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Edited Transcript of ALLO.OQ earnings conference call or presentation 7-Aug-19 12:30pm GMT

Q2 2019 Allogene Therapeutics Inc Earnings Call

Aug 14, 2019 (Thomson StreetEvents) -- Edited Transcript of Allogene Therapeutics Inc earnings conference call or presentation Wednesday, August 7, 2019 at 12:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Christine Cassiano

Allogene Therapeutics, Inc. - Chief Communications Officer

* David D. Chang

Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director

* Eric Thomas Schmidt

Allogene Therapeutics, Inc. - CFO

* Susie Jun

Allogene Therapeutics, Inc. - Chief Development Officer

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Conference Call Participants

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* Benjamin Jay Burnett

Stifel, Nicolaus & Company, Incorporated, Research Division - Associate

* Biren N. Amin

Jefferies LLC, Research Division - MD and Senior Equity Research Analyst

* Charles Anthony Butler

Roth Capital Partners, LLC, Research Division - MD, Senior Equity Analyst & Head of Biotechnology Research

* Cory William Kasimov

JP Morgan Chase & Co, Research Division - Senior Biotechnology Analyst

* Dane Vincent Leone

Raymond James & Associates, Inc., Research Division - Research Analyst

* Kelsey Beatrice Goodwin

Guggenheim Securities, LLC, Research Division - Associate

* Marc Alan Frahm

Cowen and Company, LLC, Research Division - VP

* Mark Alan Breidenbach

Oppenheimer & Co. Inc., Research Division - Executive Director & Senior Analyst

* Maryana Ilya Breitman

Goldman Sachs Group Inc., Research Division - Research Analyst

* Raju Yashaswi Prasad

William Blair & Company L.L.C., Research Division - Senior Research Analyst

* Tyler Martin Van Buren

Piper Jaffray Companies, Research Division - Principal & Senior Biotech Analyst

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Presentation

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Operator [1]

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Good morning, ladies and gentlemen, and thank you for standing by, and welcome to Allogene Therapeutics' Second Quarter 2019 Conference Call. (Operator Instructions) Please be aware that today's conference call is being recorded.

I would now like to turn the conference over to Christine Cassiano, Chief Communications Officer. Ms. Cassiano, please go ahead.

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Christine Cassiano, Allogene Therapeutics, Inc. - Chief Communications Officer [2]

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Thank you, operator, and good morning. Before market opened today, Allogene issued a press release that provides a corporate update and financial results for the quarter ended June 30, 2019. The press release is available on our website at www.allogene.com. We will be discussing our ALLO-715 Phase I clinical trial protocol today and I've posted on our website a slide, which provides an overview of the trial. This can be found in the Investors section under news and events. We remind listeners that today's call is being webcast on our website and will be available for replay. Joining me on the call today are Dr. David Chang, President and Chief Executive Officer; and Dr. Eric Schmidt, Chief Financial Officer.

During today's call, we will be making certain forward-looking statements. These may include statements regarding the success and timing of our ongoing and planned clinical trials, regulatory filings, future research and development efforts and manufacturing capabilities, 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, including our Form 10-Q for the quarter ended March 31, 2019 as well as our upcoming Form 10-Q for the quarter ended June 30, 2019. 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 Dr. David Chang.

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [3]

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Thank you, Christine. Good morning. Thank you all for joining our second quarter earnings call. We are very pleased to be speaking with you this morning to review our recent progress. The second quarter was an important one on many fronts from advancing our pipeline to designing our state-of-the-art manufacturing facility and recruiting highly skilled employees who are passionate about bringing allogeneic cell therapy to patients. To that end, our full-time head count now has grown to over 170 employees.

Top of mind for many of you is the progress we are making in our clinical programs. The second quarter marked the initiation of Allogene's first sponsored clinical trial as we began treating patients in our ALPHA study, our Phase I/II study of ALLO-501 in relapsed or refractory non-Hodgkin lymphoma or NHL. We are pleased with how this dose escalation study is progressing and believe that success in this trial has the potential to de-risk our anti-CD19 AlloCAR program as well as our AlloCAR T platform more broadly, including the use of our proprietary lymphodepletion strategy that is anchored around our anti-CD52 antibody ALLO-647.

During our first quarter earnings call, we discussed at length the protocol for the ALPHA study. I think it bears repeating what we view as the key components for success in this trial. First, we would hope to see good cell expansion. We believe early expansion of CAR T cells correlates well with tumor-killing activity, regardless of whether the CAR T therapy is autologous or allogeneic. Second, we want to gain a better understanding of the safety profile of ALLO-501 in Phase I portion of the study. Adverse events of interest will include known risks associated with autologous CAR T therapies, including cytopenia, cytokine release syndrome and CNS toxicity as well as graft-versus-host disease or GVHD, which is unique to allogeneic CAR T therapies. Third, we will evaluate patients for signs of early tumor response, bearing in mind that in the Phase I dose-escalation portion, the initial cohort will be receiving a fixed dose of 40 million CAR T cells, which is below the approved CAR T cell dose for Kymriah and Yescarta in relapsed and refractory DLBCL. We know based on data from autologous CD19 trials that tumor cell killing occurs early on and the depth of the initial response in the first several months is perhaps the best predictor of whether a patient will experience a durable long-term remission, which leaves us to the last critical component of ALPHA study, durability.

While we are still in the early stages of our Phase I trial, we look forward to following patients over time to understand the potential by AlloCAR T therapy to have a transformative impact on long-term patient outcomes. We believe we are in an enviable position and that we began our Phase I study with clinical data enhanced from UCART19 in relapsed or refractory acute and lymphoblastic leukemia. As ALLO-501 and UCART19 shared the same molecular construct, we believe the available UCART19 data is informative for the ALLO-501 ALPHA study.

As presented at the ASH conference last year, the UCART19 safety profile appeared manageable. The most common adverse event was cytokine release syndrome and GVHD was limited to grade 1 adverse events in this allogeneic setting. The UCART19 data also demonstrated that early cell expansion and deep anti-tumor responses can be achieved when deploying a lymphodepletion regimen that contain anti-CD52 antibody. We are hopeful that data from the ALPHA study will serve to reinforce what we have already learned from UCART19 experience and that such data can be used to accelerate the advancement of ALLO-501 into Phase II portion of the ALPHA trial, expected to begin in 2020.

Beyond ALLO-501, we are developing ALLO-715, our anti-BCMA allogeneic CAR T therapy for the treatment of relapsed or refractory multiple myeloma patients. We noted in our last call that we have submitted our IND for ALLO-715. And in May, we were pleased to receive clearance of this IND. We are fortunate that we have been able to apply learnings from our ALLO-501 programs, ALLO-715 program. We remain on track to initiate the ALLO-715 UNIVERSAL trial in 2019.

The protocol for ALLO-715 UNIVERSAL trial will be similar to the approach we have taken with ALLO-501. The Phase I study is designed to assess the safety and tolerability at increasing dose levels of ALLO-715 with a goal of identifying an optimal dose of ALLO-715 for a potential Phase II study, which could be a pivotal study for a BLA submission. This trial will also utilize ALLO-647, our proprietary anti-CD52 monoclonal antibody as a part of the lymphodepletion regimen. Importantly, this trial includes the potential for secondary exploratory cohorts that will allow us to study additional lymphodepletion regimens, including one that only uses ALLO-647 without fludarabine or cyclophosphamide.

In the main portion of this study, we plan to enroll up to 24 patients with relapsed or refractory Multiple Myeloma, who have failed at least 3 prior lines of therapy in a dose escalation, 3+3 trial design. Details on the starting cell dose and the initial lymphodepletion regimen, both of which are the same as in the ALLO-501 ALPHA study can be found on the slide Christine referenced earlier in this call. The UNIVERSAL study may also include additional cohorts to assess the potentially milder lymphodepletion regimen where the chemotherapy components, specifically fludarabine and cyclophosphamide, will be stepwise removed. As we look ahead, we will be looking at end points such as safety, response rate and the duration of response as key determinants of success for ALLO-715.

Last quarter, we touched upon our initial thoughts as we explore the potential for CAR T therapy in solid tumors. We very much think of solid tumors on a spectrum and believe that it is important to first explore the viability of this modality and targets that have commonalities with blood cancers and where we have already seen CAR T therapy be successful. Many of the targets we gained through our acquisition of assets from Pfizer are in solid tumors. So we have the option to expand our research quickly where we see opportunity. Our focus in this area today includes CD70 in renal cell carcinoma and DLL3 for small cell lung cancer. We are also excited about the headway we are making in the build-out of our manufacturing facility in Newark, California. We have completed design for the facility and look forward to starting internal manufacturing suite construction by the end of this year.

Finally, we issued a press release on Monday, announcing that Dr. Rafael Amado will be joining Allogene as our Executive Vice President of R&D and Chief Medical Officer. Rafael brings a skill set to Allogene that is as impressive and highly complementary to the rest of our leadership team. We also focus our discussion on the science and our trials, but people are the key component of success. Our teams are largely made up of people with our shared histories, passion for innovative science and communal drive to advance cellular therapy for the benefit of patients. Many of our team members have spent years together before taking separate journeys. Now in a very fortunate circumstance, these team members have been reunited, creating an opportunity to complement each other.

Rafael represents that perfectly. Many at Allogene have known Rafael for years and have worked with him in his previous positions. In fact, Arie Belldegrun and I both knew Rafael while at UCLA, and he and I started our industry careers around the same time with Amgen. Subsequently, Rafael has spent years in oncology and advancing cellular immunotherapies. I know firsthand how talented Rafael is, and I am thrilled that we will be back on the same team. All of our efforts to build Allogene and our intense focus on accelerating AlloCAR T therapy over the last 15 months is now beginning to bear fruit. As we advance into the clinic, we look forward to what we envision. We see a very exciting next 12 months by Allogene.

I will now pass the call over to Eric.

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Eric Thomas Schmidt, Allogene Therapeutics, Inc. - CFO [4]

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Thank you, David, and thanks to everyone for dialing into this call. I will provide a brief overview of Allogene's financials. Additional detail on our second quarter financial results can be found in our press release issued earlier today and in our 10-Q, which will be filed with the SEC.

We are pleased to report that we remain in a strong financial position. As of June 30, 2019, Allogene had cash, cash equivalents and investments totaling $650.2 million. In the second quarter, our research and development expenses were $31.8 million, which includes $4.7 million of noncash stock-based compensation expense. General and administrative expenses were $14.2 million for the second quarter of 2019, which includes $6.7 million of noncash stock-based compensation expense. Our net loss for the second quarter of 2019 was $41.2 million or $0.41 per share, including noncash stock-based compensation expense of $11.5 million. We are continuing to invest heavily in advancing our clinical programs, building out our manufacturing capabilities and hiring exceptional talent. As guided previously, we expect full year 2019 net losses to be between $200 million and $210 million. This includes an estimated noncash stock-based compensation expense of $45 million to $50 million and excludes any impact from potential business development activities. With that brief review of our financials, we will now open the call for your questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) And our first question comes from Marc Frahm with Cowen & Company.

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Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [2]

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Congrats on the progress. In prior calls, you've mentioned that the kind of preconditioning regimen that you're starting within the ALPHA trial is based on kind of modeling from what you've seen from UCART19 as well as other programs, but you had the flexibility to adjust depending on what you actually saw in terms of lymphodepletion and cell expansion. Have you guys gotten to the point that you've confirmed that, that regimen is doing what you wanted it to do? Or is it still an outstanding question for you?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [3]

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Marc, Dr. Chang here. Let me take that question. As we have indicated, a lot of thought went behind how we set up the initial lymphodepletion regimen. That includes not only fludarabine and cyclophosphamide but our ALLO-647 or anti-CD52 antibody. Some of the questions that you're asking now, it's getting into the clinical data. And I think it will be better be left for us to present those findings at a conference in 2020, as we have indicated in the earnings call.

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Marc Alan Frahm, Cowen and Company, LLC, Research Division - VP [4]

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Okay. And then I guess, thinking of conditioning regimens for the UNIVERSAL trial, you mentioned possibly trying to remove either cy and/or flu from the regimen. Is there something unique about BCMA and Multiple Myeloma in your view that would allow that? Or is that just the most convenient place to kind of test using the antibody by itself?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [5]

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Yes, that's something that we have been internally discussing for some time. I mean we know that anti-CD52 antibodies are very important lymphodepleting agents. The initial addition of our anti-CD52 is built from the existing lymphodepletion regimen and fludarabine and cyclophosphamide, but we do believe that we have an opportunity to further optimize with a view that at some point, it may be possible to create the lymphodepletion that allows the expansion of the cells as well as protection of our AlloCAR T cells from the destruction by the endogenous lymphocytes, simply by using anti-CD52 antibody. And given that we proactively designed the UNIVERSAL study to have the opportunity to specifically test that hypothesis, and we will be, as I've said, stepwise, removing chemotherapy reagents to the point that we will have an opportunity to study anti-CD52 antibody alone. And that's all going to be based on what we find in the initial lymphodepletion in the UNIVERSAL study.

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Operator [6]

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And our next question comes from Salveen Richter with Goldman Sachs.

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Maryana Ilya Breitman, Goldman Sachs Group Inc., Research Division - Research Analyst [7]

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This is Maryana Breitman for Salveen. Following up on Marc's question about the lymphodepletion, would elimination of fludarabine and cyclophosphamide allow the possibility of AlloCAR Ts is being infused as not only the academic sort of centers but also in more community settings with just ALLO-647?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [8]

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Great question. It's probably too early for us to go into the details of what may happen. But within the company, there is a lot of thinking that's going behind how we can continue to improve the CAR T therapy with a whole set. At some point, this can be done as an outpatient regimen rather than the current situation where the therapy has to be given in specialized centers or in close proximity to the transplant centers. So taking out the fludarabine and cyclophosphamide obviously we are triangulating many different points, existing data, some of the early findings that we are getting from the ALPHA study as well as what we are hoping to achieve eventually. So at this point, we are giving some suggestions about how we are approaching this through the study design. But let's just wait for the data to mature, and as we generate the additional data during the conduct of UNIVERSAL study.

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Operator [9]

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Our next question comes from Biren Amin with Jefferies.

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Biren N. Amin, Jefferies LLC, Research Division - MD and Senior Equity Research Analyst [10]

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David, maybe just starting on 501, how many patients should we expect to get in the first half of 2020 when you present the data on the ALPHA trial?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [11]

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Yes. So Biren, we have previously indicated that the way that we will communicate the emerging data from the ALPHA 1 study is that we will wait for some meaningful interpretation of the data to be -- when we get to the point where we can meaningfully interpret the data, we will present it in a scientific forum. So it really doesn't matter how many patients. It's really the quality of the data and the consistency of the data. The Phase I study as designed can enroll up to 24 patients. But in terms of how many exact patients will be treated, it all depends on the emerging data, including specifically around the safety finding. So the number could be very few, but could be up to 24. So let me leave it there without going into the details about how many patient data may be expected as we present the data in early 2020.

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Biren N. Amin, Jefferies LLC, Research Division - MD and Senior Equity Research Analyst [12]

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Okay. And then on the 715 program, given you're evaluating, or potentially evaluating different lymphodepletion regimens, potentially without cy/flu, what are your thoughts on possible re-dosing of patients? Because I think one thing that we've seen in the literature is a type of BCMA may have some influence on response or how long a remission occurs, although this is still (inaudible). So just thoughts on, I guess, with the trial of ALPHA re-dosing of 715 cells.

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [13]

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So currently, we are building the design of the study with assumption that a single therapy can achieve the treatment effect that we are desiring, which is a deep response in higher proportion of patients, and that's very durable. In terms of re-dosing, which frequently comes up, especially in the allogeneic setting because of the allogeneic products provides such a ease of re-dosing, we have entertained the possibility of re-dosing. But at this point, we are keeping re-dosing as an option, not something that we will specifically build into the protocol from upfront.

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Operator [14]

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And our next question comes from Cory Kasimov with JPMorgan.

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Cory William Kasimov, JP Morgan Chase & Co, Research Division - Senior Biotechnology Analyst [15]

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So first following up on ALPHA 1. Given that this is using the first-gen 501 that contains a Rituxan switch, just curious on your thoughts on how representative the patients might be of the broader relapsed/refractory NHL patient population?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [16]

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Great question. So I think you are asking about the fact that from 501, as we advance the program into the pivotal Phase II stage, we will be making 1-minute change of taking out the Rituxan switch. We went in details about why this Rituxan switch still exist in ALLO-501. That's really a historical reason. And we have planned from the beginning to take the switch out. And we also have outlined the speed and the sequence events that will allow us to introduce a ALLO-501.1, which is our second generation that lacks the Rituxan switch. For now, because of the Rituxan switch, there are certain criteria that we have set to screen out the patients who does not have high levels of Rituxan from the previous treatment. So far, despite that unique requirement, we have not run into any significant issues with the patient enrollment. And currently, the patients that we have enrolled, I would say is very representative of the relapse and refractory large cell lymphoma patient population.

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Cory William Kasimov, JP Morgan Chase & Co, Research Division - Senior Biotechnology Analyst [17]

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Okay. Great. And then -- and to follow up on that, can you just help us understand, when you go to 501.1, the manufacturing difference is there. Is it a very simple switch? Does it change the total manufacturing time? Or I guess like how much of a change to the process itself?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [18]

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Yes. So the main change is taking out the switch means that you have to use a new antiviral vector. Other than that, the manufacturing process essentially the same.

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Operator [19]

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And our next question comes from Mark Breidenbach with Oppenheimer.

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Mark Alan Breidenbach, Oppenheimer & Co. Inc., Research Division - Executive Director & Senior Analyst [20]

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David, I was wondering if you could just quickly comment on how you chose the 40 million cell starting dose in the UNIVERSAL study, especially given what we know about the autologous BCMA CAR Ts and where they start showing efficacy? And also I'm wondering if the UNIVERSAL protocol or a future version of it might leave any room for including a maintenance therapy for patients who respond to treatment and if it will be worth trying something like a lenalidomide potentially extend PFS beyond what we've seen in other BCMA CAR T trials?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [21]

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Mark, great questions. In terms of the starting cell dose, 40 million cells, and that includes the [vial size] for the production of the cells as well as what we believe can be potentially active dose. But obviously, that is dose-escalation study, we want to start at relatively low dose and go up the dose escalation. I mean that's the sort of underlying premise where we came up with the 40 million. It could have been 60 million, it could have been 20 million, I think it's a choice that we made. And 40 million we felt was a reasonable number.

Through the course of the study, we can definitely more than double the dose as we go up a dose escalation. So we will be able to explore a range of doses that will inform us in how we choose the recommended Phase II as we advance the program into the pivotal stage.

In terms of the second question, the maintenance. I mean I think the question is really reflecting the treatment paradigm in Multiple Myeloma. This is a field that underwent a revolution over the last 20 years with the introduction of many novel and highly effective agents and both the combination as well as a maintenance therapy is very much in play. And that's something that we are closely working with the investigators as well as key opinion leaders to how to position the CAR T therapy in this complex setting of Multiple Myeloma treatment. So we're keeping all these options often. However, initially, the study will be done as the ALLO-715 as a single agent in the relapse and refractory patient population.

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Mark Alan Breidenbach, Oppenheimer & Co. Inc., Research Division - Executive Director & Senior Analyst [22]

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Okay. And just a quick follow-up. I'm also wondering if there would be any value or if you have any plans to share ALLO-647 with Servier or selective, so you can potentially gain some clinical experience in a broader range of indications beyond what you're testing in your own trials?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [23]

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Yes. So ALLO-647, which is a propriety anti-CD52 antibody, I mean it has a potential broader use in a setting where utilizing the deletion of CD52 gene in the product as a selective lymphodepletion approach. And we are obviously developing, advancing for our own use, not just for ALLO-501 and ALLO-715, but as a platform approach on any other programs where we have the leading anti-CD52 genes. And as we go forward, our plan is that we will make these ALLO-647 available for others to use. I mean I think that's really a business development discussion between the companies. And our goal is to advance the AlloCAR T and anything that we can do, not just within the company, but for the field, we will be trying to push the field.

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Operator [24]

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Our next question comes from Dane Leone with Raymond James.

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Dane Vincent Leone, Raymond James & Associates, Inc., Research Division - Research Analyst [25]

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Congrats on all the progress and update. So a few for me. So when we think about the UNIVERSAL program, obviously there's a lot of BCMA agents in clinical testing right now, ranging from CAR T to ADC bispecifics. What's kind of been the feedback as you're working with your PIs to understand what the phenotype is going to be for the patients like we enroll in the study?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [26]

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Dane. So let me take this question, and I'm going to also ask Susie Jun, our Chief Development Officer, for the feedback from the investigators. I mean certainly, as we advance the study, we have felt a multiple different discussion. In terms of the BCMA and Multiple Myeloma, I mean despite multiple new drugs being out there, none of the current therapy curative and essentially patient go from one treatment to another. So there is always an opportunity to find the right clinical setting to conduct the studies as well as to introduce new agents in this spectrum, different regimen that the patient will undergo.

When it comes to the BCMA, our product ALLO-715, as we envision, it will be differentiated by the fact that it is an allogeneic and it is off the shelf. Unlike current BCMA CAR T program, most of them are [dose palliative]. So from that perspective, we have heard many positive feedbacks and excitement amongst the investigators about having the opportunity to study and to treat patients with the allogeneic off-the-shelf CAR T product. And certainly, this gets into the consideration of how we view our product versus bispecific, which have shown some encouraging data. I think it's a little bit too early for us to comment, but the general view that we have taken is that Multiple Myeloma is such a large indication. We can work out ways to introduce different novel reagents during the different parts of the management of patient from the initial diagnosis to second, third or sometimes in the refractory lines of therapy. So having said that, let me -- I'll sort of ask Susie to specifically comment about what the KOLs have been saying about the opportunities.

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Susie Jun, Allogene Therapeutics, Inc. - Chief Development Officer [27]

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Yes. Thank you. So the feedback we've been getting from the myeloma experts currently that may or may not want to participate in our studies, they are very strongly encouraged by the role of cell therapy for the treatment of myeloma. And they really do feel, as David has just said, that having an off-the-shelf option would give these patients an -- more -- give more these patients an opportunity to get cell therapy because of the elimination of the long lead time from the autologous approach. And I think you're hearing that as well with some of the support they have been giving for bispecifics. So overall, I would say the feedback from our potential investigators have been very positive, and they're very engaged in the conversations that we've been having.

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Dane Vincent Leone, Raymond James & Associates, Inc., Research Division - Research Analyst [28]

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Okay. Great. And maybe just another branch off of that question. If we assumed that the patient prior experience or refractory status would be something similar to what we've seen in the initial studies with the bluebird and Celgene agent, where these patients have had 7, 8 lines of prior therapy. Usually, they're coming in fairly beat up with cytopenias across the board. I'm just curious, have you received any concern, questions about risk of infection or anything like that if you're going to hit them with anti-CD52 as a preconditioning agent?

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Susie Jun, Allogene Therapeutics, Inc. - Chief Development Officer [29]

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I think overall, everyone understands that the CD52 antibody is a potent lymphodepleting agent, and their experience, at least in the hematologic malignancies field, with Campath gives everybody a strong sense of caution around the potential for other infections or the opportunistic infections to come with a prolonged lymphopenia. But that being said, our dose that we're using in the lymphodepletion regimen is much lower than what was used with Campath. And it is even lower than what the currently prescribed dose for our multiple sclerosis, the alemtuzumab. So caution is good, but I don't think anyone is too concerned given how low a dose we're using.

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Dane Vincent Leone, Raymond James & Associates, Inc., Research Division - Research Analyst [30]

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Okay. And then finally for me, kind of like a 2-part single question, sorry about that. The commentary about flu/cy, potentially moving away from fly/cy or not needing it or experimenting with not using it, it's interesting for a couple of reasons: one, if we go back to the classic CD19 example. There is a -- I think, at this point, you might disagree with me, I'll be interested for your thoughts, a pretty close tie to that, the flu/cy regimen in and of itself helped with initial debulking, which also helped control CRS and potentially neurotox rates. Obviously, we haven't seen those types of rates in the BCMA spectrum of Multiple Myeloma treatment. But curious for your thoughts on that?

And then secondly, it seems like -- and this is pure speculation on my part that if you were able to move away from flu/cy preconditioning that might actually be favorable to what clinicians really going to want to get in with any treatment in Multiple Myeloma is bridging that patient to actually a transplant therapy. Would that actually be potentially helpful, you think, in terms of making CAR T a bridge to transplant within Multiple Myeloma, if you moved away from flu/cy.

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [31]

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Yes. So Dane, let me take that question. I think there are several different concepts that are intermixed in your question. Yes, flu/cy is chemotherapy, and there has always has been questions about whether the tumor-killing coming from the lymphodepletion regimen. And I think this has been asked and this has been looked at very carefully across many different studies. There may be some slight reduction, but the general overwhelming findings are that in the refractory patient population as the CAR T study -- CAR T programs has been studied, flu/cy has a very minimal impact on as an antitumor agents. It's really for the purpose of allowing the CAR T cells to expand, which is a critical component of how the cell therapy is really impacting tumor-killing so rapidly and so deeply.

So personally, I don't think that flu/cy should be looked at as anything other than agents and/or ways to lymphodeplete so the cells can expand. And that's really where previously the idea of using CD52 antibody for the lymphodepletion -- that really didn't come up because CD52 antibody, unless you knock out CD52 in the CAR T cells, will not discriminate the lymphocyte in patients or looking at the CAR T cells, which are T cells. So there is no selective way of creating lymphodepletion with anti-CD52 antibody. However, the approach that we are taking, which is editing out the CD52 in our AlloCAR T cells that now creates an opportunity for selective lymphodepletion.

So I think this is a really unique opportunity for us to continuously advance the field and continuously refine how we administered the CAR T cells. And certainly, we will have to test this in humans, but we have enough indications that CD52 antibody alone can provide a deep lymphodepletion. And certainly, and I think at this point, my answer, my response to this is, and let's just hold on to this very important question as we generate the data through ALLO-715 study.

The second part about whether this is going to make easy for patients to undergo transplant. And that really is -- I don't think that really -- even the flu/cy at the doses that we are using, that's really not going to impact whether the patient undergo transplant or not. The purpose is not really to facilitate the transplant, but it's really to simplify the lymphodepletion. And I'll say, just taking out the cyclophosphamide and fludarabine in the immediate short period after the -- during the cell therapy, that's going to -- I'm hoping that will reduce the neutropenia or other impact that cyclophosphamide will have on platelets as well as white blood cells that can -- that requires additional management during the early days. So simplification that could lead to the easier administration of CAR T without losing the cell expansion or the efficacy, that's the main goal of testing different lymphodepletion regimens.

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Operator [32]

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And our next question comes from Raju Prasad with William Blair.

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Raju Yashaswi Prasad, William Blair & Company L.L.C., Research Division - Senior Research Analyst [33]

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Just a kind of conceptual one on the ALPHA, UNIVERSAL trial in regards to preconditioning. So in both trials, you'll have kind of the optionality to tinker with the preconditioning regimen. Is there conceptually a way that there could be 2 different preconditioning regimens you end up coming out with based on indication? Or do you think that it will kind of be synergistic and kind of determining the best preconditioning regimen from both trials to move forward with for increasing and engraftment and persistence?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [34]

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Great question. I think from the flu/cy perspective, I don't think there has been a clear indication whether there is any difference in how lymphodepletion can be achieved in patients with lymphoma versus Multiple Myeloma. I think if you continue to expand that question into other tumors and solid tumors, at this point, I think we still have to see. I mean that's a question that really has not been tested in a meaningful way. So hold on to that. I mean certainly, in the ongoing ALPHA study, we are carefully monitoring the depth of lymphodepletion, not just measuring the lymphocytes but specifically measuring T cell subsets and K cell subsets and B cell subsets. And we are generating very interesting data. And this is really informing how we are thinking about the lymphodepletion and also forming the basis for us to think about a different lymphodepletion regimen.

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Raju Yashaswi Prasad, William Blair & Company L.L.C., Research Division - Senior Research Analyst [35]

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Great. And then one just a small question on the UNIVERSAL trial design it says that the upper bound dose is 320x10^6 and ALPHA it's 360, is there a reason for that?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [36]

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Raju, looking at dose information very carefully, we are wondering whether somebody will catch the difference between 320 and 360. It really is coming down along how we are thinking about the [vial size] of the outflows and product and that went in. There's many different sort of considerations about how we are setting the dose range. So that's probably a main reason. I mean personally, do I think that we need to go up as high as 320 or 360? I don't think so all the indications are that the CAR T cells will be effective somewhere between 500 -- I'm sorry, 40 million to 50 million to about 200 million in that range. But as I've said previously, in the Phase I, we really want to get some dynamic range of dose information, which is one of the reasons that we are bracketing the doses that we are testing across a wide range.

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Operator [37]

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And our next question comes from Tyler Van Buren with Piper Jaffray.

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Tyler Martin Van Buren, Piper Jaffray Companies, Research Division - Principal & Senior Biotech Analyst [38]

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A follow-up on the potential of a pure ALLO-647 regimen. Can you speak towards what potential magnitude of dose would be required to completely remove flu/cy? And as you think about the initial upfront doses of 3 days or expanding beyond that and dosing longer, what do you think might be more optimal when you think about a pure anti-CD52 regimen? And at what time points -- can you remind us at what time points you're measuring cell counts by flow cytometry and how that could inform how you move forward?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [39]

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So that's a very loaded question in terms of the dose of ALLO-647. As we have indicated in previous calls, the current dose that we are using, which is 13 milligrams daily for 3 days, which comes up to about 39 milligrams about, we say 40 milligrams. And we believe that this will achieve a deep lymphodepletion. Certainly, as we have not tested CD52 antibody ALLO-647 alone without fludarabine or cyclophosphamide that needs to be confirmed in studies as the way that we have designed ALLO-715 study. So let's hold up on some of the -- what may happen on actual clinical data beyond current speculations that we are making based on modeling and other things.

In terms of the dosing, I think you -- correct me if I'm wrong, you're asking the potential of re-dosing ALLO-647. That's something that we have definitely considered. And because of the selective lymphodepletion nature created by how we are engineering cells, that opportunity does exist. And certainly, that's an option that we can also explore as we continue to try to refine and improve the lymphodepletion. And in terms of the last question, the time point and frequency of the measurements of NK, T cells and B cells, early on, what I mean early on within first 2 weeks, we do fairly frequent measurements. And as time goes on, it becomes less frequent. But the details, I will defer to the scientific presentations and exactly how we are following the extent, depth and the duration of lymphodepletion.

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Tyler Martin Van Buren, Piper Jaffray Companies, Research Division - Principal & Senior Biotech Analyst [40]

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Okay. That's helpful. And if I'm not mistaken, one of your potential large competitors with respect to the DLL3 program paused their CAR T program. Do you have any insight into why they paused it as we think about the potential implications for Allogene's program?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [41]

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Yes. I mean I think you're referring to the comments made by Amgen in their earnings call last week. We don't have any more details than that. I think the commentary referred to that. It was their strategic decision and considering that they have both bispecific and the CAR T. Beyond that, we don't really have the details on how the decision was made.

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Operator [42]

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And our next question comes from Ben Burnett with Stifel.

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Benjamin Jay Burnett, Stifel, Nicolaus & Company, Incorporated, Research Division - Associate [43]

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I have a follow-up on the second-gen ALLO-501 program. I guess would you anticipate needing to do any dose ranging for this specific product before moving the secondary product into registrational studies? And then I guess, also has the ALL switch ever been used in the 501 or UCART19 program thus far. So I guess, in other words, has there ever been an instance or position needed to eradicate the CAR T cells with rituximab?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [44]

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So let me answer second question. The simple answer is, no. The whole idea -- you got to sort of think about now, which will be almost 7, 8, possibly 10 years ago when people were initially designing the CAR T construct, all different thoughts went in, and some are very cautious as well as sort of the right decision to have some kind of safety switch. And to the extent where the safety switch need to be triggered, just thinking that's just in terms of the UCART19 programs, but in other programs that has a sort of similar switch. I don't think there has been many incidences. And to my knowledge, I'm not aware of any specific case where the switch had to be triggered for the safety reasons.

I mean people certainly have used high dose steroid in the case of cytokine release syndrome. And certainly, it appears that the steroid now with the growing evidence that it doesn't really impact the efficacy. It's being more widely used. And I'm sort of recalling my earlier conversations with Dr. Steve Rosenberg in NCI around the switch. And he frequently said, "You know what, why do you need switch? High dose steroid. I mean they are very lymphocytic, and they will do the same job as a switch." But frankly, we have never had a reason to trigger the switch in the UCART19 program to my knowledge. And certainly, in the ongoing 501 ALPHA study, we have had no occasions to consider using the switch.

And now I forget your first question.

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Benjamin Jay Burnett, Stifel, Nicolaus & Company, Incorporated, Research Division - Associate [45]

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The other question was just asking is, do you anticipate needing to do any dose ranging with the second-gen product performance, moving that into the Phase II registrational study?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [46]

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Yes. I think that possibly -- that possibility does exist. I mean there are many different ways that we can handle that. Frankly, we aren't going into so much into those details. I feel very comfortable that we will be able to ease in ALLO-501 into the ongoing ALPHA study without any delay in the time line. And as I've said in the prepared statement, we currently project that the pivotal part of the ALPHA study will start in 2020.

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Benjamin Jay Burnett, Stifel, Nicolaus & Company, Incorporated, Research Division - Associate [47]

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Got it. Okay. And then just one last one, if I may, just on the CALM and PALL studies, I guess, when can we expect to see additional data, either longer-term follow-up data or data from the new patients entering the study. When might the next readout be?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [48]

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Yes. So the CALM and PALL study, these are the UCART19 study in ALL that's sponsored and led by Servier. And earlier this year, there was some manufacturing issues that delayed the study. But those issues have been resolved and the studies, both studies are currently enrolling the patient. And given that there may be some incremental data that gets presented in the upcoming scientific presentations. But let's hold off on the details of what may be presented because it's really Servier that's making the decision and on when and what to present.

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Operator [49]

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And our next question comes from Tony Butler with ROTH Capital Markets.

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Charles Anthony Butler, Roth Capital Partners, LLC, Research Division - MD, Senior Equity Analyst & Head of Biotechnology Research [50]

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David, I have 3 brief questions, if I may. One is given the dose of 647, what is the half-life of the antibody? That's question one. Number two, in ALPHA and UNIVERSAL, the first 24 patients in the dose-finding stage. Could I ask, will they be eligible to roll over for the Phase II portion? And then the third question is, as you alluded to thinking that the real dose for, let's say, 715 might be between 40 million and 50 million, could be 200 million. So I'm going to ask, what is the -- when you think about that next dose as you're escalating, is that like 160 or are you going to push even further? Or are you going to incrementally move from 40 to 50 to 80, or just a couple of thoughts around that would be very helpful because it does relate to timing needing to wait to see what those patients look like before you move further?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [51]

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Okay. So on the half-life of 607, which is a complex question. I'm going to ask our Chief Development Officer, Susie, to answer the question. But let me just answer the easy ones first. So I'm going to go to your third question about how we are dose escalating. I mean we haven't specifically stated how many cohorts we'll be studying in the dose-escalation phase of ALPHA study or UNIVERSAL study. But when we say we will study up to 24 patients, usually in terms of how most protocols will say in a 3+3 dose-escalation study, they always assume the maximum possibility in each cohort, which is 6. So from there, you can more or less sort of figure out how many dose cohorts may be studied. So it's not going to be incremental 10 million to 20 million dose increase as we go to the next cohort, it will be 2 to 3 fold increases in the cell dose as we go from the initial dose of 40 million and to the next dose cohort. Now as the morning gets late, I'm sort of forgot your second question. Can you repeat the second question?

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Charles Anthony Butler, Roth Capital Partners, LLC, Research Division - MD, Senior Equity Analyst & Head of Biotechnology Research [52]

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Yes. Sure. That -- it's actually the third one, I guess, but the question was, the 24 patients that are dosed, do they get to roll over to the Phase II portion?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [53]

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Yes. So generally, in pivotal study, we do not do that because we tend to treat the pivotal study separate from the Phase I, but keep in mind, the pivotal study in the CAR T space. It's going to be relatively small size, anywhere between I'm just throwing out the number, but I'm not going to give you the exact number that we are planning, but it's going to be somewhere between 70 to 80, 90 in that range. From that sense, what the experience from the Phase I study gets used is as additional efficacy information as well as the additional safety information. So at the end, we will use all the available information coming from Phase I and Phase II and no matter how you dice it, the total number of patients that we are talking about for the CAR T is going to be relatively a small number of patients. And now I'm going to defer to Susie for the most challenging question about the half-life.

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Susie Jun, Allogene Therapeutics, Inc. - Chief Development Officer [54]

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Yes. For the half-life of ALLO-647 that's certainly something we don't really have a clear answer on yet. We're testing ALLO-647 for the first time in our ALPHA study. So we will measure all the pharmacokinetic parameters as we would for most -- for any other typical monoclonal antibody. So the answer is I'll figure it out as we go. But if you think about alemtuzumab, which is what we based it off of, the half-life for alemtuzumab is slightly different depending on which disease indications you look at. So the expected range of the half-life is somewhere between 6 to 21 days.

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [55]

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Yes. Right. Yes, and -- this assumes the half-life issue about CD52. Antibodies -- I mean the reason that the half-life can vary, depending on the indication and depending on the setting is that there is a phenomenon known as target dependent sort of clearance of the antibody. So if there are a lot of targets, a lot of B cells or T cells, CD52 antibody will clear a little bit faster than somebody who starts the treatment would slightly being lymphopenic. So there is some variability. But I would say this is not anything unusual compared to the clearance of other antibodies as we know.

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Operator [56]

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And our next question comes from Michael Schmidt with Guggenheim Securities.

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Kelsey Beatrice Goodwin, Guggenheim Securities, LLC, Research Division - Associate [57]

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This is Kelsey Goodwin on for Michael. Just a couple of quick ones. I think you've previously said you plan to use multiple manufacturing lots to complete the Phase II portion of ALPHA. I guess can you just provide some color on kind of the regulatory checkpoints for multiple runs, maybe kind of how and when the specs would be assessed? And then more broadly, just could you provide some color on quality assurance and control burden for allogeneic cell therapies from a regulatory point of view, maybe how that compares to autologous?

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [58]

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So in terms of the quality assurance and release criteria for the allogenic CAR T. I mean it follows the standard, the CMC rules about how we prepared drugs. I mean that includes the purity identity, potency, among many other things. So there are many different assays that we incorporate to make sure that the product that we use in patients are safe and well controlled.

Given that these are cell products, I mean the variability that we will see in the cell product, it will be, in general, much greater than the kind of variability that we are used to seeing in small molecule where people talk about product identity and antibodies or biologics where people will talk about the equivalence of one antibody or one biologic from another. So there are many different considerations. And this is something that FDA is keenly aware of and are working very closely with different sponsors to set appropriate standard for the release criteria. So this is an area that we -- I personally and some other people who have joined Allogene from Kite Pharma has experiences in. And this is -- will be an ongoing discussion as we advanced the program from Phase I to pivotal to eventually and hopefully into the marketing state. So that's an ongoing discussion. And I would say that we have a pretty good understanding, and we are continuously addressing the issues that will come up throughout the product development.

In terms of whether there are any differences between the criteria that gets used for the allogeneic versus autologous, the main thing that really goes in here relates to the additional engineering that we do in the allogeneic. We use gene editing, and with gene editing there is always a concern for off-target cuts and changes in nonintended sites and that we already have developed assays to test that pretty robustly. And I think that's an issue that doesn't concern me a lot, and doesn't mean that we are continuing to work on that.

And then the other one that we pay attention to is the degree of editing of the T cell receptor and any residual piece of receptor-positive cells that still may be present in the final product. And that's something that we've been working on for several years. And I would say that we have pretty much that under control. So from the product perspective, we will go through the usual path, but there's nothing that really stands out as an outstanding issue. And that doesn't mean that there isn't a lot of work that we need to do. We have a lot of work still that's cut out for us, but that's one of the reason that we are investing heavily in building the highest quality CMC tech ops group to address these issues that we know as of today as well as additional issues that we may run into as we advance the manufacturing process.

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Operator [59]

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That concludes our question-and-answer session. I'd like to turn the conference back over to Dr. Chang for any additional comments.

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David D. Chang, Allogene Therapeutics, Inc. - Co-Founder, President, CEO & Director [60]

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Well, thank you for your continued interest in Allogene and support as we now move firmly into the clinical stage of our key pipeline programs. We look forward to seeing many of you in the near future as we plan ahead into the fall conference schedule. Operator, you may now disconnect.

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Operator [61]

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Thank you. Ladies and gentlemen, thank you for your participation in today's conference. This concludes the program. You may now log off and disconnect. Everyone, have a great day.