Program and the Vice Chair and Associate Member of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center. Dr. Locke, an investigator in the ALPHA studies, will be discussing updated data on ALLO-501. He will then be followed by Rafael, who will walk us through the first look of interim data from the ALPHA2 trial of ALLO-501A, and safety, biomarker and correlative analysis on ALLO-647, an antibody that anchors our proprietary approach to lymphodepletion. Rafael will then moderate a session on the future of allogeneic CAR T therapy in non-Hodgkin's lymphoma, which will include Dr. Locke, Dr. Michael Tees, associate member physician at the Colorado Blood Cancer Institute and Sarah Cannon Cancer Center; and Dr. Lazaros Lekakis, Associate Professor of Clinical Medicine, Transplantation and Cellular Therapy at the Sylvester Cancer Center University of Miami Health System. It's our honor to have these leading KOLs with us today on behalf of all of the incredible investigators who are participating in our trials. As the final portion of our pre-recorded session, our Chief Financial Officer, Dr. Eric Schmidt, will provide some early perspectives on how the market views the opportunity for AlloCAR T therapies in non-Hodgkin's lymphoma. We will then move to a live session with a Q&A moderated by our CEO. Joining David in this session will be Rafael, Eric and Dr. Locke, Dr. Tees and Dr. Lekakis. While you're welcome to join us in listen-only mode, we'd like to offer the opportunity to ask a question during the event. I will serve as the operator for our Zoom Q&A session. [Operator Instructions] Before we start our official presentation, we'd like to share a video of someone who reminds us why Allogene exists. The patient in this video is more than just an illustration of what can be possible with AlloCAR T. The hope and trust that he has placed in us is symbolic of all of the amazing people who have chosen to participate in our trials. As we present data today, we'll look at many numbers but we must always remember the people behind the numbers. Their willingness to be a part of our trials and lead the way for others who may benefit down the road is heroic. They are the reason we have the opportunity to change the way cancer is treated. We're honored you took the time to join us today and I'd now like to introduce you to George. [Presentation]

And for that, I thank you, George. And every patient, we have the privilege of treating in our trials, remind us why Allogene exists and of our ultimate goal of making CAR T therapy available to many more patients in need. I'm Dr. David Chang, President, CEO and co-Founder of Allogene. I'm excited to speak to you today about our vision of what is possible as we begin to demonstrate the unique benefits of allogeneic cell therapy. In only 3 years since Allogene's founding, we have treated approximately 95 patients across 4 different AlloCAR T studies. We believe this is more than any other company in the space. With close to $1 billion in cash on hand and our own state-of-the-art manufacturing facility known as Cell Forge 1 completed, we are well positioned to maintain our leadership in the field. But we are not content with simply executing on our existing programs. We are passionate about innovation, and we are continuing to push forward platform advancements, including TurboCAR's novel ways of overcoming rejection, CAR T therapy in solid tumors and iPS drive approaches to cell therapy. We are incredibly proud that 2021 will feature multiple firsts for Allogene: our first combination trial, our first solid tumor trial, our first TurboCAR trial and more of what we will talk about today, potentially our first pivotal trial. Our lead program targeting CD19 and perhaps the most advanced allogeneic CAR T program in the field is today's focus. Our forum will highlight the latest result from our ongoing Phase I trials of ALLO-501 and ALLO-501A. But before we get into data and what it means to the field, I think it is important to talk about why progress in allogeneic cell therapy matters, patient access. What good is scientific innovation, even innovation that has the potential to radically change how we treat cancer, if patients cannot gain access to it? Our strategy is to exploit all of the inherent and unique benefits of allogeneic CAR T therapy, both from a clinical perspective as well as operationally so we can find ways to treat every eligible patient no matter how advanced their disease, where they live or how quickly they need therapy. So how do we get there? It all starts with innovation, a firm understanding of biology, creative thinking, access to gene engineering and leading process optimization capabilities. We believe these attributes will take us to a product profile that is well beyond what is possible with autologous cell therapy. Next is access. The potential to treat all eligible patients regardless of their lymphocyte counts, speed of disease progression or ability to tolerate recent chemotherapy, and to even be in position to consolidate or repeat dosing, if appropriate, without the need for complex logistics. Third is cost, scalable and efficient manufacturing with potential to treat 100 or more patients from a single manufacturing run, an opportunity to create product that can be used in all eligible patients in an HLA-independent manner with reduced ancillary cost of care. And finally, speed and reliability of an on-demand treatment. This benefit becomes very apparent as you look at the result from our trials as compared to autologous trials. The ability to treat every eligible patient on-demand matters, especially in the context of aggressive and rapidly progressing disease. The approval of first autologous cell therapy in 2017 turned skeptics into believers. We were able to show everyone that cell therapy was possible. It's time to do that again. Our vision with allogeneic cell therapy is to go beyond the boundaries of autologous and establish again the new standards for CAR T therapy. Today, we will show you data that demonstrate the potential of AlloCAR T therapy. Like autologous cell therapy, it can generate significant and durable responses with a onetime cell infusion. Our data will also show that our AlloCAR T platform may bypass the risk of graft-versus-host disease altogether and induce deep lymphodepletion that allows AlloCAR T cell expansion and persistence. As we optimize all levers at our disposal and continue our Phase I trials in lymphoma, we will not be constrained by the inherent limitations of autologous therapies. We believe we are in position to continue advancing our programs, including executing our plans to initiate a potentially pivotal study by the end of this year. Unlike autologous cell therapy, our allogeneic approach provides us with a spectrum of opportunities to achieve our ultimate goal of providing outcomes for more patients. Furthermore, the available safety profile of AlloCAR T therapies opens up the possibility of exploring dosing in an outpatient setting and potentially in the community setting that would significantly broaden the reach of cell therapy. And we won't stop at hematologic cancers. Our goal is to investigate the power of allogeneic CAR T therapy to solid tumors as well. While it is important to review the totality of the data, I would like to highlight for you a few case studies that show why we are excited about AlloCAR T therapy. The first is a 73-year-old male patient with recurrent large B cell lymphoma. This patient had failed 4 prior lines of therapy, including an autologous stem cell transplant. As we know from SCHOLAR-1 study, patients with these characteristics have a poor prognosis. This patient enrolled in the ALPHA study in late 2019 and was treated with ALLO-501 at the 120 million cell dose. He achieved a complete response and now represent one of the longest ongoing responders in our trial at 15-plus months. His experience highlights the dramatic outcome that can be achieved with a single infusion of AlloCAR T therapy. Our consolidation regimen allows patients who have not progressed after initial dose of cell therapy to receive a second scheduled administration of AlloCAR T cells with the goal of eliciting or deepening their response. We know that initial depth of response is perhaps the best predictor of long-term outcomes. Yet in clinical trials on autologous cell therapies, 1/2 or more patient fail to achieve a complete response. Our next patient highlights what is possible using this strategy. This 66-year-old male has Stage IV large B cell lymphoma, and as you can see, had a number of lesions in chest and abdomen. Based on the International Prognostic Index for lymphoma, he was deemed high risk. We treated patient with an initial dose of 120 million cells of ALLO-501A, following lymphodepletion with 60 milligrams of ALLO-647 and flu/cy. The patient had a partial response at day 28, making him eligible for a second scheduled dose of ALLO-501A, also at 120 million cells but this time, with lymphodepletion consisting of just ALLO-647 at a dose of 30 milligram. This regimen was well tolerated with Grade 1 and 2 infusion reactions and no ALLO-501A-related adverse events. As you can see here in the graph, the second infusion prolonged the window of cell persistence, and the patient was able to achieve a complete response at month 2, which is ongoing through the most recent follow-up. We are excited about the prospect of putting a greater number of patients into remission using a consolidated dosing regimen. The third case report highlights the potential benefit that redosing can provide. Here is a patient with Stage III follicular lymphoma. He had received 3 prior lines of therapy, including R-CHOP, Gazyva-bendamustine and the CD20-CD3 bispecific antibody and was refractory to his last line of therapy. After receiving 120 million cells of ALLO-501, he obtained a partial response but experienced an early disease progression. The patient was subsequently re-treated with the same cell dose of ALLO-501 at 120 million cells. Re-treatment was well tolerated with only Grade 1 and 2 adverse events. The patient achieved a complete response to redosing with a duration of response lasting 5 months, longer than his last line of therapy, something that is uncommon in this disease. He ultimately relapsed after being on study for a total of nearly 12 months. But this case, an additional data we will cover during this forum demonstrates the potential benefits of redosing. The breadth of our efforts underscores our vision for allogeneic CAR T, providing as many patients as possible with access to this modality and further exemplifies how we are shaping, defining and advancing the field of CAR T therapy. We are proud of the depth of our pipeline and how quickly we are able to progress our programs alongside our pursuit of next-generation technologies. Every time we make a new construct, conduct the preclinical experiment, dose our patient or collect biomarker data, we learn something new about allogeneic therapy. And as a company, our singular focus on this field allows us to apply the key learnings from our work to expand our pipeline in new cancers and with new technologies. We believe we are uniquely positioned to lead the field of exploring allogeneic levers such as redosing, consolidated dosing, adjustment to the lymphodepletion regimen and the use of proprietary technologies such as TurboCAR. Six years ago, I had honor of presenting some of the first Phase I data on an autologous CAR T therapy, data that ultimately supported approval of the first CAR T therapy for non-Hodgkin's lymphoma. It is now my pleasure to ask Rafael to share with you data from Allogene's Phase I trials, the first to demonstrate durability for an allogeneic CAR T, and data that we believe reveals what may be the future of cell therapy.

Thank you, David. Allogeneic CAR T cell therapy offers the opportunity to address and overcome the logistical and manufacturing challenges of autologous CAR T. ALLO-501 and ALLO-501A are identical except that ALLO-501A lacks the rituximab mimotope kill switch, enabling the rapid initiation of treatment in all lymphoma patients. In a few moments, Dr. Locke will discuss the long-term data of ALLO-501 as a follow-up to the data presented at ASCO in 2020. At that time, the composite response rate for patients with follicular lymphoma and large B cell lymphoma treated with 39 and 90 milligrams of ALLO-647 was 63% overall response rate and 37% complete response, but evaluation of durability was limited, given the short median follow-up of only 3.8 months. As Dr. Locke will be given the formal poster presentation from the abstract at ASCO, we've asked him to focus on presenting full data from the ALPHA trial with ALLO-501. I will summarize the data from ALPHA2 and ALLO-647. The latter will be formally presented by Dr. Tees at ASCO. The data to be presented today is the most recent analysis as of May 12, and as such, it contains slightly more information than that which will be presented at ASCO. So let me first start with the strategy we employ at Allogene for avoiding graft-versus-host disease and host-versus-graft and briefly outline the design of our ALPHA studies. Depicted in the top left is the unique design of ALLO-501, which also applies to ALLO-501A. This design strategy addresses the fundamental issues of allogeneic CAR T strategy, namely the bidirectional rejection tendencies of the allogeneic graft in an HLA unmatched host. ALLO-501 and ALLO-501A contain TALEN nuclease-mediated TRAC knockouts to prevent graft-versus-host disease and the CD52 gene editing to protect CAR T cells from the donor from ALLO-647, which is a monoclonal antibody directed against CD52 and is used to deplete host lymphocytes for extended duration beyond that afforded by chemotherapy alone. This prevents host-versus-graft rejection and allows the allogeneic CAR T cells to expand and exert antitumor activity. The ALPHA trial enrolls patients with recurrent relapsed refractory large B cell lymphoma or follicular lymphoma, who had at least 2 lines of therapy. The protocol allows redosing of patients who have progressed on study. There was a dose escalation following a classical 3+3 design using 40 million, 120 million and 360 million cells, which has completed, and recently, we began a consolidation arm for patients who obtained disease stabilization, partial response or complete response. This is accomplished by redosing with 120 million cells, preceded by 30 milligrams of ALLO-647 if the patient meets hematologic criteria for reconditioning. The design of ALLO-501A is very similar as it was meant to confirm that ALLO-501 and ALLO-501A function the same way as this will be the construct we intend to move into the registrational phase. To that end, the ALPHA2 trial only enrolled patients with large B cell lymphoma, and the dose escalation was performed up to 120 million cells. We subsequently amended the protocol to introduce consolidation using the same design paradigm outlined in the previous slide. The key questions that we answered with data from ASCO 2020 were that we could successfully manufacture product from normal donors using technology involving genetic editing in addition to the CAR engineering that we could selectively lymphodeplete delaying graft rejection while sparing myeloid precursors to allow a sufficient window of immunivation of the allogeneic T cells and allow the graph to expand and persist long enough to cause antitumor effects. We also established that ALLO-501 could lead to clinical responses on par with those of autologous CAR T therapies. Other findings from this trial so far are that we treated nearly 100% of enrolled patients, and we established the feasibility and generated proof-of-concept for redosing and consolidation. And now, today, with the data that we're presenting, we can show that a proportion of these responses are durable with patients in complete response past month 15 as well as treatment failure-free survival, which we define as the time from the first dose to the last observed progressive disease or death as well as the more conservative calculations from day 0 to the first progression being also similar to those observed in trials of autologous therapies. And with that, I'd like to introduce Dr. Locke, who will walk us through the ALPHA data.

Thank you so much. I'm pleased to be presenting results from the ALPHA study. This slide shows the patient disposition demographics and disease characteristics on the ALPHA trial. 41 relapsed/refractory patients were treated across 3 dose levels and consolidation cohorts. A significant number exhibited high-risk features such as an IPI over 3, LDH higher than the upper limit of normal, GCB subtype and double- or triple-hit lymphoma. 42 patients were enrolled on the ALPHA trial. The number of patients enrolled and treated was almost identical. Only 1 enrolled patient was not treated due to an acute kidney injury associated with progressive disease. Both the median and mean time from enrollment to treatment was only 5 days. As you can see in this table, 5 patients were given a second ALLO-501 treatment upon disease progression, and 3 more received a second infusion of ALLO-501 in the consolidation arm of the trial. Here, we present a safety profile update on the ALPHA study with additional patients treated since the ASCO 2020 presentation. The ALPHA study update demonstrates a continued manageable safety profile. Since the ASCO 2020 presentation, most infusion-related reaction events were Grade 1 to 2 and did not result in dose reduction. There were no Grade 3 or higher CRS events observed, and all Grade 1 to 2 CRS events resolved. There was a single Grade 3 ICANS event. The Grade 3 and higher infection rate was 24%, and this is very similar to what we've seen in autologous CAR T cell therapy settings. During this study, there were 5 treatment-emergent Grade 5 events in the absence of disease progression, 1 from fungal pneumonia, 1 with arrhythmia, 1 from stroke and 2 instances of acquired COVID-19 in the community setting after cell count recovery. Three of these patients were in ongoing response at that time. We focused this efficacy analysis on patients who had not previously received an autologous CAR T cell therapy. Updated response data in this patient population demonstrates that a single dose of ALLO-501 allogeneic CAR T cell therapy can achieve objective response rates and complete response rates in follicular lymphoma and large B cell lymphoma on par with results from autologous CAR T cell therapy products. Remarkably, the objective response rate was 75% and the complete response rate was 50% in the combined cohort of follicular lymphoma and large B cell lymphoma. The modified intent-to-treat and intent-to-treat analyses were almost identical in contrast to the pivotal autologous CAR T cell therapy trials where weeks of manufacturing are necessary. The ongoing 6-month complete response rate in large B cell lymphoma was also similar to autologous CAR T cell therapies at 36% in the modified intent-to-treat and 33% in the intent-to-treat analyses, respectively. This slide shows swimmers plots of autologous CAR T cell therapy-naive patients treated on the ALPHA trial, demonstrating deep and durable responses. Among the 5 large B cell lymphoma patients who attained a CR, 3 remain in ongoing CR at month 6, 12 and 15 following treatment. Seven follicular lymphoma patients are in ongoing CR, with 3 past month 9, including a patient at 12 months and another patient at 15 months. Four additional patients attained CRs after retreatment, 1 ongoing at month 7 and others lasting up to 13 months from initial day 0 of ALLO-501 treatment. It is important to note that 3 patients were in ongoing CR, 1 in the large B cell lymphoma and 2 with follicular lymphoma but died from other causes as noted earlier. Off-the-shelf allogeneic CAR-T cell therapy offers the unique opportunity to tailor the therapy as either a single dose, as a consolidated dose or as a retreatment with CAR T if progression occurs. This can best be characterized by the time-to-treatment failure as measured by the time to death or to the stopping of further allogeneic CAR T cell therapy. This analysis, again focused on autologous CAR T cell therapy-naive patients enrolled on the ALPHA study, demonstrates that redosing appears to provide clinical benefit in the overall patient population, with a treatment failure-free survival at 6 months of 64% in follicular lymphoma and 61% in large B cell lymphoma. Both first and second infusions had a similar manageable safety profile. Across 10 subjects with follow-up who have either been retreated or consolidated, the second cell infusion successfully induced an objective response in 8 out of the 10 patients, 7 of which were complete responses. Importantly, the Kaplan-Meier estimate of overall survival at 12 months was 63% and 57% for follicular lymphoma and large B cell lymphoma, respectively. Median overall survival has not been reached. For comparison, autologous CAR T cell therapy studies in large B cell lymphoma have demonstrated a 12-month overall survival ranging from 50% to 62%. CAR T cell therapy expansion was observed on the ALPHA study. Greater expansion was seen in patients who achieved a CR as compared to patients that did not obtain a CR. Persistence of ALLO-501 was also observed until day 120. In conclusion, ALLO-501 produced deep and durable responses in patients with relapsed/refractory non-Hodgkin's lymphoma. Objective response and complete response rates were 75% and 50%, respectively, in autologous CAR T cell-naive patients. 36% of large B cell lymphoma patients obtained and remained in complete response at month 6 following a single infusion of ALLO-501. The longest ongoing CR is 15 months and counting. 98% of enrolled patients received ALLO-501 at a median time of 5 days from enrollment to the start of the therapy. ITT results are nearly identical to the modified ITT results. No dose-limiting toxicities or graft-versus-host disease were observed, and ALLO-501 had limited rates of immune effector cell-associated neurotoxicity syndrome and cytokine release syndrome. Thank you very much. Rafael will now present to you some of the initial results with ALLO-501A, and I look forward to presenting that data at the ASCO annual meeting in June. Thank you.

Thank you, Fred. In the next few slides, I will briefly summarize the ALPHA2 study with ALLO-501A, which is the primary subject of the poster presentation at ASCO as well as the results of ALLO-647 in terms of safety, pharmacokinetics and pharmacodynamics. This data will also allow me to discuss some of the biomarkers that were done in both the ALPHA and the ALPHA2 studies. The dose escalation of the ALPHA2 study consisted of 2 doses. One patient was treated with 40 million cells and 4 patients with 120 million cells, all 5 with a single dose. 5 subjects were enrolled in the consolidation arm of the study. 9 patients are evaluable for response. The response rate in dose level 2 was 50%, and all of them were complete responses. In the consolidation arm, 60% of patients responded with all 60% being complete responses. The overall response for CAR T-naive patients, including both single dose and consolidation in all 9 patients, was 56% for a complete response of also 56%. The swimmer plot on the top right shows all 9 patients in ALPHA2 with 5 CRs ongoing at 9, 4 in dose escalation, and 4, 2 and 2 months, respectively, in consolidation. In the second table, you can see the complete picture of the consolidation arm of both ALPHA and ALPHA2 for 6 patients for whom we have day 56 outcomes. 3 patients in ALPHA2 had diffused large cell lymphoma and 3 in ALPHA had follicular lymphoma. In ALPHA2, 3 patients developed partial response at day 28, followed by complete responses at day 56. One of the patients reached month 4 and remains in complete response. In the ALPHA1 study, 1 patient attained a complete response and 2 attained partial responses at day 28. The complete response remains a complete response at day 56. And of the 2 PRs, when converted to a complete response and the other remain a partial response. Those 2 last patients had recent day 56 scans and are included in this table. So in summary, in the consolidation cohort, while the numbers are still small, the overall response rate is 75%, including 2 patients who did not qualify for consolidation with a rate of 63% complete response across both diffuse large B cell lymphoma and follicular lymphoma. In the ALPHA2 study, no patients experienced dose-limiting toxicities. There were no Grade 3 infusion reactions. One patient had Grade 3 CRS. There were no instances of ICANS or GvHD. There was 1 Grade 3 infection in a single patient. The most common adverse events in general were cytopenias, with Grade 3 occurring in 77% of the patients. In the consolidation arm, the second dose of ALLO-647 and ALLO-501A were very well tolerated. As shown in the ALPHA study, the ALPHA2 study also showed that CAR T cell expansion and persistence correlated with response. Shown here are the geometric means of the vector copy number per microgram of DNA over time in peripheral blood. You can see the patients with CRs attain a higher level of vector copies and that allogeneic CAR-positive cells were detectable out to day 120. This figure shows the results of the minimal residual disease, or MRD, assessed in peripheral blood samples as a function of time from a next-generation genomic assay in patients both in the ALPHA1 and 2 studies. It is important to note that unlike in leukemia and myeloma, MRD is still an experimental tool in non-Hodgkin's lymphoma, and this analyses are exploratory. Some patients could not be evaluated for MRD status because of technical deficiencies or lack of sample. Quadrants in green indicate best overall response of complete response versus quadrants in purple, which indicate response other than CRs. Data are depicted from days 28 to month 6. The Y-axis and the numbers in the boxes indicate percent of subjects within each MRD-negative or positive group. Each graph has a negative and a positive column for MRD. In general, MRD is negative in patients with complete responses, especially at later time points, and patients without CRs, in general, have MRD positivity. Of all day 28 MRD-negative subjects, 66.6 achieved CRs as best responses, suggesting a deep and robust response to ALLO-501 and ALLO-501A. ALLO-501A and lymphodepletion containing ALLO-647 were well tolerated with low-grade infusion reactions, no evidence of Grade 3 CRS, no ICANS or GvHD and 1 episode of Grade 3 infection. Consolidation could be safely administered without evidence of Grade 3 toxicity. Let us now turn to the safety and pharmacokinetics and pharmacodynamics of ALLO-647. Recall that ALLO-647 is a humanized anti-CD52 antibody and a component of our lymphodepleting strategy. As I stated previously, our allogeneic cell product contains a gene edit in the CD52 gene to allow the use of ALLO-647 without compromising the infused T cells. In this analysis, we have combined data from all 3 studies, ALPHA and ALPHA2 studies and in the UNIVERSAL study, which uses the anti-BCMA CAR T ALLO-715 for patients with multiple myeloma. We did this to get a more comprehensive view of the safety and benefits of ALLO-647 across patient populations. This slide shows the demographics and disease characteristics of the patients enrolled in these studies. First, you can see that across studies, as of the cutoff date, we have treated close to 90 patients in this data set, some with more than 1 dose. The disease characteristics are consistent with those of advanced relapsed/refractory multiple myeloma, where 44% had high-risk cytogenetics and had received a median of 6 prior regimens, and in the lymphoma studies, where 49% to 69% of patients had elevated LDH and about half had IPI scores that were 46% or were double- or triple-hit lymphoma in ALPHA2. We evaluated adverse events attributable to ALLO-647 or ALLO-647 and flu/cy across all 3 trials. Except for infusion reactions, there does not appear to be a significant dose response with regards to adverse events. Hematologic adverse events were also both expected and observed. Importantly, given our experience with ALLO-647, CMV and other opportunistic viral infections were monitored and prophylactic antivirals were used to reduce the risk. As stated by Dr. Locke, there were 2 unrelated Grade 5 events of COVID-19 infections acquired in the community setting occurring at 6 and 7 months, respectively, 1 event each of Grade 5 pneumonia, stroke and arrhythmia. All Grade 5 events, except for the pneumonia event, were deemed unrelated to study drug. In the UNIVERSAL study, as previously reported, there was a Grade 5 fungal pneumonia related to progressive myeloma and conditioning with cyclophosphamide and ALLO-647. Separately, an event of adenoviral infection was observed in a 78-year-old man who was heavily pretreated and had ongoing lymphopenia and adenovirus reactivation. In this slide, the box plot figure shows the free drug concentrations at day 0. Patients who have a higher lymphocyte count tend to have lower ALLO-647 serum concentration. At lower doses, drug is bound to the recipient lymphocytes, demonstrating a lower free drug availability and at higher drug doses, more free drug is available. However, those with higher lymphocyte counts, as seen in the last tertile of each dose level, generally have a lower free drug availability of ALLO-647 compared to those with lower lymphocyte counts, meaning that ALLO-647 demonstrate a target-mediated drug disposition by binding to CD52 in the patient's lymphocytes. The adjacent table shows that no patients in the ALPHA or ALPHA2 studies were found to develop anti-ALLO-647 antibodies. In the UNIVERSAL study of ALLO-715, our BCMA-directed CAR T cell therapy, about 25% of patients developed antidrug antibodies. However, it did not affect drug concentrations, and it is, therefore, unlikely to be clinically relevant. This slide shows the effect of ALLO-647 dose tertiles in T cell depletion, the effect of ALLO-647 concentrations on endogenous IL-15 and the association of exposure to expansion of allogeneic CAR T-positive cells. As you can see in the first figure, the higher the dose of ALLO-647, the lower and deeper the lymphodepletion, indicating that ALLO-647 is an important component of allogeneic cell therapy conditioning. It is important to note that there were several lymphodepleting dose levels and timing of infusion and those have been investigated and grouped in tertiles of doses. Based upon the different levels of exposure, the central figure demonstrates that the higher the total concentration of ALLO-647, the higher the level of IL-15. This association between T cell depletion and increase in IL-15 has been previously reported, and it is likely to represent a response to T cell homeostasis. As such, IL-15 levels are a good indirect measurement of the efficiency of lymphodepletion. Lastly, the third figure shows the probability of CAR T cell expansion as a function of ALLO-647 concentrations in patients treated with a single lymphodepletion regimen, that is patients excluding consolidation. In summary, these figures indicate that the doses of ALLO-647 correlate with the depth and durability of T cell depletion, the concentrations of ALLO-647 correlate with IL-15 levels, an indirect measurement of the quality of conditioning therapy, and that CAR T expansion is a function of ALLO-647 concentration. Not shown here but will be shown in the poster as a correlation between 647 and outcomes, there is a correlation between concentration and probability of response. This correlation was observed across individual and combined studies. Taken together, this data, along with the tolerability of ALLO-647, support the use of anti-CD52 therapy as part of the conditioning regimen in allogeneic cell therapy. And as such, it remains a cornerstone of lymphodepletion in Allogene studies. So what can we conclude thus far from the CD19 and ALLO-647 data that we have presented? First, we saw that ALLO-501 and ALLO-501A produce deep and durable responses in patients with relapsed/refractory non-Hodgkin's lymphoma with 36% of large B cell lymphoma CAR T-naive patients in CR at month 6 following a single infusion of ALLO-501, and early results from ALLO-501A showing a similar complete response rate. Second, intent-to-treat analysis are nearly identical to mITT results, reflecting our ability to treat nearly every enrolled patient. Third, no dose-limiting toxicities or graft-versus-host disease or ICANS or cytokine release syndromes were observed. Fourth, consolidation doses show early promise, with 4 patients converting from partial response to complete response following the second dose of ALLO-501A. Fifth, safety and PK/PD data from trials of ALLO-647 with fludarabine and cyclophosphamide across ALPHA, ALPHA2 and UNIVERSAL trials demonstrated manageable safety profile, exposure-dependent deep lymphodepletion, correlation with circulating homeostatic IL-15 and expansion and clinical responses. We remain on track to initiate the Phase II study of ALLO-501A in patients with high-grade non-Hodgkin's lymphoma by the end of the year. We believe that the response data that the durability of the responses provide strong support for the development of ALLO-501A, with the inherent benefits of being able to treat almost all patients enrolled in a short period of time, together with the ability to consolidate, which has shown promising initial results. We will continue to enroll patients and collect additional follow-up data on consolidation to evaluate longer durability. Importantly, in the coming months, we plan to finalize the design of a potential pivotal Phase II study of ALLO-501A in large B cell lymphoma and seek alignment with FDA on the design of this pivotal program. Please now join me in our next session, a panel discussion where we will further put all results in context and discuss what the future holds for allogeneic CAR T therapy in non-Hodgkin's lymphoma.

We're very excited today to welcome with us 3 distinguished clinicians, each of whom have played a key role in investigating the potential of our anti-CD19 allogeneic CAR T therapies. Dr. Lazaros Lekakis is an Associate Professor of Clinical Medicine, Transplantation and Cellular Therapy at the Sylvester Cancer Center, the University of Miami. Dr. Frederick Locke is a co-leader of the Moffitt Immuno-Oncology Program, Vice Chair and Associate Member of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Moffitt Cancer Center. And Dr. Michael Tees is an Associate Member Physician at the Colorado Blood Cancer Institute at SCRI. Dr. Locke, Dr. Tees and Dr. Lekakis, thank you so much for joining us today and for providing additional first-hand insight into the data that was just presented for ALLO-501 and ALLO-501A. We often get detailed questions about our therapies but reading the data doesn't really tell us the full story of what each of you sees in the clinic. So we hope that this session will provide some color about what the experience is like for you and for your patients to use allogeneic cell therapy.

So let's start with Dr. Locke. Dr. Locke, in the ALPHA trial, we saw an overall response rate of 75% and CR rates of 47%, and a CR rate of 36% at 6 months for patients with diffuse large B cell lymphoma. As someone who has been deeply involved as an investigator in CAR T therapy, how do you think about the comparability of this allogeneic therapy to approve autologous therapy, both with respect to the response and also the durability of the response?

Yes. So as you know, I have a lot of experience with treating patients with autologous CAR T cell therapy products and, in particular, large B cell lymphoma patients. And I do think that these response rates and the durable response rate at 1 year are in the ballpark. This is comparable to what we're seeing with large B cell lymphoma patients, at least for refractory and relapsed/refractory large B cell lymphoma patients with autologous CAR T. Certainly, there's a lot more patients treated with autologous CAR T than we have in the ALPHA and ALPHA2 trials, but I'm very encouraged. We were concerned that these therapies wouldn't lead to durable responses via rejection, right? And now here, we're seeing up to 1/3 of the patients with ongoing remission -- for large B cell lymphoma patients with ongoing remissions and that's, again, right in the ballpark of what we see with autologous CAR T cell therapies in the relapsed/refractory setting.

Great. Thank you, Dr. Locke. Dr. Lekakis, in your opinion, what may be the advantages for choosing an allogeneic treatment over an autologous treatment? How would you make that choice?

The most obvious is the fast turnaround because it usually takes 3 to 4 weeks for an autologous product to come back but also takes about 2 weeks negotiations with the insurance company, so it takes about 6 weeks. On the other hand, we have the allogeneic and CD19 CAR product available in 10 days. And the other thing is that because of this fast turnaround, we don't need to give a lot of bridging chemotherapy. And that is good because the -- we see less -- we so far have seen less prolonged cytopenias, and we believe that we'll continue to see the same. And then the other thing is that with autologous products, we give those bridging chemotherapies and then the fitness of the CAR T cells that are produced is not perfect. Any -- every next line of chemotherapy we give, more cycles of chemotherapy we give, the fitness of the lymphocytes and their efficacy may go down. And the other obvious thing is that we don't have any failures on production. They are given to us off the shelf. They are ready, fit. They have not been exposed to chemotherapy, the allogeneic CAR T cells. The autologous cells, sometimes, will have failures on the production. We have delays and sometimes, we have suboptimal products that do not meet the FDA requirements. And we -- there is some controversy there, but Fred probably knows the data better than me, the ZUMA-9 trial. So that if they didn't meet the FDA requirements, they were -- some of them, they were not as effective. So we avoid all of these problems by having off-the-shelf product.

Thank you for that comprehensive answer. Let's talk about safety in this area as we now have experience over a few years with autologous CAR T therapy. This question is for Dr. Tees. What is your perspective on the overall safety profile of ALLO-501 and 501A as a contrast with autologous therapies in your view?

Well, so I'm very comfortable with the safety for both agents. But just for clarification real quick is that the ALLO-501 product had that anti-CD20 kill switch, which at this point, all of us are very comfortable with the management of cytokine release syndrome and neurotoxicity and so that was not a concern whatsoever. So I think we're all very happy when the 501A product came about because it did allow us to enroll more patients. But the -- if you look at what was presented, the incidence of cytokine release syndrome and neurotoxicity is actually a lot lower than what you would even see in the 4-1BB products that are actually already available right now and definitely a lot lower than the anti-CD28 or the CD28 CAR T agents. But I think most importantly, what we haven't seen is any incidence of graft-versus-host disease. And that's one thing that off -- right off the bat, you think, okay, well, an allogeneic CAR product, could there be a risk of graft-versus-host disease? In fact, there's been no evidence of that to date. So I'm pretty excited about this possibility as a treatment option, and I think all of us are very excited about the responses that we've seen and the safety.

Thank you. And Dr. Lekakis, can you tell us a little bit about how your patients tolerated ALLO-501 and ALLO-647 in the ALPHA trial?

Yes. So they tolerated very well. So far, I didn't have any severe ICANS and -- immune effect or cell therapy-associated neurologic syndrome, we call it ICANS. And didn't have any serious cytokine release syndrome. I didn't have to give corticosteroids and this is important, right? Because if you give high doses of corticosteroids, even though not proven 100% but there is always a concern that you kill the CAR T cells. And the efficacy may go down. The data and the literature, a little controversial, but -- and plus the discomfort of the patient. And yes, we say the neurotoxicities are always reversible but we have seen, probably all of us, if not, I hope you never see it, cerebral edema with the autologous CAR T products. And so it's not 100% reversible. We don't -- I haven't seen that with the allogeneic CAR T, with ALLO-501. The other thing that I was expecting to see is -- and I haven't seen it, not at all yet, is those -- the opportunistic infections because we give a good dose of ALLO-647, which is a humanized anti-CD52 antibody so it kills all the mature B and T cells. And I was expecting CMV reactivations. I haven't seen CMV reactivation because we give prophylactically letermovir now. We learned the lesson, we give letermovir so I haven't seen -- biochemical CMV reactivation, I haven't seen. And I don't see also mold infections by giving posaconazole. We prevent those by giving posaconazole. Of course, we don't see Pneumocystis jirovecii pneumonia because of we give either a Atovaquone. But -- and there are still some concerns about later adenovirus infections, human herpesvirus 6 infections. Most of those are in the heavily pretreated patients and also some of them are asymptomatic. And we do have treatments for that. The trick is to check, to know how -- when to check and how to treat. If you see an adenoviral load of 100,000 and you see a patient with pneumonia, you have to give Cido. But so far, so good, not much of infection, not much of cystic can be given our patient. I am very satisfied. And the ALLO-647, except for mild infusion reaction, low-grade fever, nothing else. It's a very, very...

Thank you for sharing your perspective. And Dr. Tees, we discussed before the safety of the cells, and you will be presenting at ASCO on ALLO-647, both safety and PK/PD data. What do you think is the most important takeaway from that data?

Yes. Well, I just want to follow up with Dr. Lekakis, what he was saying earlier is that ALLO-647 is a reasonable, safe product. Now that's necessary in a combination with fludarabine and cyclophosphamide to provide the lymphosuppression necessary for the allogeneic CAR T cell expansion. But it's not a novel product necessarily, and it's used for the treatment of patients with hematologic conditions. And because of that, we're quite familiar with what we are expecting. And on top of it, these patients are already heavily pretreated. So these patients are already lymphosuppressed to begin with. So the risk of infection is present but is definitely manageable. And one of the most common side effects that, at least from an academic standpoint or from a standpoint that you always make an association with anti-CD52 therapy, is the risk of CMV. What is nice now and the past couple of years, we do have letermovir, which is a prophylactic agent which does provide some benefit. But the risk of fungal infections are present, but most programs that are familiar with CAR T cell treatment as well as transplant do know what we need to be looking out for to reduce that risk and -- such as PJP, that type of thing. But essentially, I think those are the takeaways. This is a manageable safety profile of this agent in combination with fludarabine and cyclophosphamide. It's an excellent option for lymphosuppression.

Thank you, Dr. Tees. Dr. Locke, as we and others allogeneic trials, the discussion has been turning more and more to time to treatment and the ability to treat all patients. This has been really evident when you look at the efficacy through the intent-to-treat versus the modified intent-to-treat, which is a concept that is being discussed quite a bit recently. In your experience, how important is this in the context of disease severity for your patients as well as the potential need for using bridging therapy as Dr. Lekakis referred to before?

I think it's extraordinarily important that we get CAR T cell therapy to patients as soon as possible. We know from our experience in the autologous CAR T cell therapy arena that patients who have had many more prior lines of therapy, patients who had a long manufacturing time and have rapidly progressing disease that requires bridging therapy, these are the patients who do worse with their treatment. We published a large series with autologous CAR T patients, and it was clear that bridging therapy was associated with worse outcomes probably because they have this more aggressive disease. So if you can get the therapy to the patient earlier, that's key. We also know that the size of disease, the amount of lymphoma present also impacts outcomes. And the longer you wait, the larger that lymphoma tumor burden becomes. So earlier is better. And then finally, we know that patients who have a rapidly progressive lymphoma tend to have a pro-inflammatory state. And again, these are the patients that earlier intervention is better. And then finally, the different autologous CAR T cell products in the market have different success rates in terms of adequate manufacture, Dr. Lekakis has kind of already talked about this, with rates -- success rates as high as 97% but sometimes as low as 2/3 of patients are being successfully manufactured. And that makes a huge difference if you have a patient in front of you or if you are the patient. You want to know that you can get that product successfully and on time and use it, right? And so if we can quite simply get the authorization and use the CAR T cell therapy, I think that has -- can have a huge impact on outcomes. And again, you mentioned the modified intent-to-treat. I think intent-to-treat analysis is important and it's something that in autologous CAR T cell field, we're starting to see more reports on intent-to-treat and, again, differences across the products. And here, where allogeneic CAR may be a differentiator in that we can get this therapy to the patients very rapidly when they need it and probably make a difference.

Great. Thank you. Dr. Lekakis, just wanted to turn to consolidation. You've had some experience with that in our patients. Can you just speak a little bit about the safety and feasibility of the treatment of consolidation therapy?

This is upon the initial infusion, because you don't give the chemotherapy part, you give only the ALLO-647. So we give the humanized anti-CD52. And even the reaction to ALLO-647 probably is less. It's a very easy therapy. We should start giving it out to patients. There is no reason to keep those patients in the hospital. The cytopenias after the consolidation are less. Lymphopenia and immunosuppression is a problem. But we know that it's an inherent part of the therapy. And we have to continue to prophylax the patient to give them prophylactic antimicrobials. We need to maybe give intravenous immunoglobulins if they have a level more than 400 milligrams per deciliter. But it's -- in fact, I believe both the consolidation and the initial one can be given out to patient. And in terms of ICANS and CRS, I, haven't seen them, especially after the infusion, I haven't seen them. One would think about the consolidation, meaning the reinfusion of the cells on day 29 or 30, is that some limited data that I'm aware of, the expansion may be even better. And that is because the patient is already lymphodepleted. I don't know what damage we have done in other innate or adaptive immune responses with the chemotherapy and the ALLO-647 before and probably doesn't have the power to reject the ALLO-501 product. So we see better expansion. That means that we may not see the response initially as deep as we would like to and we may see deeper responses after consolidation.

Thank you, Dr. Lekakis. So you spoke about consolidation. I wanted to follow up with Dr. Locke about redosing because you published and presented a lot about this in the autologous setting. And I wonder if you could summarize that experience and also what do you think allogeneic therapy can offer with regards to redosing.

Well, we do have some experience in the autologous CAR T cell setting with re-treating patients with another treatment of CAR T cell therapy. We've only had limited success, and it's really been the patients who had prolonged remissions and then relapsed and then we're successfully able to re-treat them with autologous CAR T. Now of course, they've had plenty of time to recover their cell counts. We know that the therapy worked the first time. What we're seeing here with allogeneic CAR T cell therapy with ALLO-501 and ALLO-501A is that we can give the therapy sooner perhaps as a re-treatment and have success. And as Dr. Lekakis said, if we move it into a consolidated phase, and again, we utilize ALLO-647, we may be able to sort of give more of the CAR-T early on, preempt the need to give it again every treatment by doing consolidated doses. And really, as we talked about earlier, the concept of time to treatment failure, time to when a patient no longer is having successful allogeneic CAR T cell therapy, yes, maybe they're getting multiple infusions, but that's okay if it's safe and effective. And again, they can get it quickly at the very beginning and can have very long ongoing remissions. That's certainly something that will be easier to do in the allogeneic CAR setting than in an autologous CAR T cell setting, where you have to remanufacture and you have to do all these other things.

So Dr. Tees, before we spoke about 647 and the safety of 647, I think in your presentation at ASCO, you will talk about pharmacokinetics and pharmacodynamics of 647. I wonder if you could speak a little bit about the role of ALLO-647 in your view as part of the lymphodepletion regimen that we employ in the allogeneic setting.

Yes. Well, the -- fludarabine and cyclophosphamide alone is probably not going to cut it. We know that for effective CAR T cell and CAR T cell expansion. But essentially, what we've seen is that the higher total exposure of ALLO-647, the more effective the lymphodepletion is. It's simple. But we could keep going up and up on ALLO-647 but that would increase the risk of infection and acute infusion reaction. So there -- we have to find basically the happy balance of that. And we do know that the onetime dosing, onetime period dose, I guess, you could say the higher dose of 90 milligrams does have a higher incidence of infection. But if you dose moderately and perhaps even adding the consolidation, you get the exposure needed but it allows a safe AlloCAR T cell expansion and a manageable safety profile. So I think that's kind of the important take home, higher dose, more effective but higher risk.

Thank you. So as we close this portion of the forum, I'd like to ask each of you, what is the most important learning from the data that we discussed today. And I will start with Dr. Lekakis.

The first one is the low toxicity. The second one is that I have seen some responses that I was not expecting. I have seen similar ones with autologous anti-CD19 CAR T. But -- so we -- I think there are some patients who already had the benefit from this treatment. The most important part, I think, is the consolidation. You may have made some mechanisms of resistance there. We don't know everything but it's a very easy step. And we have a better expansion without chemotherapy is nice to be able to give the CAR T cell back-to-back, if you say, and obviously effective. And the most impressive case I had, it was a double-hit lymphoma refractory to a potent defects, completely refractory, I have even pictures to show you, but had the disease in the liver and everywhere, in the lungs, huge abdominal wall mass about 11 centimeter and now is in complete remission. And it's not only in complete remission, didn't have any neurotoxicity, doesn't have any residual tremor, has an excellent quality of life. The last PET scan that we had a little activity on the shoulder and I asked him if he exercised and so, and he told me, "Yes, I don't know what to do and I started doing push-ups." So the shift in the quality of life, the improvement was significant. And he is a 69-year-old with a nice wife. And so we have seen sometimes surprises here. And we've made very low toxicity so far.

Thank you. We're certainly pretty happy for that patient. Dr. Tees, your key takeaways?

Yes. The key takeaway for -- that I think is most important is that AlloCAR T cell therapy is a viable treatment strategy with reasonable response rates. And if we do safe augmentation of lymphodepletion, which we're demonstrating, whether that's by early lymphodepletion or the combination of early lymphodepletion with the consolidation strategy, we'll get the responses that would be expected, which is very exciting, making this a very viable treatment option moving forward.

Thank you. Dr. Locke?

Yes. I would just echo what Dr. Lekakis and Dr. Tees are saying. I mean we do have anecdotal reports of phenomenal responses. And it's very clear that allogeneic CAR T cell therapy with ALLO-501 or ALLO-501A can lead to deep and durable remissions that can be sustained. And I would agree that the concept of consolidated or dosing re-treatment is something that is advantageous for ALLO-501 and ALLO-501A as compared to the autologous CAR T cell therapy. So I'm excited to continue the trials and see where we can go with this therapy. But very pleased to date, and thank you for having us.

Yes. Thank you so much for joining us today in this discussion, and importantly, for the ongoing support and expertise that you offered to us as we continue these clinical trials.

We are indebted to you that gave us one more opportunity for some of our patients.

Thanks, again, for your support.

Hi. I'm Eric Schmidt, Chief Financial Officer at Allogene. In my former professional life, one of the things I found most valuable were insights that only practicing physicians could provide. Today, we're incredibly grateful to Dr. Locke, Dr. Tees and Dr. Lekakis for sharing with us some of their direct patient experience with AlloCAR T therapies. When joining Allogene, one of the things that excited me most was the opportunity to expand the boundaries of CAR T therapy, one of the most exciting new modalities to be developed in decades. While there's still work ahead, given the clinical progress we've now shared with you on ALLO-501 and ALLO-501A, one of the next key questions that presents itself is how we translate the unique clinical attributes of allogeneic cell therapy to maximize any future commercial revenue potential in NHL. To answer that fundamental question, we engaged an independent research firm to conduct a survey of more than 200 hematologists and oncologists at academic medical centers who treat large B-cell lymphoma, the methodology allowed for physicians to choose a preferred profile for a particular patient scenario. The profiles were designed to capture features associated with both autologous and allogeneic CAR T as well as other potential therapeutic interventions and included attributes such as efficacy, safety, dosing parameters and time to treatment. To ladder out to how we might see an allogeneic therapy perform in the marketplace, we focused on 4 key aspects: number one, how are the unique benefits of an allogeneic approach value; two, can the benefits of allogeneic therapy be leveraged to expand the market for cell therapy; three, how do physicians view consolidated dosing; and four, how important is time to treatment. On the next few slides, I'll share with you a high-level summary of this market research and some preliminary conclusions that we can draw when looking at our data versus what has been reported from autologous studies. As you might expect, when deciding how to manage Non-Hodgkin's Lymphoma, physicians consider all aspects of a potential treatment option. However, some product attributes carry more weight than others. What we've captured on this slide is the output from over 2,000 separate physician appraisals of various treatment scenarios, and you can see the relative level of importance physicians place upon product attributes, ranging from efficacy, safety, dosing schedule and delivery. In some cases, attributes such as efficacy have been further subcategorized to differentiate between depth of response and durability of response. The higher the relative importance of the attribute, the greater the influence it may have on impacting a treatment decision. Therefore, the better a product performs within a highly influential attribute, the better it can be expected to perform in the marketplace. One expected finding from the survey is that efficacy, both the ability to achieve a complete response and maintain that response at month 6, is a primary importance to physicians when they are evaluating different NHL therapies. This view underscores our interest in taking the time to interrogate the levers at our disposal to fully optimize our product candidates' potency. But importantly, while efficacy is the single most important consideration, other factors, including some that are inherently favorable or unique to our allogeneic approach, can be highly influential. These include the likelihood that a patient receives the prescribed treatment, the time to treatment and other logistical considerations. Let's dive into the factors that determine physician prescribing, starting with efficacy, the single most important attribute. As outlined in the earlier presentations today and discussed at length by the panel, ALLO-501 has demonstrated that an allogeneic therapy may be able to match the level of efficacy achieved by autologous therapies in large B-cell lymphoma. The ALPHA trial delivered an overall complete response rate of 46% and a 6-month complete response rate of 36% in large B-cell lymphoma following a single infusion with ALLO-501 in autologous CAR T naive patients. These values fall well within the range of what has been reported from autologous therapies. Assuming these results can be replicated in subsequent larger trials, we believe we could have a competitive profile in terms of both depth and duration of response. But we aren't keen to stop there. As David mentioned, we can activate levers that are only readily available to allogeneic CAR T therapy such as upfront consolidation or even redosing to potentially further enhance our clinical profile. With regard to consolidation, the early data are quite promising. And as discussed by Dr. Lekakis, we may have the ability to increase the number of patients who achieve a complete response. Similar to Dr. Lekakis' views, physician survey do not consider administration of a second dose of therapy to be a barrier to adoption. In fact, our early experience with consolidation suggests that the second dose could be administered in an outpatient setting. And as Dr. Locke noted, this treatment strategy is not usually feasible with autologous therapies as patients may require time to recover their cell counts prior to be considered for redosing. As we consider efficacy, we are not limited to the constraints of the autologous world and have the inherent flexibility to dose our therapy in a manner that may benefit more patients. As you've heard throughout today, Allogene has treated approximately 95 patients in our clinical trials of allogeneic cell therapies, all within 3 short years since our company was founded. We believe this is more than any other company. But there are hundreds of thousands of patients with hematologic malignancies and solid tumors in need of improved treatment options. And physicians and, certainly, patients recognize the importance everyday holds when facing a life-threatening diagnosis. AlloCAR Ts are key to delivering cell therapy to more patients in a timely manner. As the market research attests, the ability to treat every eligible patient factors heavily in the decision-making. In fact, after efficacy parameters, the likelihood that a patient receives treatment is the next most important consideration in prescribing. This makes sense. The inability to treat a patient as intended amounts to a treatment failure and stands in stark contrast to the ability to provide a patient with a potential disease-altering intervention. Our survey suggested particularly high physician preference for therapies that could be delivered to greater than 90% of eligible patients. This, of course, speaks to the importance of our approach. As you can see from this slide, not all patients, even when carefully screened for a clinical trial, are able to receive autologous products. This occurs for a variety of reasons, including the challenge of collecting adequate cells, manufacturing times, which can be 3 to 4 weeks, and manufacturing failures. In comparison, in the ALPHA trial, only one patient was unable to receive our therapy. This slide depicting data on a more rigorous intent-to-treat analysis illustrates the impact of not being able to treat patients on outcomes. It highlights why the failure to provide 9% to 36% of intended patients with an autologous therapy is a concern for physicians. They can't know in advance who might miss out on receiving the product. As Dr. Locke noted earlier, it is also vitally important that patients with relapsed/refractory NHL get treated as soon as possible. We know from the experience with autologous CAR Ts that patients who face extended manufacturing times or who have rapidly progressing disease that requires bridging therapy are patients who may be less likely to respond and may not be able to withstand the side effects that could come with this modality. Physicians want a readily accessible off-the-shelf therapy. They want to know that all of their patients can be treated when they need to be treated, and that is exactly what Allogene intends to deliver, predictable access. Moving to safety. Our solid track record provides an opportunity to expand the potential reach of CAR T therapy. Although our survey did note some reluctance on the use of an anti-CD52 antibody for lymphodepletion, likely based upon historical use of Campath and CLL, this did not parallel any concern around infection. In fact, when asked about managing infectious risk for patients on CAR T therapy, physicians reported this was not a meaningful consideration in their choice of therapy. A variance of up to 15% in grade 3 infection rates did not meaningfully impact physician preference. Importantly, as discussed by Dr. Tees during the panel, physicians who treat hematologic conditions are quite familiar with lymphodepleting agents, and the potential side effects are manageable. So perhaps what we've encountered here is an opportunity to educate the marketplace about some of the preconceived notions around CD52 antibodies. We're pleased that ALLO-647, our selective lymphodepleting agent, has demonstrated the ability to enhance AlloCAR T cell expansion and persistence with an initial safety profile that is in line with other products and well within the boundaries of physician preference. In addition, in our ALPHA trials, there were no dose-limiting toxicities or instances of graft-versus-host disease. We believe enhanced education around the safety and utility of ALLO-647 has the potential to promote confidence in its use, not only in the current hospital setting, but beyond, as we look to explore opportunities for treatment in an outpatient or even in a community oncology practice setting. We've talked a lot today about preparing for a potentially pivotal trial, but what we're really excited about is a potentially pivotal change, a change in the outlook for cell therapy. We have the opportunity to raise the bar for CAR T therapy, to improve its profile and make it more accessible to more patients. Physicians were clear in what they are looking for in an ideal product for NHL. They want an off-the-shelf option. They want clear efficacy and favorable safety. They want a product that can be delivered quickly to all eligible patients. If we can deliver this profile with 1 or even 2 doses of AlloCAR T therapy, we have the potential to introduce a product that should be preferred above all others. This brings us back to where David started in today's forum. Allogene is working to establish a new standard in CAR T therapy. It is grounded in our science, our data, our work with clinicians, and perhaps most importantly, a shared desire to treat every eligible patient, each one. We see the potential of AlloCAR T to meaningfully improve patient outcomes beyond what is possible today, and we're just getting started. In the end, our success will be defined by having many more patients like George. We appreciate the support we have already received from many of you and hope that you are just as excited about what we view as the next revolution in cancer treatments. I'd now like to begin our live Q&A session. Thanks for joining us today, and we're looking forward to the discussion.

As we get set up for the Q&A, I would like just to take a few minutes to thank all the patients, investigators, employees and partners, including those in the investment community, who had made a data that we proudly presented today [indiscernible]. We are incredibly pleased to provide this exciting look at our Phase I data and believe that it is groundbreaking, not just for Allogene, but for the field of CAR T. It's hard for me not to think back to November 2015, when at Kite, we initiated Phase II trial of KTE-X19. Now YESCARTA, based on 7 patients in the Phase I ZUMA trial, and early work from the National Cancer Institute. At the time, in the ZUMA trial, we had 3 out of 7 patients in complete response and roughly a short follow-up of approximately 3 months. We now have 53 patients as part of the ALPHA trials with CRs lasting as long as 15 months. With ALPHA2 alone, we have shown equivalent, if not better result, than what we had back then with YESCARTA. Consequently, our conviction that we have a unique and compelling profile to offer to patients is very high, and we are excited as we think ahead to the start of the pivotal trial by the end of this year. So let's start the Q&A.

Great. Thank you, David. Our first question is going to come from Salveen Richter at Goldman Sachs.

Great. Congratulations on the data. Maybe if you could just walk us through what still needs to be done to finalize the dosing schedule for the pivotal trial. And do you plan to use consolidation just given the benefit that you've seen here?

Salveen, thanks for that very important question, something that we are thinking about. I'm going to ask back to Rafael Amado to answer your question. Rafael?

Yes. Thank you, Salveen. I mean, definitely, we are gearing up to starting the study by the end of the year. And one of the questions is whether consolidation will be part of the design. At this point, we are inclined, based on what we've seen, to include consolidation, but we need a little bit more follow-up. So our current CR rate, as you know, is 50% in lung cell lymphoma, and the composite complete response after consolidation is in the 60% range. And we only have 8 patients enrolled thus far with a relatively short follow-up. So we plan to treat more patients, about 9 patients or so in ALPHA2, continuing to enroll patients, mostly follicular lymphoma, in 501, in the ALPHA study, continue to observe the durability of these responses that are going out to 15 months, as you have seen, and then make a decision sometime in the fall. But given the trend that we're seeing with consolidation, it's likely that, that may be a component of the design.

Salveen, I would say that we have all the right pieces of the puzzles, and we are just lining them up nicely as we start working towards the potential pivotal study by year-end.

Our next question is going to come from Phil Nadeau from Cowen.

One question on the safety profile, in particular the deaths that were reported in the study. Rafael Amado, could you go back through the timing of those deaths and whether they were attributed to therapy or not? I believe you said only one was attributed to therapy, but I want to make sure I have that correct. And then the question to the physician panel, how do you put into context this rate of treatment-related death? Is that very similar to what you see with the current autologous therapies in your hands?

Yes. Thank you for the question. I mean the deaths were, as you correctly point out, unrelated to the treatment as per investigator and also our careful review of the cases. In some cases, the patient had progressed already. In other cases, the patient was in complete response. We were unfortunate to have 2 cases of COVID. Some studies have closed actually because of the pandemic, and this happened earlier in the pandemic as well where there was no routine vaccination, which is something that is happening now. And it happened after the patient have recovered [ the counts ]. It happened 6 to 7 months after day 0. So it was an unfortunate event that had to do with the trend worldwide. We had a case of a stroke, and we had a case of a patient who had a related pneumonia, as you correctly pointed out. So the cases are -- again, because of the time course as well as the nature of the event, and they were being unrelated by the investigators, and then except for the pneumonia, we carefully, again, as I said before, confirmed that, that was the case.

Maybe, Dr. Locke, you can sort of give the perspective as an investigator and also make some comparison to what you are seeing in the autologous studies. Certainly grade 5 events is something that we all try to avoid, but there's something in the patient population that you're dealing with is unfortunately almost unavoidable. So Fred?

Yes, yes. I agree. Thank you, David. Yes. Overall, I think the safety profile is very impressive when compared to the autologous CAR T cell therapies on the market. The treatment-related mortality rate for autologous CAR T cell therapy ranges from 3% up to 5% patients, right? And we're talking about nonrelapse mortality here in the time of COVID. Patients were getting COVID. We're seeing that same thing in our CAR T and transplant-treated patients that the mortality rates of COVID are pretty high in these patients, 70% or so across the board with CAR T or transplant. So to me, I think this is acceptable -- within the acceptable range with the number of patients treated overall in the study. So yes.

Yes. Perhaps one more point to make. I think, Fred, you made it before, which is that the 12-month mortality, it's right on par with what the autologous setting has shown. So it is really, I think, a consequence of the kind of patient population that we deal with.

That's exactly right.

Although it's the beginning, I feel safer when I give the ALLO-501 -- and again, I don't work for the company, and I treat patients. The reason is that with axi-cel, for example, which is probably the most effective, even though we don't have a comparison [ head-to-head ], we have seen so much grade 3 and grade 4 cytokine release syndrome. We have seen ICANS. And so we had patients who were almost in coma for 2, 3 weeks. And now we have modified our algorithms how to treat those toxicities, and we give a lot of steroids. Yes, but this probably killed some of the CAR T cells, and we lose the figures. Here, if they -- the cells have 4-1BB co-stimulation, co-simulatory molecule, so the expansion is more gradual. And we -- I don't know if the ALLO-647 has to play any role in the toxicities because probably kill some monocytes, and we don't have so much monocyte inflammation that contributes to cytokine release and ICANS. But it's very impressive. I don't -- I didn't give them steroids so far in the patients that they treated. Nothing. For toxicity, I didn't give any dose of steroids. So it's very easy. It's easy to give it out [indiscernible], the consolidation is a piece of cake.

Excellent, colleagues, [ for ] the perspective. Phil, as it happens, I think you sort of squeezed in about 4 questions into that one question. So let's move on.

Our next question is going to come from Cory Kasimov from JPMorgan.

Great. I know this wasn't part of the primary efficacy analysis, but is there anything you can say about how the patients that were previously treated with the auto CARs performed in the study?

Yes. Look, [indiscernible] I mean, this is something that we have looked at very carefully. Maybe, Rafael, you can answer. And either, Dr. Tees or Dr. Locke, maybe you can comment about [indiscernible] auto CAR T patients in our study. Rafael?

Yes. Yes. So Cory, we had treated 3 patients that were primary refractory to autologous CAR T at ASCO last year, but we didn't see any responses. And the protocol continue just because we had seen responses in the allogeneic setting. So it was a stark contrast between what we were seeing in autologous and allogeneic. And as David said during the presentation, some of these responses in the allogeneic setting upon retreatment were even longer and deeper than they were before. So we thought that perhaps we should continue to treat some more patients that have failed autologous CAR T therapy. And indeed, we actually didn't see responses, accepting patients -- in a patient that had enjoyed a response for 4 months of autologous CAR T. So it seems like there is a difference between allogeneic following allogeneic and allogeneic following autologous and also allogeneic following autologous when the autologous response had taken place rather than primary refractory patients with -- who unfortunately do not [ build ] to benefit from allogeneic therapy. And perhaps, Fred, this -- you've looked at this in detail, and you can maybe add some color to it.

Yes, yes. Thank you. So I presented the retreatment data with axicabtagene ciloleucel on clinical trials, and that was very much restricted to patients who are in remission beyond 3 months and ongoing remission and, as I said earlier, relapsed. And you also have to realize that most of these patients had to be remanufactured, too, whether it be a recollection or take an old frozen PBMC collected from the old apheresis and remanufacture CAR. And so they got through that process. They got through the time to manufacture. They got it again. And yes, about half have responded. And then the durability is completely unknown because they're getting consolidated with transplants for relapsing. So I think it's just a very different thing when we talk about the allogeneic followed by more allogeneic cells, right? We're not -- we're trying to make sure that there's enough cells and the cells are doing what they need to, and it's very different than [ a forward ] relapse where the patients aren't going to respond to any CAR. Maybe there's a window for those very late relapsers, but it's hard to capture those patients on the trial. So I think the current strategy is the right one, and we'll see down the road if we can salvage auto CAR patients?

Yes. I mean, in my opinion, I don't think this is where this is going to be effective, salvaging in AlloCAR after an auto failure. And I think where we're going a couple of years or, hopefully, sooner than that is different target. CD20 CAR, for example, or dual target CARs. But this strategy -- the off-the-shelf CAR, CAR T cell therapy is really going to prove beneficial for our patients, more quicker time to treatment, less cytotoxic lymphodepleting therapies even before they get to true lymphodepleting therapy, how much could reduce the risk of infection. But yes. That's my thoughts.

The next question will come from Michael Schmidt from Guggenheim.

Congrats on the very detailed update here this evening. Just perhaps a follow-up on the infection rate, which seems to be a topic of interest. At the 90-milligram at a high 647 lymphodepletion dose, the rate seems to be a little bit higher. It's mostly grade 1, too, as far as I can tell. I guess do you already have enough information to judge on how the infection rate looks when you do the consolidation where you split the 90 mg over 3 doses, 4 weeks apart? And again, the physicians, I guess, indicated, it doesn't seem to have -- seem to be very manageable, but just wanted to just get your sense of how big an issue this really is.

Rafael, do you want to take the question?

Sure. So I mean, overall, the infection grade, particularly the grade 3 plus infection grade, is in the 20s, which is not very different from the autologous setting. I believe with 90 milligrams is 28%. Overall, it's about 24%. And again, with autologous is in the 20s, and the question of splitting the dose, we actually haven't seen a very steep dose infection type response. In fact, it's actually highly variable. But we are set on the 90 milligrams as a dose going forward. And I think the ability to actually split the dose into 60 milligrams for the first dose of cells and then another 30 milligrams, if anything, maybe more advantageous. We don't plan to study higher doses, but that split may -- for instance, we get fewer infusion reactions because the doses are lower. But from the infection point of view, it may be better. Although when the data that I presented, for instance, it was really difficult to kind of lean any difference between 60 and 90. But logically, for the sake of benefit risk, we want to be able to lower the dose if possible. So I think the 60 and 30 is a really good paradigm that we intend to follow.

I think it's really important to understand that these patients are already functionally lymphodepleted. No matter what you do to them, there is a high risk of infection. And so flu/cy risk of infection, flu/cy ALLO-647, yes, risk of infection, but it allows that expansion to occur to get the treatment that we needed for the patients. The nice thing about ALLO-647, and I think I brought it up in the panel, is that -- or the discussion earlier that this is not unknown to us. We know what the risks are. We know that there are -- is an increase risk of viral infections and risk of fungal infections as well. And that risk exists no matter what, but we know what we need to be following, and we're very lucky that we have a lot of prophylactic agents that are effective and well tolerated by patients. So from the perspective of the physicians, I think that it's not a major concern. And really -- we're -- literally speaking, we're talking life or death a lot of times for these patients. And it's a manageable safety profile. It's a manageable issue that we know that's going to be present no matter what we do.

The infections also we screen. So we check by DNA once or twice with -- for cytomegalovirus epstein-barr virus, human herpesvirus 6, adenovirus. I also check for glucan and galactomannan for mold infections. Also, the patient usually tells if has any cough or anything [indiscernible]. And then I have a low threshold to order a CAT scan. So is -- we not only give good prophylaxis with letermovir and posaconazole, Bactrim, Acyclovir and maybe one of the fluoroquinolones at the time of the neutropenia. But also, we screen for those infections. And we preemptively treat. We don't wait for the symptom to come.

Our next question is going to come from John Newman from Canaccord.

Maybe a question here for the physicians. We've already heard how you think about efficacy for ALLO-501 here in allogeneic CAR T versus the autologous CAR Ts in lymphoma. Let me pose this question. If you explained your views on the allogeneic versus the autologous treatments to your patients, including the wait time for autologous CAR T, do you think many would opt to wait for autologous treatment? And I'm curious if you hear concerns now about waiting for autologous therapy.

Yes. I'll go. Sure. Yes. Absolutely. Every single patient we see says, "Oh, my gosh, we've got to work you off. We've got to make sure you're well enough and do some testing." And then we have to schedule apheresis date, and then we have to wait 3 or 4 more weeks. So yes, they are absolutely anxious. And my practice is to not get bridging unless absolutely necessary. And when it's necessary, it is necessary. And so -- and that adds a whole new layer of wait and concern and whether it's safe to proceed after bridging. If we can give the therapy right away -- every patient -- listen, every patient we do apheresis on, we think, is well enough to get CAR T. And yet, we're not actually infusing it to all our autologous transplants -- or autologous CAR T patients because things happen over that time period. So it's -- I mean to be fair, it's early, right? I mean until we know exactly how this is all going to work, we can't say how would we explain it to a patient or not. We say there's a trial. We think it has great efficacy. Here's the advantages, and you can decide on which therapy they like to pursue.

And I think it's also important to note that like even though that's called diffuse large B-cell lymphoma and even though there's non-germinal center type, germinal center type, there's double-hit lymphoma, there's a huge spectrum of disease within all of that. And we all see those patients. Even though the LDH is not that elevated, their disease is just blossoming right in front of us. And in a lot of times, you don't know who those patients are actually because they're sent to us, and we're kind of getting a feel for that. There's a lot of unknowns. We're trying to get patients who auto CAR T. And a lot of time there's insurance approval process. Obviously, that's not -- we probably don't have that issue no matter if it's allo or auto, but that 3 to 4 weeks is crucial sometimes, and it's going to be so helpful. I mean, I don't work for the company either, but this is something that's profoundly promising. And I don't think that's actually a relevant issue for patients because, honestly, if you -- let's just -- let's give a hypothetical situation where AlloCAR T, maybe because of issues with expansion in a handful of patients, doesn't have the efficacy that we see in an auto CAR T. Let's just say maybe like 8% to 10% difference. We'll just throw that one out there. Does that matter to the patient that's sitting in front of you at that time whose disease is going to be taking off. And so we've got an option now or do you want to wait 3 to 4 weeks. And with the possibility that the disease might progress and you lose that ability, your performance [ that has ] actually give you that treatment because of the potential risk that happen. And then it's complex just like Dr. Locke was saying. So I think it's a reasonable question to ask, but I don't think it's as relevant, I guess, you could say, as you would think. So...

So in terms of the different spectrum of the broad spectrum of this disease, imagine now, if you have primary mediastinal B-cell lymphoma and you have a huge mass in the middle of [indiscernible] anterior superior mediastinum compressing the venous return to the heart and someone is telling you that you need to wait 4 to 6 weeks for the insurance to give the approval and for the product to be manufactured, if it's good to be used. And then you need some chemotherapy because, obviously, we cannot leave you with this mass compressing your heart here. And then you have the other option to get the allogeneic cells in few days. Yes, it's obvious the answer, right? And we are talking now about bridging therapy that didn't work before. [indiscernible] refractory or multiple times relapsed. So the chance to work the bridging therapy is not very high. And then we're going in other issues, the fitness of that, the cells. And then the efficacy we give the bridging therapy, we have taken data from NCI, they don't -- the efficacy is not as great. It bridge the -- yes. So now that is on clinical trial, it's easy because I always tell my patients if this product fails, we can go to and autologous product. But -- and the if you respond, I will take you to [ transplant ], which is crazy, because then we are talking about $1.5 million cost -- total cost, but anyway. Yes.

Our next question will come from Kelly Shi from Jefferies.

Congrats for the great progress. And I have one same question for all 3 doctors. At your practice, what percentage of DLBCL patients who are eligible for CAR T treatment cannot actually receive the treatment eventually due to the factors, including manufacturing failure and also disease progress and also reimbursement pushback?

So let me just start. I think that's a difficult question to answer, and we're trying to tease that out because the time that patients referred is different than the time they were apheresed, is different than the time they get CAR T cell therapy, and those are all captured in different ways. I think the best data to look at right now is our U.S. lymphoma consortium data with axi-cel. And here, we collected data apheresis on 299 patients or 98 patients, and 275 got the treatment. So -- and that's the product that's most reliably manufactured, right? And some of those numbers are actually the out-of-spec products on trial. So you have about -- at best, about 90% of patients who are apheresed who are going forward. And to the point about if there's differences in efficacy, you've got to think back to when the patient apheresed for autologous CAR because that's the time of comparison for allogeneic CAR T.

The next question comes from Raj Prasad from William Blair.

Congrats on the data. Really impressive. My question maybe for the doctors. As the company is thinking about the consolidation regimen and getting additional data there, what data would you like to kind of see compared to the 501 and 501A early data that would give you confidence to tell them to kind of push the consolidation regimen forward in the pivotal trial?

I mean I have to say with Michael, Fred and Lazaros being here, our job is so easy. We don't even have to answer any questions. Go ahead, please.

If I have a 50% complete remission rate with initial infusion and consolidation, then -- and at 6 months, I had the 30% to 40% presence in CR, this is both the result. Heavily pretreated patients probably selected, meaning that they referred for ALLO -Allogene maybe because they were not -- they knew that they didn't have the ability to go for all of those 6 weeks of waiting and bridging chemotherapy. So if I see those are the worst of the worst patients perhaps here. If I had this result, the 50% CR, right, after consolidation would be very [ helpful ]. The consolidation -- my prediction is that will increase the CR rate. They have seen already one of my patients. And I don't see a good reason to not do it, meaning that is not [indiscernible]. You just give 30 milligrams of ALLO-647, you give the cells. And you have the unique opportunity here to have back-to-back CAR T products that you can prevent the relapse that would happen with only one infusion. Back-to-back infusion of autologous CAR T cell product are with probably 3 or 4 exceptions that I have in my mind, it's not curative. So yes, we can induce a second response. Because someone else asked this question before, if we give back-to-back autologous CAR T products, yes, we can induce a second response, but usually those patients relapse again with the exception of 3, 4 cases in my mind, usually it take those patients would respond in the second infusion to allogeneic [ terms ].

Our next question comes from Ben Burnett from Stifel.

I wanted to ask about -- also your -- the prophylactic treatment for infections. I guess I think, Dr. Lekakis, you spoke to that a little bit. Is prophylactic treatment in terms of infections, is that something that's common in the CAR T setting? Or is that something that would be -- maybe not that common and requires some [ medication ]?

I can take that one. I mean it's pretty common to be on prophylactic agents, those CAR Ts out there. Each institution has their own probably SOPs on this one. And we've recently updated it to expand out, for example, [ batch 1 ] through 1 year. We had a patient at 14 months, get PCP pneumonia after axi-cel. So we said, let's do it for 12 months. I don't know if that's going to help, but each program has their own kind of standard on this. And so yes, because it's expected that the risk of infection is there. The one difference is, I think, for -- is the CMV, which Dr. Lekakis talked about earlier, that we -- we're monitoring that primarily because of the anti-CD53 antibody. And the wonderful thing is that their term of year is now available for patients that is -- demonstrated in our allo post -- allo patients -- standard allo patients, not AlloCAR T, to reduce their incidence of CMV reactivation. And I think all -- most of us have been using that in our patients on the study. And I've noticed that actually that the incidence has gone down. So...

I haven't seen [ a single ] reactivation since I started using [ the term ].

At least a meaning -- not a meaningful one that you would want to do preemptive therapy on. So yes.

And so our next question comes from Mark Breidenbach from Oppenheimer.

Probably, this is kind of a 2 parter probably in the -- Rafael, just so we're 100% clear on the discrepancy between the 42 patient intent-to-treat population in ALPHA and the 32 patient efficacy evaluable set. Can you just remind us where the dropouts are coming from? I know 1 patient had the kidney injury, and there were some that were auto CAR failures. But what about the rest? The second part of the question, I'm wondering if you are getting to the point where you can accurately predict future response and maybe depth of response by simply following ALLO-501 expansion in peripheral blood, is there a specific threshold of expansion that tracks well with complete response.

Yes. Thanks for asking the question. The attrition, if you will, from 42 patients is a single patient with acute kidney injury due to disease progression. And the rest of the patients are all patients with primary refractory disease to autologous CAR T. So those are the 2 reasons. With regards to prediction, it's -- really, it bodes very well, I think, for complete response to have very good expansion, and that is something that we can often see in our patients. And we are doing the same thing for durability to start looking to see how durable. As you can see, there are some patients going on to 120 days, but we have patients in the mid-teens that go even further, either peripheral blood or in the bone marrow. And those patients tend to do very well with regards to disease progression. Obviously, it's not a one-to-one correlation, but it is definitely something that when we see, we feel pretty good about in terms of the outcome of the patient.

Our next question will come from Jason Gerberry from Bank of America.

Just wanted to follow up on Salveen's question just about sort of next steps between now and starting the pivotal. You're only going to get like maybe 4 or 5 additional months of follow-up, [ at least ] these handful of patients with consolidation. So I imagine you're not going to learn a lot more. It seems like probably you're pretty confident moving forward with consolidation in the pivotal unless you see something really unexpected. Is that a fair characterization? And then just quickly for Eric. I think autologous treatment rates might be sort of sub-15% on our math. When you did the survey work, was the key to really unlocking use of CAR T in the community setting more, the safety, which we've heard historically from doctors or some of the easy use factors that you get with allogeneic?

So Jason, on the first question, as we have said, we believe the data we have on our hand are very compelling and will allow us to move to the Phase II. In terms of what's needed is for us to just essentially start preparing. First thing that will happen is interaction with the FDA where we will present the data and present the design of the Phase II and then getting their buy-in. And then essentially after that, it's going full speed to the assigned initiation. So I guess it's our nature. I mean, that's what the guys in R&D do. We always follow and get additional data. But essentially, we have all the pieces of puzzle at this point. Eric?

Yes. Thanks for the question on the community use and our market research, Jason. Our survey was restricted to academic centers. So it didn't directly address the question of what it might take in order to get this therapy into the community setting. But based on our anecdotal conversations with folks, certainly, safety, as you mentioned, is primary important and the ability to dose safely in the outpatient setting as well. So those are attributes, we think, we have advantages with an off-the-shelf allogeneic product, and we're certainly keen to further explore that via discussions with community oncologists and see if there's a path forward there.

Our next question comes from Luca Issi from RBC.

Congrats on the progress in the data. I think you mentioned that the second dose of consolidation is not viewed as a barrier to adoption as it can be done in the outpatient setting. Can you elaborate on that, maybe how you're planning to transition from inpatient to outpatient for the second dose? Is that something that you're planning to pursue in your pivotal trial? Or is it maybe something that you will explore post approval?

Luca, let me take that question and give our panel a little break. I mean, certainly, we're just seeing the data. And we are, frankly, in a very encouraged and somewhat amazed about how well the consolidation dosing is tolerated. I think Dr. Lekakis made that point very clear. That gives us a lot of opportunity in terms of how we design the Phase II to allow exactly what you're talking about. So this is much work in progress. Don't forget, we just did a data cut for this presentation not long ago. So we've been quite busy, but I think we will keep ourselves busier next few months as we finalize the Phase II design. And the point that you're making is certainly very hard topic internally, trying to leverage the benefit that we can create with our consolidation based on 501A.

I'll just add something to this. The outpatient CAR T cell is a necessity, actually, for viability for some programs. And primarily, it's because of the cost of the inpatient care, making the cost of treatment very difficult for the single-pay agreements and the [ illness that ] I don't really understand. But I do know that most programs are moving towards outpatient CAR T cell therapy. And the nice thing is, I mean, for the 4-1BB products, like I think -- may Dr. Locke brought up earlier that the slower expansion of those T cells, and therefore, kind of a slower and reduced risk of the CR's neurotoxicity in some regards, which makes it more viable strategy in the outpatient setting regardless. I think the reality is, is that this was a novel therapy to start with. And for PK analysis and everything, sometimes it's easier to do that kind of stuff in an inpatient setting and, of course, monitoring these patients. I have no reservations whatsoever about doing this treatment in the outpatient setting. But I also want to clarify what we're saying by outpatient versus community oncology. Outpatient treatment doesn't equal community oncologists doing this type of treatments. And I think that's a dangerous correlation to make. And really, I think what the idea being -- like this is not a pharmaceutical product that -- I mean it is, but this is not a new oral HSV medication that you can give to oncologist. This is a cellular product that does require some level of experience and understanding of how to manage the toxicities. And I don't think community oncologists in Montana, for example, or Wyoming kind of our referral base here in Denver should ever be or would ever even be comfortable considering that type of treatment. So outpatient therapy, though, is much more viable. Patients love it. It's -- patients -- when we look at the auto transplant, the allo transplant data, the outcomes are just as good if they're inpatients. Infection rate is somewhat lower, and it's kind of how the field is going -- moving forward anyway. So...

Our next question will come from Ren Benjamin from JMP Securities.

I guess just on what Dr. Tees just talked about, my question has to do more of the real-world setting and the economic factors that are involved in these academic centers, right? So significant investment has taken place for these autologous therapies. And it seems like with that kind of investment that's taking place, maybe these academic centers don't necessarily want to have that easily replaced. And so I'm kind of curious, what do you think -- is that true? Or is it easy enough for them to replace this with autologous centers and -- sorry, with the allogeneic therapies? And you mentioned again not to consider this as much in the community setting, but that was something that we were thinking about with allogeneic therapies, at least over time. I guess I'd love to kind of unpack that a little bit more. And in the patients that have progressed from the ALPHA studies, have any of them been treated with an autologous treatment to date?

Let me answer the first...

[indiscernible] to Rafael. I mean do we have anybody treated with autologous after allogeneic cell therapy?

Not to my knowledge. No, nobody has been treated with autologous cell therapy.

Do any -- Fred?

I don't believe we've done that with a patient. I can answer the other part of the question as I run the cell therapy program at a large academic medical center. We're about to do our 500 CAR T cell therapy treatment. So we're excited about that. Yes, we have invested, right? We built a new unit. We have -- we built new outpatient space. But CAR T is coming from multiple diseases. We've got a line, even for multiple myeloma. Like we're scheduling out for like July and August apheresis, and we need more space, and that's where outpatient CAR T can make a difference, right? We're not worried about not doing best, right? We're worried about treating patients effectively and rapidly.

Maybe, David, I'll just make a quick comment on the market opportunity here. We're aware that at current run rates, the autologous products and large B-cell lymphoma are running upwards of $1.5 billion. That's mostly, obviously, in the academic settings. We certainly aspire to, over time, get to the community settings if we can further establish the safety and convenience of this product. But certainly, we believe this initial marketplace, LBCL, in the academic setting is very substantial, and that is, of course, a marketplace that today is not able to treat all of the patients in academia that could be appropriate for therapy. So we think that will continue to grow in an academic marketplace for our product once we're able to launch, assuming we're able to launch.

And let me just -- because this is an important topic for us, I mean, how to expand the use of the CAR T therapy. And when I think about 2014, 2015, I would say, at that time, autologous CAR T therapy was essentially ICU-based therapy. I mean, Fred, you may remember that. And 5 years now, we are talking about potential outpatient therapy for autologous CAR T therapy. And I always like to look ahead into the future. And certainly, from the company perspective, we will be looking way to safely develop and demonstrate the use of allogeneic CAR T therapy as an outpatient and potentially in the community setting as well. So it's something that we will be working [ for ].

Think about the [ unit in ] the Allogene product is that you don't need apheresis unit. You don't -- not every hospital has an apheresis unit. So you can give it in a community hospital that is not doing autologous or allogeneic stem cell transplant, theoretically, if you have the right doctors to do it.

Our next question will come from Dane Leone from Raymond James.

So 2 questions. One is easier, and I apologize, just given the breadth of all the ASCO stuff that came out, I might have missed this. But for the ALPHA2 analysis, there were 5 patients in DL2 in the [ A table 6 ] in consolidation. Can you just help me with why there are 4 in the valuable for DL2 and then 5 in consolidation, just why those patients were included? And then the second question, you're probably going to groan at because it's complicated, but some of the discussions we've had with hem oncs -- hemo trauma specialists has been trying to figure out has allogeneic CD19 CAR T moves forward to think about that in the scope of CD20 by CD3s being used potentially across lines of therapy and then auto CD19 CAR T potentially used maybe in the second line setting and the implications that have for how you position something like ALLO-501A.

So Rafael, first question. Eric, maybe the second question, you can answer.

Yes. So the first question is about the consolidation. So these are the table and the swimmers plot are different. So the table summarizes the consolidation experience across ALPHA1 and 2. And so there are 3 patients in ALPHA1 and 5 patients in ALPHA2. So it has the totality of the data there. The consolidation data that is in the swimmers plot has 5 patients in total, 2 of whom never received consolidation because they progressed at day 28. So we just wanted to be comprehensive to show the totality of the consolidation data in this slide when we talk about consolidation in ALPHA2. So I hope that clarifies the question.

And then on bispecifics, Dane, we did include questions or survey about the potential use of that future modality. Obviously, there's a lot less data today to support the use of bispecifics, but the early data are promising. I'll just come back to the highlights of the survey, efficacy, efficacy and more efficacy. That's clearly the #1 parameter here. And I think the data support that a modality like cell therapy, be it autologous or allogeneic, right now is the most powerful and most potent therapy that we have for NHL, and for that matter, in other hemalignancies as well. So it may be until the bispecifics are able to match the profile that's set forth here by these cell products, I think they're viewed a little bit differently. Interestingly, in our survey also, physicians preferred a one-and-done or two-and-done therapy, a time-limited therapy over anything chronic. And maybe perhaps the physicians can speak to the impact it has on patients to come into the office every week or every 2 weeks for chronic therapies. But if you can have a one-and-done therapy that's safely administered or time-limited therapy, like we're looking to launch with consolidation, that [indiscernible] got higher mix than a chronically administered drug.

Yes. I mean I think most -- everybody looks like CAR T cell therapy and auto transplant and allotransplant is what we would call a definitive therapy, not necessarily time-limited therapy. We call that definitive therapy where the bispecifics right now, while exciting, might not be something that's a definitive therapy. And I know that we're really not seeing that. So I don't put those in the same category by any means whatsoever. I think it could be a great bridge. It could be something if they fail auto CAR T, which you are seeing about 20% response rates in the CD20, CD3 [ rites ]. I'm using that actually as a bridge to an allo, in that case, but...

It's not specific. And so that -- sorry to say that so clear. But bispecifics CD3, CD20 are not as effective as CAR T. We know that from a retrospective data and acute lymphoblastic leukemia. And we know that from diffuse large B-cell lymphoma. So for example, that bispecific blinatumomab, which is CD3, CD19 in acute lymphoblastic leukemia is not as effective as the [indiscernible]. Retrospectively, this has been solved in diffuse large B-cell lymphoma. If you notice, the main company that makes the bispecific mosunetuzumab is the name of the bispecific CD3, CD20 has -- The FDA has not approved it yet. And the company tries to combine it with polatuzumab. That means that is not satisfied with the single-agent [ CAR T ], and the durability of response is another. But if there are some cures there, which no one claims yet, but if there are will be 10% to 15% at the most. So the -- in cancer, in general, the most effective therapy has to be given first. You cannot play with the [ pricing ] especially in that setting, relapse, refractory.

Our next question comes from Tony Butler with ROTH. It looks like Tony's line might still be muted. I will actually go to the next one as we wait for Tony. Asthika, I'm going to unmute your line. There we go. Asthika, from Truist.

Just want to talk about the MRD-negative data. Dr. Locke, some work by your colleagues at market have established some correlation between MRD-negative and durable [indiscernible] benefit with axi-cel. So maybe to tag on to a previous question on predicting durability, how do you interpret the initial MRD data that we associate today? And is the depth of MRD comparable to the work that your colleague did? And then maybe to the rest of the panel, is this something you want Doctors Amado, Chang and Schmidt to include in their pivotal study? And maybe what other data would you like to gather to help us predict durability?

Yes. So you're referring to work that was a collaboration between Moffitt, Maryland and led by [ David Nicholas ] at Stanford. We have a paper that's coming out shortly in JCO describing MRD using the clonoSEQ platform. And so the real use of that -- or that modality in CAR T, I think, is that at day 28 after autologous CAR T, we sometimes see PET positive disease. And MRD can tell us if that PET positive disease is false positive or not. It doesn't mean they're pseudo progression. It just means that it's not a CR. There's still something there, some inflammation or something. So that's the biggest utility. In fact, some larger studies have looked at MRD and DLBCL, and it showed it wasn't helpful to predict progression. So I don't know that it's necessary. I think it's helpful data to collect. It's also -- it can be cumbersome sometimes to get in real time MRD data on that short time line. So I think it's still a bit early to say that it's necessary for clinical development.

Maybe more accurate if you combine it with other. More accurate predictor if you combine it with other things. For example, the degree of the expansion, the pretreatment and bulk of the disease as reflected by the LDH, the degree of inflammation that time you give the cells by measure -- by [ CRP ] or by therapy. If you put all of those together, then probably you'll come up with more accurate predictive algorithm. But MRD, by itself, is not -- will not be 100% accurate. I got patients with MRD-negative DLBCL post auto CAR T, they did relapse, some of them.

Our next will now be from Tony Butler from ROTH.

Very, very simple question. What would be the minimum and maximum interval that you might think would be most optimal for redosing? For example, if you were to see a patient that is out beyond, let's just say, 12 months, 18 months, do you have any thoughts around you would simply redose that patient where did they progress? Or what would you think about a patient that is even post consolidation, even as shorter time as 2 months post consolidation?

With the redosing, I'm going to ask Dr. Locke. I mean I think you have most experience with redosing. So yes.

Yes. So first off, I -- if a therapy works and has worked for a period of time, unless I have evidence that it's a relapse associated with loss of the target, right, in CD19, then I absolutely think -- the first thing I think is let's give it again. I work for 14 months, oh, my gosh, like, we have to give it again. What else are we going to do? So that's pretty straightforward. As far as the consolidation, and then if a patient progresses, I think there is a path for this therapy of patients if things do grow and it's not wildly out of control, you could redose that patient. You could give multiple doses and keep someone in remission. That's not going to be every patient. I expect that the consolidation alone will be enough to put the majority of these or 50% of these patients in the complete response at 6 months, but it also allows for you to redose and redose again and redose again, which is off the shelf. We can give this 647 and move on. So I think it's a big plus for the therapy.

Our last question is going to come from Kalpit Patel from B. Riley.

Just a quick question on the data for the 6-month CR rates. Can you comment on why the 6-month CR rates are lower for follicular lymphoma patients than for LBCL patients in the CAR T naive cohort in ALPHA? Is it just a small number, sample size issue that may be causing this? Any color there would be useful.

Rafael, do you want to take that question?

Yes. I mean I think it's a combination of the numbers, the types of patients. I mean many of these patients were pretty advanced patients. And I think what we're looking forward to is what's going to happen when we use consolidation in these patients, if we can really get that CR rate to be much higher. I think there is a wide range still of CR in the follicular lymphoma. And it's -- I have a hope and no doubt that, that number is going to go up with time as we put more patients on and we consolidate the patients. So stay tuned.

Fred, any commentary as an investigator follicular lymphoma versus DLBCL?

Yes. So I mean these are different diseases, right? I mean they have different biology. We publish a paper in [indiscernible] looking at why patients don't have durable responses to axi-cel, and the biology of the disease matters within DLBCL alone. So I'm hopeful that the consolidation cohorts will give us those higher CR rates that are ongoing, and we'll just have to see. But again, follicular is a more indolent disease, and we have the option to give the therapy again, right? So I don't know. I think we need to see more data. But it's certainly very exciting overall about the response on this thing.

And I would also add, follicular lymphoma is more, I think, diverse disease. And with the sample size that we have, I think it's premature to draw any conclusions. I mean, certainly, I would say that if you look at the history of CAR T therapy, large B-cell lymphoma is much harder disease to control than the follicular lymphoma. So stay tuned.

So this will conclude our call. We just want to thank everybody. We know it's getting very late for those of you on the East Coast. Thank you for sticking with us. Thank you for all the questions. Our thanks to Dr. Locke, Dr. Tees and Dr. Lekakis for joining us and for all the work you've done on the trial as well. So thanks to all of you. Have a great night, and we look forward to continuing the conversation during the daylight. Thanks. Bye.

Thank you. Thank you.