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

Hello. Thank you for standing by, and welcome to Allogene Therapeutics ASH 2021 Conference Call. [Operator Instructions] Please be aware that today's conference call is being recorded. I would now like to turn the call over to Christine Cassiano, Chief Communications Officer. Ms. Cassiano, please go ahead.

Thank you, operator, and welcome to all who have joined this call. Earlier today, Allogene issued 2 press releases discussing data on our ALPHA, ALPHA2 and UNIVERSAL trials presented at this year's American Society of Hematology Annual Meeting in Atlanta. These press releases, today's webcast and corresponding slides are available on our website. We're looking forward to discussing the latest results from these programs as we progress toward our goal of making AlloCAR T therapy a reality for cancer patients. On the call today to review the data presented at ASH are Dr. David Chang, President and Chief Executive Officer; and Dr. Rafael Amado, Executive Vice President of Research and Development and Chief Medical Officer. Dr. Eric Schmidt, Chief Financial Officer, will join David and Rafael for the Q&A portion of this call. During today's call, we'll be making certain forward-looking statements. These may include statements regarding the timing and ability to advance our clinical trials, including our ability to resolve the clinical hold on our clinical trials and advance to a pivotal trial with ALLO-501A and clinical data among other things. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, and the company disclaims any obligation to update such statements. I'll now turn the call over to David.

Thank you, Christine. We are excited to be presenting updated clinical results here at ASH and perhaps even more excited to have our clinical team on site in Atlanta to see many of our investigators in our trials as we prepare for an eventful 2022. As we look back over the past year, we are very proud of all we have accomplished, not just for Allogene as a company, but also for patients in need of better therapeutic options. We uphold strongly that the work we are doing, including the trail that we are blazing to better assess and understand all aspects of our AlloCAR T products, will pave the way for a bright future for allogeneic cell therapy. Our team takes pride in this work as it is important for all those who have chosen to dedicate their livelihood to bringing the next generation of cell therapy products to patients. As we continue to push the field forward, our confidence in our platform is based on what we have already accomplished in our clinical trials. On Slide 3, you will see that more than 130 patients have been treated with our AlloCAR T product candidates. We continue to have a strong cash balance, which has allowed us to build and operationalize our Cell Forge 1 manufacturing facility in support of a pivotal trial, advance our research capability and preclinical pipeline and strengthen our corporate infrastructure as we look ahead towards another year of clinical progress. As illustrated on Slide 4, the automobile began to make its presence in society in the early 1900s. Early models were quite functional. Sears even sold them out of their iconic catalog. But assessing a new automobile was difficult. Obtaining one required waiting at the train depot, uncrating the vehicle and assembling it on your own. A few years later, Ford's Model T changed everything. It was easier to drive, more powerful and most famously, produced at scale on an assembly line. It rolled out a factory ready to drive. Ford didn't invent the automobile or make it fashionable, but by making it accessible, Ford changed how the world thought about cars. Oncology is on the cusp of a similar transformation, autologous CAR T therapies were a major step forward for patients with late-stage blood cancers. Several innovative new therapies that leverage an individuals own T cells to defeat cancer are changing the game, but they rely on bespoken manufacturing process that is incompatible with scale. And much like the customers who purchased the first automobiles, patients must wait: wait to secure a manufacturing slot; wait for harvesting of cells; wait to see if cell engineering is successful; and finally, wait for their cells to return to the clinic and reinfused. The next great leap will be technology that can democratize access to cell therapy, the way the Model T did, making it easier for patients to access potentially life-changing therapy. This has always been our goal at Allogene, and we believe the data we are sharing today is demonstrating that this goal is closer to a reality with allogeneic cell therapy having the potential to revolutionize the field. Slide 5 is a slide we presented to you in May at our CD19 Forum. It summarizes the market research that helped to inform how we progressed our Phase I trials, including: areas we wanted to better understand as we prepare for a pivotal trial; our assessment of the unique attributes of an allogeneic cell product, including how we might be positioned to expand the market, lead the potential benefits of consolidated dosing and understand the importance of timely treatment for patients. The relative level of importance physician place upon key product attributes range from efficacy, safety, dosing schedule and delivery are depicted here as you look at Slide 6. As we interrogate the levers at our disposal to fully optimize a product candidate like ALLO-501A, it became clear that efficacy parameters were the primary importance to physicians as they evaluated various NHL therapies. This included both the ability to achieve a complete response as well as maintain that response. While efficacy and durability are the most important considerations, other factors, including some that are inherently favorable or unique to our allogeneic approach, are highly influential. These include the likelihood that a patient receives the prescribed treatment, the time to treatment and other logistical considerations. Slide 7 depicts the balance we have been aiming to achieve in our trials. Physicians have been clear in what they want in terms of an ideal product profile for NHL. They seek an off-the-shelf option with durable efficacy and favorable safety that can be delivered quickly to all eligible patients. We believe the data Rafael will review with you today as it relates to the ALPHA trials and the updated data for the UNIVERSAL trial demonstrates that we are on the right track in terms of achieving the optimal balance between efficacy, specifically complete responses that are durable, and safety and convenience to ensure that all patients are able to access treatment. This is why we are focused and committed on our work to resolve the clinical hold on our trials and remain confident then in our ability to do so. I will now turn the call over to Rafael to review the data presented today at ASH.

Thank you, David. I'm excited to walk everyone through the latest clinical results that are being presented at the ASH Annual Meeting today. We'll start first with the ALPHA trials. These data sets are highly complementary to one another as both trials were designed to sequentially understand the key levers at our disposal for optimizing cell therapy, including cell dose, lymphodepletion and consolidation therapy. We started exploration with ALLO-501, where patient follow-up times are a bit more mature and then transitioned to our potential commercial candidate, ALLO-501A. But as you view the results, you will see a great deal of consistency across the trials, which fosters much confidence in their conclusions. Following the ALPHA studies, I will walk you through the UNIVERSAL data, and we will end with a Q&A session. This morning, Dr. Lekakis from the University of Miami presented data from our Phase I ALPHA2 trial, evaluating ALLO-501A in patients with relapsed/refractory large B cell lymphoma. And later this evening, Dr. Sattva Neelapu from MD Anderson Cancer Center will present a poster containing data from our Phase I ALPHA trial, evaluating ALLO-501 in patients with relapsed/refractory large B cell lymphoma or follicular lymphoma. Slide 9 provides a brief overview of both dosing regimens and enrollment. Perhaps most important on this slide and in the box area is that more than 97% of all patients who were enrolled in the trials were able to initiate treatment with a median time from enrollment to initiation being 5 days in ALPHA and just 2 days in ALPHA2. This was not unexpected given the off-the-shelf nature of our products, but nonetheless, gratifying to observe. In both trials, patients received lymphodepletion consisting of 30 milligrams of fludarabine for 3 days, 300 milligrams of cyclophosphamide for 3 days and various doses of ALLO-647, followed by escalating doses of ALLO-501 or ALLO-501A. In the consolidation dosing phase of the studies, 2 different consolidation regimens were explored. Consolidation 1 used the standard cyclophosphamide dosing of 300 milligrams prior to first-time infusion. Consolidation 2 explored a higher cyclophosphamide dose of 500 milligrams. Patients with stable disease or better at day 28 were eligible to receive a chemotherapy-free lymphodepletion regimen consisting of ALLO-647 only followed by a second dose of 120 million AlloCAR T cells. Slide 10 illustrates the consistent and manageable safety profile of our products. In both trials, there were no dose limiting toxicities of or cases of graft-versus-host disease and minimal observations of Grade 3 Immune Effector Cell-Associated Neurotoxicity Syndrome, known as ICANS, or Grade 3 cytokine release syndrome. Of note, Grade 3 blood infection rates were observed at a rate similar to that seen in autologous CAR T trials. In ALPHA, there were 5 treatment-emergent deaths in the absence of disease progression, all of which have been previously reported. And in ALPHA2, there were no treatment-emergent deaths. As you know, we reported earlier on a single case of chromosomal abnormality observed in the setting of severe pancytopenia in a patient in ALPHA2 treated with Consolidation 2, which has resulted in a clinical hold on our trials. Overall, both ALLO-501 and ALLO-501A have been well tolerated. But perhaps most critical is that Consolidation 1 in ALPHA2 and in the box area was associated with a superior safety profile across all metrics, including lower rates of cytopenias and infections. This may reflect our ability to provide the second dose of AlloCAR T cells following lymphodepletion that is chemotherapy-free, a key differentiating feature of our platform. These safety results lay the groundwork for AlloCAR T to potentially be deployed in an outpatient setting, a paradigm that could radically transform the use of CAR T therapies. On Slide 11, you can see that across the board, we are observing complete response rates on par with approved autologous CAR T therapies. In ALPHA, the overall response rate in autologous CAR T naive patients was 75%, and the complete response rate was 53%, with the longest CR ongoing at 18 months. Consolidation dosing demonstrated similar safety and improved efficacy versus a single higher cell dose with an 82% ORR and a 64% CR rate in 11 patients treated to date. Similarly, in ALPHA2, roughly half of the patients responded, and 28% had a CR. With the Consolidation 1 cohort of ALPHA2, 44% had a CR. Response rates in the consolidation arm are especially encouraging given the poor baseline characteristics of the patients treated with this regimen. 62% of the patients had Stage 4 disease, and 38% had an IPI score of 4. The longest ongoing CR is over 15 months, and the longest ongoing CRs in the consolidation cohort are more than 9 months. Slide 12 demonstrates why we believe Consolidation 1 strikes an optimal balance between efficacy, in particular, CR rates that are on the higher end of the range of approved autologous therapies and the safety profile discussed earlier, which lends itself to outpatient treatment. Based on the clinical profile of Consolidation 1 in both ALPHA and ALPHA2, we plan to initiate a Phase II pivotal trial in relapsed/refractory large B cell lymphoma utilizing this dosing regimen. As noted in the last slide, we continue to see ongoing and durable responses in patients dosed with ALLO-501. This swimmer plot on Slide 13 breaks into detail the responses in the ALPHA trial. Among the 21 follicular lymphoma patients and 11 large B cell lymphoma patients who were autologous CAR T naive, 33% and 36%, respectively, achieved a CR at 6 months. While follow-up times with consolidation dosing are shorter, the early data are encouraging. All responding follicular lymphoma and large B cell lymphoma patients remain in remission with the longest ongoing response being at more than 7 months. Slide 14 indicates that the initial durability results from the ALPHA2 trials are mimicking those of ALPHA. 6 out of 7 patients who achieved a CR remain in remission with 4 of those patients having between 9 and 15 months of follow-up. Additionally, 3 of the PRs in the Consolidation 1 cohort have converted to CRs. Slide 15 depicts a closer look at the large B cell lymphoma patients treated in both ALPHA and Alpha2 who achieved a CR. Importantly, with the exception of the one patient previously noted who died of an unrelated cardiac event, all patients who achieved a CR at month 6 remain in complete remission. We believe these results are compelling and similar to what has been observed in the autologous setting. They indicate that response to our therapies at 6 months may be a similarly good predictor of longer-term benefit. We're optimistic that as these data mature, they will support the possibility of large B cell lymphoma patients achieving functional cures following treatment with ALLO-501A. Slide 16 shows data from ALPHA2 demonstrating that patients treated with a consolidation regimen and experienced cell expansion and persistence after the second AlloCAR T dose. In other words, ALLO-647 alone with our Flu/Cy chemotherapy was sufficient to enable expansion of the second dose of CAR T cells. This is a critical and differentiated aspect of our platform with 2 potential benefits: one, we can spare patients the adverse events of a second course of chemotherapy; and two, as the graph indicates, by avoiding the use of Flu/Cy, we prevent eradication of cells from the first dose of AlloCAR T, allowing for ongoing antitumor activity, which we want to preserve. Now that I have walked you through the data, I want to take a few minutes on Slide 17 to put our CD19 program into context. These results have demonstrated that an allogeneic CAR T therapy may be able to match the level of efficacy achieved by approved autologous CAR T therapies for patients with large B cell lymphoma. The ALPHA trial delivered a complete response rate of 36% at 6 months in large B cell lymphoma following a single infusion of ALLO-501. In ALPHA2, a 44% complete response rate was achieved with Consolidation 1. This year rates fall well within the range of what has been reported by autologous therapies. And assuming these results can be replicated in larger trials, we believe we could have a very competitive profile in terms of both depth and duration of response while providing the benefits inherent to an allogeneic product. Meanwhile, on the bottom of the slide, you can see how our adverse event profile stacks up relative to autologous therapies. The safety of our product candidates remains a relative strength. And given the favorable tolerability of Consolidation 1 dosing in particular, treatment in the outpatient setting may be possible. Given the design parameters of ALPHA and ALPHA2, we have been in an enviable position to fully explore multiple means to optimize the delivery of our allogeneic cell products. This is noted on Slide 18. Not only will these results inform our future trials, they will also inform the field. We have generated robust data sets and a solid understanding of the properties of allogeneic CAR T therapy in large B cell lymphoma, including ways to optimize patient demographics, lymphodepletion and cell dose and schedule to deliver an outcome for patients that achieves a promising combination of efficacy, safety, convenience and access. We're pleased we have been able to generate these learnings in just over 2 years since our ALPHA trial began. With the data from ALPHA and ALPHA2 2 continuing to validate the promise of our AlloCAR T products as a safe and durable alternative to approved autologous CAR T therapies, we are finalizing the Phase II trial design based on input from the FDA. We expect to start such Phase II study on ALLO-501A in 2022 subject to FDA approval and pending the lift of the clinical hold by the FDA. Our other ASH data set was presented by Dr. Sham Mailankody of Memorial Sloan Kettering. This is an update from our Phase I UNIVERSAL trial evaluating single-dose ALLO-715 in patients with relapsed/refractory multiple myeloma. UNIVERSAL is the first allogeneic CAR T study in multiple myeloma. We believe that the safety and efficacy data highlighted in the oral presentation this morning provides the first and still only proof of concept data for an AlloCAR T in this disease setting. Today, BCMA-directed cell therapies, including Abecma, the first FDA-approved therapy, and several next-generation constructs have shown remarkable efficacy. However, several logistical challenges, including supply constraints, may be limiting access. And for many patients with multiple myeloma, time is of the essence, given the prospect of rapidly progressing disease. Allogeneic treatment offers the potential for all eligible patients to receive treatment. And as noted on Slide 20, with no bridging therapy required and minimal wait times to infusion. The UNIVERSAL study has 3 key parts. The focus of our ASH presentation is part A, a single infusion of ALLO-715 cells preceded by lymphodepletion. This part of the study included a dose escalation phase followed by a dose expansion phase. Part b is a combination arm with ALLO-715 and nirogacestat, a gamma secretase inhibitor provided by SpringWorks Therapeutics. And part C is an evaluation of consolidation dosing with repeat administration of ALLO-715. The dose escalation phase of the trial evaluated lymphodepletion followed by ALLO-715 of 1 of 4 dose level: dose level 1, 40 million cells; dose level 2, 160 million cells; dose level 3, 320 million cells; and dose level 4, 480 million cells. And 2 lymphodepletion regimens: FCA, fludarabine, cyclophosphamide and ALLO-647; or CA, cyclophosphamide and ALLO-647 only. The updated data shared today primarily focuses on the optimized DL3 dose and FCA lymphodepletion. The higher CAR T cell doses were associated with an increased response rate and greater AlloCAR T cell expansion. The key eligibility requirements included relapsed/refractory multiple myeloma with at least 3 prior lines of therapy, which includes all major classes of myeloma therapy. Patients were required to be refractory to the last line of therapy and 3 of donor-specific antibodies. Because ALLO-715 is available off the shelf, there was no need for bridging chemotherapy. The primary objective was safety, and the key secondary objectives included the recommended Phase II dose of 715, antitumor efficacy, the cellular kinetics of ALLO-715 and the pharmacometrics of ALLO-647. This slide also shows the schema for part A of the UNIVERSAL trial. Following screening, patients were enrolled, followed by lymphodepletion and a single infusion of ALLO-715. The different doses of lymphodepletion are listed here. Shown on Slide 21 is the patient flow. As of the October 14, 2021, data cutoff, 48 patients were enrolled in part A, with 43 patients starting lymphodepletion, receiving ALLO-715 and evaluable for safety and efficacy. Five patients became ineligible for treatment due to rapidly progressing disease despite the short turnaround time, which speaks to the fragile nature of relapsed/refractory myeloma and the immense need for timely initiation of therapy. Patients in this arm received a single dose of ALLO-715 with a median time of enrollment to start of therapy of 5 days. Patients did not receive bridging therapy and proceeded with treatment soon after enrollment. This stands in contrast to the experience with autologous therapies where bridging chemotherapy is common and wait times often amount to many weeks from enrollment to dosing. Patients who were treated at dose levels 1 and 2 were presented at ASH last year, so the focus of ASH this year were patients treated at dose level 3 or 320 million cells, as noted in the box area. The baseline characteristics of patients treated on this study are shown on Slide 22. All patients were heavily pretreated with refractory advanced-stage disease. Specifically, patients had a median of 5 prior lines of therapy and were refractory to their last line. 91% of patients were triple refractory. 84% of patients were penta exposed, and 42% were penta-refractory, meaning the disease has ultimately become nonresponsive to other approved therapies. Of this patient pool, 19% had ISS Stage III, and 21% had extramedullary disease. Additionally, 37% had high-risk cytogenetics. ALLO-715 and ALLO-647 demonstrated a manageable safety profile. As shown on Slide 23, there were low rates of high-grade CRS, only 1 patient had a Grade 3 reaction, and there were no instances of Grade 4 or 5 CRS. Grade 1 and 2 CRS was reported in 23 patients but was manageable with standard therapies. Additionally, there were no cases of GvHD or Grade 3-plus ICANS. In this heavily pretreated patient population, observed infection rates were in line with those seen in autologous CAR T cell studies and occurred in 54% of patients. This included 3 Grade 5 infections, 2 of which were previously reported. Grade 3-plus neutropenia occurred in 70% of patients. The data presented on Slide 24 demonstrate encouraging efficacy with additional patients at dose level 3, which was the dose chosen for expansion. A total of 24 patients were treated at this dose level and the FCA lymphodepletion regimen. The ORR in this cohort was 71%, with 46% of patients achieving a VGPR+ and 25% of patients achieving a CR or stringent CR, namely 3 patients each. We are encouraged that these response rates have improved over time, including since our ASH abstract was submitted. The ORR increased from 60% reported at ASH 2020 to 71%, with 46% of patients achieving a VGPR or better, up from 40%. We are also encouraged that response rates to ALLO-715 are similar to or better than several recently approved therapies for advanced multiple myeloma, including Abecma. Slide 25 summarizes the key findings from ALLO-715 UNIVERSAL trial, the first study of its kind. Data presented at ASH this year demonstrates that a single dose of an off-the-shelf AlloCAR T product is capable of inducing deep clinical and meaningful responses that are similar to approved autologous CAR T therapy. Demonstration of this potential in patients with relapsed/refractory multiple myeloma provides important validation of our platform in a second refractory tumor indication. In addition, off-the-shelf AlloCAR T cells have the potential to address significant unmet need in patients with rapidly progressing myeloma. Allogeneic treatment eliminated the need for bridging therapy, allowed for quick turnaround with a median time of 5 days from enrollment to start of therapy and enabled 90% of all patients being able to receive treatment. The combination of ALLO-715 with ALLO-647 was well tolerated with low-grade CRS, low-grade reversible neurotoxicity, no GvHD and an overall manageable safety profile. At the dose of 320 million cells with FCA conditioning, the ORR was 71% with a VGPR+ of 46%. 92% of the VGPR+ patients were also MRD negative, and the median duration of response for this cohort was 8.3 months. Our data to date provides proof of concept that our AlloCAR T platform can potentially mimic results achieved with the currently approved autologous therapy while providing unique benefits in time to treatment, thereby eliminating the need for bridging therapy, as shown in Slide 26. While we are very pleased with the results of our initial work with a BCMA-directed AlloCAR T product, we know that next-generation autologous approaches continue to raise the bar for the field, at least in terms of offering greater potency. And as I will discuss in a moment, we too are focused on next-generation approaches designed to enhance our product profile. But before we delve into our efforts to further optimize therapy, I want to take a moment to highlight the unique advantages of our AlloCAR T products. This is highlighted on Slide 27. Manufacturing is scalable, and there is less product variability our product candidates can be engineered to express not just CARs, but other genetic elements that can potentially enhance antitumor activity and lend themselves to repeat dosing. The data from our UNIVERSAL trial fuels our enthusiasm and supports our commitment to developing BCMA-directed AlloCAR T therapy. Slide 28 highlights our broader anti-BCMA strategy. UNIVERSAL has established clear proof of concept for ALLO-715, and that trial is planned to progress with consolidated dosing of ALLO-647 to selectively extend the window of lymphodepletion. In addition, UNIVERSAL is evaluating our 715 in combination with SpringWorks Therapeutics' investigational gamma secretase inhibitor, nirogacestat. Lastly, I'm excited about ALLO-605, the company's first TurboCAR candidate. The Phase I dose escalation portion of the IGNITE trial was initiated in 2021. David started this presentation talking about how like the Model T AlloCAR Ts have the potential to change everything, greater access, on-demand dosing, scalable manufacturing and simpler logistics. As you look at Slide 29, we intend to exploit all of the inherent benefits of allogeneic cell therapy, both from a clinical perspective as well as operationally, so we can find ways to treat every eligible patient no matter how advanced the disease, where they live or how quickly they need therapy. And with that, we will now open the call for your questions.

[Operator Instructions] Our first question comes from Michael Yee of Jefferies.

We had a 2-part question. On the overall CD19 data, I think that people came away looking at perhaps the consolidation of 2 cohort a bit puzzling with the 1 out of 10 CR rate. Can you put that into context for us how to think about that? Are there a lot sicker patients? Are there people who failed prior CAR T? Or do you think it is, in general, based on clinical trial design, you're just getting sicker patients these days. Maybe talk about that a bit into context. And then on durability, which I think is going to always be a question about all these things. Where do you think you stand on that? You think you've kind of cemented that sort of for a while and you think you're on par with autologous. I'm looking at a lot of data out there. There's not much durability for anybody out there, and I guess NK did also just hit the type 2, which is a bit interesting. So that would be great if you could comment on durability.

Michael, good afternoon, and thank you very much for that question. We actually presented a lot of data today, essentially summarizing past 3 years of work at Allogene where we have treated over 100 patients with AlloCAR T, probably the most in the field. So before I get to your question, let me sort of reiterate some key points, specifically as it relates to the ALPHA trials. I mean, there are important lessons that we can learn from the ALPHA trials. I mean, foremost is that our allogeneic platform is allowing robust cell expansion and complete responses that are on par with autologous cell therapy. And also consolidation, which I know has been focus of a lot of people's attention, is extremely well tolerated. And especially in Consolidation 1, we have ways. And even today, Dr. Lekakis reiterated a comment that this can be given as an outpatient. And overall, in the complete responses that we are seeing is, we believe, is on par with what we have seen in other autologous CAR Ts. And also notable is the durability of the responses that we are seeing. During Rafael's presentation, we summarized the patients who have achieved CRs. They were altogether 14 of them. And if you look at the durability of their response, I mean, this is just spectacular. I mean patients who have gone past 6 months, they continue to be in remission as we follow them. And in fact, none of the patients who achieved CR at month 6 had progressed. And also, there are other patients who haven't gotten to that. But overall, out of 14, 10 patients in response, including the ones who have passed a 7-month time point. So I think these are very important points of the allogeneic cell therapy, I mean, certainly, over the past few months, we have seen data coming from other approaches from other companies, and I believe that our data stands very strong in terms of the complete response rate as well as the durability of the response. So to answer your question specifically, about the Consolidation 2, this was tested in the ALPHA2 study. And what we did was going up slightly on Cytoxan. And this is also coming after we presented the data on our CD19 Day. And obviously, as we looked at the data, Consolidation 2 cohorts stood out, and we've been looking into it very carefully. But we also have to look at the data in the context of over 60 patients with non-Hodgkin's lymphoma that we have treated between ALPHA and ALPHA2 study. So there are different ways to look at the data. So some of the speculation that we can come up with of our Consolidation 2 is really time period as well as some of the excitement by the investigators, especially after seeing the Consolidation 1 safety data as we presented in our CD19 Day. And when we look at Consolidation 2 cohort more closely, patients in general had more poor prognostic factors including a majority of them having very high LDH, which is a well-known negative predictor to treatment outcome. So this, together with a number of prior CD treatment that Consolidation 2 cohort got, and that's in our presentation that Dr. Lekakis made earlier today. So at the end, we have to look at this in the context of overall data, and we believe that Consolidation 2, for the reasons that I have said, is a little bit of an outlier, but also is an important lesson for us. As we look into this data, we are sort of taking a few lessons about how we can better control the patient characteristics who will be enrolled into our Phase II study. So we feel very confident about what we are seeing in the ALPHA1 and ALPHA2 study. And the issues with the consolidation at this point, we are viewing that as an outlier.

Okay. Okay. But just to be clear, and I'm sorry for taking time, but it's 3 out of 10 people at prior CAR T. Was that number in the slide? Or what?

Yes. So I think in the presentation, in the Consolidation 2, I think there were altogether 10 patients. And our clinical data indicates that 5 of them had a prior CAR T -- I'm sorry, 5 of them had prior CD19 therapy. And we're trying to find the details, and we don't have that information yet about how many of those are prior CAR Ts versus other anti-CD19 therapies. So stay tuned.

Our next question comes from Tyler Van Buren with Cowen.

Just wanted to further parse out the difference -- potential difference in consolidation in ALPHA2 versus a single dose in ALPHA. It's difficult for me to believe that the increased expansion in persistence after a second CAR T dose isn't going to add something. And clearly, the initial CR rates appear similar. But I guess, is it just too early to really tell if there's going to be an improvement in terms of durability with consolidation dosing? I guess, if you look at the 14 CRs, which conveniently is split 7 and 7, you do appear to have 3 progressors in ALPHA versus only 1 in ALPHA2. So is there maybe a hint there? And then just the second question related on the same topic is why would consolidation dosing potentially have an improved safety profile? What's the hypothesis there?

Okay. Tyler, thank you for very insightful questions on our data. I mean, certainly, you are looking at every angle. I mean, in terms of consolidation, if we bypass -- I failed to answer some of the specific questions that you're asking. We are providing cell infusion over 4 to 5 weeks, 2 different cell infusions. And certainly, we are seeing evidence of cell expansion with a second cell infusion, which I think is the most exciting findings. And a lot of times, we constantly talk about the importance of persistence. But as we are beginning to talk about, I think the real question is importance of functional persistence of the CAR T cells. And that's exactly what the consolidation is doing. You're giving a fresh cell -- batch of cells for the second infusion. And when those cells expand, they are functionally active. So not only we are improving the overall persistence, I think we're having a pretty significant effect on the functional persistence of the single-acting CAR T cells. And to the specifics about the patients and the CRs and the duration of response, I'm going to pass off to Rafael.

Yes, Tyler. So I mean, we are pretty excited about consolidation, particularly Consolidation 1. We did this experiment of increasing cyclophosphamide. And the number of patients that we've accrued has allowed us to look at different dosing and schedule, and also the availability of ALLO-647, our process to do these kinds of experiments because we don't use chemotherapy to eliminate the first batch of cells of skin at day 0. So I'd like to look at the data in an overall fashion, both on ALPHA and ALPHA2. And the responses are when you just parse out C1 are in the 70s overall and north of 40% CRs. And so -- and then obviously, it's a little early to know the durability, but we are starting to get durability that is surpassing 9 months. So that is actually boding well for potentially adding to that Slide 15 graph that you were referring to before. I think you were pretty insightful when you were talking about why should it be safer. We think that part of it may be because we give 60 milligrams first and then the rest of the 30 milligrams are given 28 days later without chemotherapy. So we managed to give 90 milligrams, which we think is optimal in a split fashion. And we also give cells that re-expand. So I think taken together, there's really the best balance, I think, between efficacy and safety, particularly with C1. And ALLO-647, given on 90 milligrams is probably the ideal dose, and this big dose allows for better safety.

Our next question comes from Salveen Richter with Goldman Sachs.

This is Andrea on for Salveen. Maybe one for Rafael or David. Just wondering if you could comment on how the profiles that have emerged from the consolidation treatment compared to your initial expectations. And do you believe there are still levers that need to be optimized here?

Yes. So I think, as I said before, what we've been most impressed with is the tolerability, particularly with Consolidation 1, both the initial dosing and more importantly, the second dose, which is pretty easy to give patients and receive as an outpatient, and it helps us to get higher doses of cells and split ALLO-647 in a way that supports the safety that I just talked about. So we will continue, obviously, to accrue particularly large B-cell lymphoma in ALPHA2 with Consolidation 1 because we think that it strikes the best balance between safety and efficacy. And that's really what this is about and potentially being able to bring this not only to the vast majority of patients, but also potentially to community setting and outpatient setting.

Andrea, let me just add on to that. I mean, when I think about what we did at Allogene over the last 2.5 years is really trying to get to the right balance of safety and efficacy. I mean, we -- our studies are complex. I think we have heard that from several today after we provided some additional updates. And part of the reason is we tested not only the cell dose, but many different lymphodepletion regimens because we believe that the requirement of lymphodepletion for the allogeneic will be substantially different than what has been used in autologous. I mean that was the early recognition, which led us to test many different regimens. And at the end, I think we have a clear understanding that the standard lymphodepletion is not going to be sufficient. We need something more. And that something more is really being provided, and we have optimized it quite a bit with ALLO-647, our anti-CD52 antibody.

Our next question comes from John Newman with Canaccord.

I was a bit surprised that you're allowing some of the very difficult patients in the consolidation study. I think you previously mentioned you had several patients that had prior CD19 experience. Should we expect that in the pivotal study those patients might be excluded? And also, would there be other parameters, you mentioned LDH, that would better allow you to treat a similar patient population, if possible, as the patients that are currently receiving autologous CD19?

Thanks, John. This is Rafael. Excellent question. I think the timing to explore multiple variables you've seen in Phase I. And sometimes, we have to explore variables that may result in patients not responding or having a lower response rate. And that's the case, for instance, of prior autologous therapy, which is really true also in the autologous setting, by the way, as you know. Patients with very high LDH also do very poorly in the autologous setting. Patients with extranodal disease also do poorly. And these -- some of these patients made it into our trial, particularly in Consolidation 2. And they were allowed, in part, because of the enthusiasm of physicians, particularly patients that couldn't wait to receive autologous therapy, but also for us to understand what are the limits of the therapy with regards to activity. And so your point about learning on these Phase I studies, what are the best patients that may benefit from therapy is a really good one, and it's certainly going to inform the design of our pivotal trial.

Our next question comes from Luca Issi with RBC.

Maybe the first on the clinical hold. Wondering if you can comment on whether you have provided the appropriate responses to the FDA. And maybe bigger picture, what gives you confidence that the clinical hold will ultimately be lifted? And then the second, maybe on cyclophosphamide, can you remind us why you almost doubled the dose from 300 milligrams to 500 milligrams for consolidation? Should we assume that, that experiment is essentially over or you're maybe planning to explore those in between the 2?

Look, let me take both questions. In terms of the clinical hold, I mean, we have made several comments in different situations. We believe that we are in control of the situation in terms of generating the data supporting our hypothesis as well as expanding the data set by analyzing some of the patient samples. So it's -- to us, I strongly believe it's not the question of whether we will get out of the clinical hold or not, it's just a matter of when. And on that regard, we are not saying much because, in part, the final arbiter of our argument would be the FDA. So let's stay tuned, and I do not want to stay ahead of what FDA may or may not say. So that's one. And then the second question about why did you go up on the cyclophosphamide. I think this is really driven by some of the preclinical work as well as available data in terms of lymphodepletion. When we do the lymphodepletion, we simply follow the peripheral blood count. But there is also cells in the tissue, lymph nodes and elsewhere. And there is data that would suggest that high-dose cyclophosphamide is more effective in eliminating the lymphocytes that may be in the tissue, not in circulation or in the bone marrow. That was the hypothesis. And as Rafael has suggested, if we were going to test that Phase I study would be in the setting that we have done, we would do it, and that's exactly what we did. And your last question, are we still going to go back and forth? At this point, I think after spending about 2.5 years and going through many different iterations of the lymphodepletion, I think we are getting fixed with the Consolidation 1 as we are looking forward to the start of our pivotal study.

Your next question comes from Michael Schmidt with Guggenheim.

I had one on durability. It's obviously nice to see that many of the CRs in ALPHA and ALPHA2 were relatively durable. Just curious, in the UNIVERSAL study, if you could just comment on durability of CR? And I thought it was interesting, I think, in the Abecma studies, we saw some of the responses deepening over time. And I was just curious if that's something that perhaps you've observed as well. And the second part of the question, again, on myeloma. Just wondering how you're weighing next development steps with 2 other programs still ongoing?

Yes. Let me take that question, Michael. So as you know, we've been very pleased to see the data mature and the durability of response increase, now being above 8 months for responders. And the VGPR+ 46%, which is pretty similar to what has been seen with the Ide-Cel. The CR rate that are maturing, we are -- we have patients in CR that are approaching a year. And we believe that there's still a lot of patients that are in response, that, that number may actually get better with time as we continue to follow these patients. And in addition to that, we are starting the consolidation cohort now, which may actually add some benefit with regards to responses. Obviously, it will take some time for that data to mature. But it will, hopefully, increase the rate of CR and overall with time, the durability of response. So stay tuned, but so far, we're very pleased with how these numbers are improving with time.

Our next question comes from Mark Breidenbach with Oppenheimer.

Just I'm looking at ALPHA and ALPHA2, and I'm wondering if you're generally seeing ongoing B-cell aplasia in patients who have ongoing responses, and if that differs at all from your experience with autologous CD19 CAR Ts? And, like, kind of second part of the question is there are obviously a few follicular lymphoma patients who lost their responses kind of late in the trial. Maybe you can comment on why that 6-month CR rule doesn't really seem to hold up necessarily in follicular lymphoma in particular?

Yes. This is a really important question with regards to B-cell aplasia. We follow the recovery of the cells very carefully, and patients remain with B-cell aplasia for several months. Eventually, they start recovering their B-cells. And likewise, their T cells also start coming back up, which starts coinciding with the decrease and disappearance of persistence. So that B-cell aplasia, it still compares pretty similar to what we've seen with the 28 CARs. With regards to follicular lymphoma, the initial response rates and complete response rates are -- we've been very pleased with them. I mean, CR rate of 75%. The 6 months rate of 32% has improved from 24%, and we think that there's may be perhaps an opportunity for that number to get better. It is true that some patients with long responses, a few of them have recurred. But this is a different disease. It tends to be a chronic disease, and it's possible that there are, for some patients, responses that are more limited than they are in large T-cell lymphoma, where 6 months responses are very predictive. So still a little bit of early days, but we are pleased with the way that the 6-month rate is really increasingly with time.

Thank you. And in recognition of participant time constraints during a busy ASH meeting, our last question will come from Ren Benjamin with JMP Securities.

For me, it's about the cell expansion data that you have in the second CAR-T dose. Can you maybe just help explain how these expansions may be correlating to the depth of the CR? So all these 3 patients ultimately got a CR. But clearly, the expansions vary quite a bit. I'd love to just kind of get your thoughts as to how you're viewing this. Can you also tell us what's the longest you've seen the cells actually persist in a patient? And is there any thoughts to dosing according to kind of, like, cell number or vector copy number within a patient?

Okay. Ren, let me take that question. In terms of second cell infusion, the fact that we are seeing cell expansion is very exciting. So cell expansion, that is really triggered by the presence of CD19, whether it's present in the B-cells or whether it's present in the lymphoma cells, which would really trigger the activation of the CAR T cells. So in the cases where we see the partial response sort of converting to CR, we have been asked and we certainly have seen it in the autologous setting after single infusion, because there's no chance for consolidation in autologous setting, sometimes initial PR improves over a period of time to CR. Those are usually some minor PET findings that prevents you from calling a good response to a CR and you just have to wait for the PET response to go away. I mean certainly, some of the patients in our study would apply to that kind of setting. But certainly, when we see the cell expansion, I mean that's a really good indication that the consolidation is doing what it is intended to do. Your other question about how long do you see the cell persistence by vector copy number. And obviously, this is by vector copy number. We don't know whether those cells are functional or not. I mean, the only way that you know whether CAR T cells are still functional or not is sort of following as a surrogate endpoint the duration of B-cell aplasia. And as Rafael said, that B-cell aplasia we see in our study is pretty -- it's very comparable to what we have seen in the autologous setting. Having said that, just if you just followed by the vector copy number, we can easily get up to about 120 days, which I believe is more than enough to get the maximum benefits of the CAR T therapy. And your last question, will we ever consider dosing based on vector copy number? I mean, I'm not going to say no. I mean, as we learn about the CAR T therapy, maybe in the future. But right now, that's not something that we are considering.

Thank you. That concludes our question-and-answer session. I would like to turn the conference back over to management for any additional comments.

ASH has been an extremely busy time for all of us, and thank you very much for joining the call today. As we said in the beginning, we are very proud of what we, Allogene, has accomplished in the allogeneic cell therapy setting. And we look forward to updating the data as we follow these patients as well as communicating additional data. So thank you very much for following us today.

Thank you. Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program, and you may now log off and disconnect.