Allogene Therapeutics - Earnings Call - Q1 2020

Transcript

Speaker 4

Good morning, ladies and gentlemen. Thank you for standing by and welcome to the Allogene Therapeutics First Quarter 2020 conference call. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one on your telephone. 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.

Speaker 5

Thank you, Operator, and good morning. We appreciate you joining us today and sincerely hope you are all doing well. Before markets open today, Allogene issued a press release that provides a corporate update and financial results for the first quarter ended March 31, 2020. This press release is available on our website at www.allogene.com. 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, Dr. Rafael Amado, Executive Vice President of Research and Development and Chief Medical Officer, and Dr. Eric Schmidt, Chief Financial Officer. Please note that we are conducting our call today from different locations, so we appreciate your patience and understanding should we have any technical difficulties. 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, data presentations, regulatory filing, future research and development efforts, manufacturing capabilities, and 2020 financial guidance, among other things. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change. These statements involve 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-K for the year ended December 31, 2019, our Form 8-K filed on March 27, 2020, as well as our upcoming Form 10-Q for the quarter ended March 31, 2020. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. I'll now turn the call over to Dr.

David Chang.

Speaker 4

Thank you, Christine. Good morning, everyone, and thank you for taking time to join us for our first quarter conference call. It has been just over two months since our last earnings call, but the world seems a different place. We hope you and your loved ones are safe and well. Our sincerest thanks to many of you who have reached out to ask about Ari Veldergren after he announced that he had tested positive for COVID-19. We all feel very fortunate that his symptoms were relatively mild and he has fully recovered. At the same time, we are profoundly sorry about how the current pandemic has claimed so many lives and created hardship for everyone globally. Across our industry, it is inspiring to see the way in which our scientific and regulatory communities have joined together to identify potential treatments and hopefully a vaccine.

The pharmaceutical and biotech industry are in the business of handling some of the toughest medical challenges. One thing is clear during this time: scientific innovation is our cornerstone and true north. At Allogene, our priorities have been to protect the health of our employees, do our best to support our community, including the patients we serve and those fighting on the front lines, and maintain as much of our business momentum as possible. On prior calls, you've heard us speak about the caliber of talents we are fortunate to have at Allogene. Now more than ever, the ability of our employees to demonstrate our values, to innovate, focus, collaborate, and lead matters. We acted quickly to protect our workforce, implementing work-from-home policy for the great majority of employees in advance of local and statewide shutdowns.

By maintaining a small lab presence directed at critical path activities and relying on the resourcefulness of our organization, we have been able to mitigate some of the effects of COVID-19 on our business. As a result, we remain on track to achieve our five key milestones for 2020. Number one, reporting initial Allo501 phase I clinical data. Number two, initiating our Allo501A phase I trial, both this quarter. Number three, initiating our Allo715 combination trial with a gamma secretase inhibitor, nirogacestat, in the second half. Number four, reporting our initial Allo715 phase I data in the fourth quarter. Number five, submitting our anti-CD70 Allogeneic CAR T candidate, Allo316 IND, by year-end. This is not to say that it has been business as usual. Our partner Servier suspended recruitment in the UCART-19 studies due to the exceptional circumstances related to COVID-19 in March.

We are working diligently to maintain much of the momentum in our trials of Allo501 in relapsed refractory non-Hodgkin's lymphoma and Allo715 in relapsed refractory multiple myeloma. We, along with our clinical investigators, recognize that many patients are not in a position to defer treatments or risk supply chain delays that could be further complicated by the pandemic. Our investigators were unanimous in their desire to keep these trials open for the patients who had rapidly progressing disease or lacked alternative treatment options. Our technical operations and supply team maintain vigilant oversight to ensure we can deliver AlloCAR T therapy to sites in time. In a world in which hospitals are overburdened and scheduling and logistics have become even more challenging, the benefits of being able to provide an on-demand allogeneic therapy have proven to be even more acute.

We adjusted to the need of each site as we worked through COVID-19-related challenges and facilitated best practice sharing between sites for study conduct. We also developed rigorous processes to maintain trial integrity while utilizing remote monitoring and data entry, as well as using the patient's local point of care for follow-up sample collection and tumor assessments to reduce trial exposure. We remain on track to initiate the Alpha2 phase I trial of Allo501A this quarter. As you may recall, we have eliminated the rituximab recognition domain in Allo501A, which allows Allo501A to be used in a broader non-Hodgkin's lymphoma patient population.

The current ALPHA study, including the ongoing work to optimize the dose of Allo647 and Allo501, has informed the design of the ALPHA2 phase I study as we seek to confirm the safety and efficacy of Allo501A ahead of launching the potentially pivotal phase II portion of the ALPHA2 trial. As we look at the differences between autologous CAR T therapy and allogeneic CAR T therapy, the foundational questions must be addressed. First, can we effectively manufacture genetically edited products from normal donor and safely administer allogeneic cell therapy without causing graft versus host disease? Second, can we safely utilize Allo647 to create a period of lymphodepletion and prevent early CAR T cell rejection?

We are making progress on these two critical questions, which allows us as an industry to focus on optimal cell dose and optimal length and depth of lymphodepletion as we work towards the goal of demonstrating durable responses. We continue to believe our lymphodepletion strategy based on the use of Allo647 allows us to explore and determine the optimal window for allogeneic CAR T cell expansion and persistence in a variety of clinical settings. Last week, we announced that our initial Allo501 data had been selected for an oral presentation at the virtual American Society of Clinical Oncology meeting later this month. Our alpha phase I trial began with a 3 plus 3 dose escalation designed to evaluate the safety and efficacy of a range of cell doses, as well as different lymphodepletion regimens that vary the dose of Allo647.

While Rafael will provide additional details on what to expect from the ASCO presentation, I would like to note that ASCO Abstract, which has data as of January, will be released on May 13th. The virtual presentation, which will be released on May 29th during ASCO, will include additional patients, including those treated with a higher dose of Allo647. On that day, we will host a conference call to review the data with you. We see this initial data as an important step towards realizing the potential of allogeneic CAR T therapy. Exactly two years ago this week, Allogene launched operations. From the beginning, we have been consistent in our goal to have allogeneic cell therapy follow the success of autologous CAR T therapy while providing major benefits in time, convenience, reliability, and scale. Our development strategy and trial design have been structured to make this goal a reality.

While there are some outstanding questions that only time and experimentation will answer, we are pleased with the progress we have made to date and look forward to sharing our study progress with you at ASCO. Before I turn the call over to Rafael, I would like to say how proud I am of all 200 plus employees at Allogene who, despite working through their own personal challenges during these times, have remained unwavering in their commitment to allogeneic cell therapy. Rafael will now update you further on the research and development activities.

Speaker 7

Thank you, David, and good morning. As David noted, our phase I trial for Allo501 has continued to enroll patients, and we're looking forward to sharing initial data from this Alpha trial at ASCO on May 29th. While the focus of any phase I dose escalation trial is appropriately on safety, we continue to use this trial as an opportunity to optimize clinical and translational outcomes using Allo647, our anti-CD52 antibody that allows us to customize lymphodepletion and provides us with unique differentiation from others in the field. As a reminder to those less familiar with the conduct of a cell therapy trial, each patient enrolled at a new dose level must be safely treated and followed for the 28-day dose-limiting toxicity or DLT window before additional patients in the cohort can be enrolled.

A dose cohort can advance to the next when every patient in that cohort has been followed for the 28-day DLT window. In our ALPHA3 trial, while we awaited clearance to move to higher cell doses, we took the opportunity to backfill patients into lower dose cohorts. As such, we enrolled a total of 11 patients across the 3-by-3 dose escalation portion of the study. Initial data from the cell dose escalation phase of the study, which utilized the initial 39 mg dose of Allo647, was included in our ASCO abstract. Upon completion of the initial cell dose escalation phase, we began to explore higher doses of Allo647, namely 90 mg. As we continue to enroll patients into this portion of the trial, the ASCO initial data will also include the first set of patients from the trial who received the higher 90 mg dose of Allo647.

While we expect to have one-month tumor assessment data on these patients, we understandably will only have very limited follow-up data on those patients treated with 90 mg of Allo647. We're often asked what would success in this study look like. I believe that at this stage of the field, a win, not just for our program, but for the allogeneic field at large, would be the ability to demonstrate a manageable safety profile, including control over graft versus host disease and understanding of how lymphodepletion can be optimized to achieve cell expansion and persistence. Even though this is not the purpose of a phase I trial, the ability to demonstrate anti-tumor activity of allogeneic CAR T cells. Longer follow-up will be required to ascertain the durability of any response.

Other correlative markers, including the pharmacokinetics of Allo647, depth of lymphodepletion, time to recovery of the patient's T cells, and cellular kinetics of Allo501 are critical to optimize the preparatory regimen prior to cell infusion. Our translational oncology team is collecting data to evaluate these and other parameters as we plan for our ASCO presentation. Our intensive biomarker evaluation efforts will also play a role in optimizing the Allo501A and Allo647 doses to be explored in the Alpha2 phase I and potential phase II pivotal trials. As a physician scientist, it is really gratifying to see science playing itself out as we investigate different variables in the ongoing Alpha1 studies. We will leverage the flexibility we have on hand as we finalize the design of the Alpha2 phase II study. Our second clinical focus is an anti-BCMA allogeneic CAR T cell therapy for the treatment of relapsed refractory multiple myeloma.

We have created a robust clinical strategy to address this field centered around the use of Allo715. Universal, our phase I trial with Allo715, continues to actively accrue and treat patients. This trial will also explore optimal doses of all components of the lymphodepletion regimen, including Allo647, fludarabine, and cyclophosphamide. We will be assessing endpoints such as safety, tolerability, depth, and duration of lymphodepletion, cell expansion, and anti-tumor activity as key determinants of success for Allo715. We're on track to report initial data from this trial in the fourth quarter of this year. Our anti-BCMA program will also investigate Allo715 in combination with the investigational gamma secretase inhibitor, nirogacestat, in collaboration with Springworks. We have finalized the protocol and submitted it for regulatory discussion before initiating the combination study currently planned for the second half of this year.

Last week, we issued a press release announcing that we would present preclinical findings that support our TurboCAR technology at the virtual American Society of Gene and Cell Therapy annual meeting on May 12th. As we have recently unveiled, the third leg of our BCMA strategy involves our internally developed TurboCAR technology, which allows cytokine signaling to be engineered selectively into the CAR T cells. In preclinical models, TurboCAR enhanced the efficacy, delayed exhaustion, and reduced AlloCAR T cell dose requirements. TurboCARs can be tailored with signaling domains from different cytokine receptors designed to enhance T cell expansion, activation, and persistence. The results of this preclinical study demonstrate that this approach could also minimize potential safety risk associated with exogenous cytokine administration, which, unlike TurboCAR technology, will stimulate not only the engineered CAR T cells, but also the endogenous immune cells, which are present in far greater numbers.

In many ways, TurboCAR T technology exemplifies the innovation we can introduce with gene engineering in cell therapy. We look forward to continuing to advance this technology, starting with our first TurboCAR candidate, Allo605, a BCMA-directed allogeneic CAR T therapy for multiple myeloma. We anticipate submitting an IND for Allo605 in 2021. We are very excited about the potential of this technology to enhance anti-myeloma effects. Lastly, we have been able to continue to progress our preclinical work on Allo316, our anti-CD70 program, as our next allogeneic CAR T clinical candidate. This work is critical as we look towards bridging use of cell therapy from hematologic malignancies into solid tumors. As we all know, despite great advances in cancer therapeutics, most metastatic solid tumors are not curable, and they represent areas of high unmet medical need.

Our Allo316 IND that is planned by the end of this year will be for the treatment of renal cell carcinoma with other malignancies planned in the future. I remain very excited with the strong momentum of both our lead programs, and we look forward to providing initial clinical results very soon. I'd like to now turn the call over to Eric to review our financials.

Speaker 4

Thank you, Rafael, and good morning. In addition to the brief financial overview I will provide on the call today, you can read additional detail on our first quarter in our press release issued earlier today and in our 10-K, which will be filed with the SEC. We continue to maintain a strong financial position with cash, cash equivalents, and investments totaling $553 million as of March 31, 2020. In the first quarter, our research and development expenses were $42 million, which includes $6.6 million of non-cash stock-based compensation expense. General and administrative expenses were $15.6 million for the first quarter of 2020, which includes $7.6 million of non-cash stock-based compensation expense. Our net loss for the first quarter of 2020 was $54.5 million, or $0.50 per share, including non-cash stock-based compensation expense of $14.2 million.

In an SEC filing in late March, we stated that construction of our GMT cell manufacturing facility in Newark, California, had been interrupted due to the COVID-19 pandemic. I am pleased to report that we have been able to reinitiate construction work. While we are continuing to evaluate the situation, we currently do not expect this temporary disruption to significantly affect our plans to bring the manufacturing facility online in 2021. As we have been able to continue with our research and development plans, as well as the build-out of our Newark manufacturing facility, we continue to expect that our full year 2020 net losses will be between $260 million and $280 million. This includes an estimated non-cash stock-based compensation expense of $70 million-$75 million and excludes any impact from potential business development activities. With that, we will now open the call to your questions.

Speaker 6

Ladies and gentlemen, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Salveen Richter with Goldman Sachs. Your line is now open.

Good morning, and thanks for taking my question. With regard to the 501 data that's going to be presented at ASCO, could you just go over those numbers again? You talked about preliminary data for the first nine patients and then 11 across the 3 by 3. How should we think about the totality of data? With regard to seeing data on patients per cohort up to one month or two months, how do we think about durability here and then comparing your data set versus the autologous programs that we've seen to date? I have a follow-up.

Speaker 7

All right, Salveen, this is Dave Chang. Good morning, and I hope you're doing well. Let me take your first question. This is one of the questions that we get asked a lot about what to expect at ASCO. Certainly, without going much into the details of the presentation, we're trying to provide as much information as possible. What we have previously said in February is that we have completed the dose escalation, and that included a minimum of nine patients that have been treated. While we were conducting the dose escalation, there were opportunities to put additional patients on previously treated and cleared dose levels. This is really trying to address the site need as well as the patient who becomes available while we are recruiting the studies.

In terms of what will be included in the abstract that will come out in a couple of weeks, the first nine patients—I'm sorry, first nine patients treated—and that is from more than nine patients who were enrolled. There were a couple of patients who are still waiting to be treated at the time of the data cutoff. That nine patients will essentially be people who are treated in the first two dose levels, as well as the beginning of the third and the final dose escalation of the cells that we were testing as the initial design, initial plan. Hopefully, that answers your question.

Yes. How should we think about, in the context of getting one month to two months of data per cohort, how should we think about durability here? Overall, just comparing this to the existing autologous data?

Yeah. Durability is another question that we get asked a lot. This is a phase I study that had been carried out. Obviously, the patients who were treated early on will have a longer-term follow-up. I should really remind that the real question around the durability should be at the cell dose and the lymphodepletion that we finalized for the phase II. That will be the real comparison as we go forward, as much of the earlier cell doses were essentially dose exploration, as well as the lymphodepletion that we started with 39 milligrams of Allo647. I mean, that is the beginning of the lymphodepletion. As you know, we have gone up on the 647 dose to the 90 milligrams.

When you think about all these in the context of the data to be looked at, yes, some of the early cohort, you will have a longer follow-up. The really relevant dose level has been treated sometime this year. In that case, in terms of follow-up, as Rafael has said in his prepared statement, the follow-up will be relatively short. Certainly, we will include one-month data, but there will be the limits of the presentation.

David, maybe just one follow-up question too with regard to your other programs. Can you talk about the lymphodepletion regimen you're using in those programs versus 501 and whether there are other optimization levers you may be playing with?

Yes. The way that we think about optimizing as we prepare the 501 program into the phase II, and that will be done with a 501A that lacks the rituximab switch, is really the three levers that we can play with: the cell dose, lymphodepletion, and we have not talked much about it, but potentially redosing. In terms of lymphodepletion, this is really dealing with a patient's immune system as we try to keep the immune cells that can potentially lead to early rejection of alloCAR T cells somewhat at bay to allow the alloCAR T cells to expand and persist and carry out anti-tumor activity. There is a little bit of the patient components, depending on different indications, how they get treated in the first, second line. Obviously, that affects the patient's overall immune system.

There is a little bit of variability that we have to consider as we think about different indications. Overall, we are doing more than one program at a time. Right now, we are studying both 501 and 715 in non-Hodgkin's lymphoma and in multiple myeloma. We are trying to leverage the learnings from each study as we try to further narrow down the lymphodepletion. There is a lot between the study data comparison as we try to optimize the lymphodepletion. Once we get to the final decision point, we will know whether the lymphodepletion across different indications will be all uniform, or there may be some differences in how we exactly lymphodeplete for different programs.

Thank you.

Speaker 6

Thank you. Our next question comes from Biren N. Amin with Jefferies. Your line is now open.

Yeah. Hi, guys. Thanks for taking my questions. Hope you're all staying safe. Just on the 501 data at ASCO, I think in the prepared remarks, there was some mention that you had backfilled some more patients on the lower doses. I think, David, you also mentioned that you might have a couple more patients than the three required in the lower doses. Just want to try to understand what drove this. Did you see any dose-limiting tox events in some of the patients in the lower doses which drove that, or was it something else? I guess, what cell doses are you administering with the higher 90 milligram lymphodepletion 647 dose?

Speaker 7

Okay. Byron, let me take that question because you are asking many different things in the same question. In terms of the simple thing that I want to just clear is that when we were doing dose escalation, the process of dose escalation in the cell therapy study is you treat one patient for each dose level and then make sure that that patient completes the so-called dose-limiting toxicity window or DLT window, which will take about 28 days. Once the person clears without any safety findings, we open up the dose level for the remainder of the patient. When the last patient in the dose level is tested again, we wait for 28 days before we clear the dose and move on to the next dose level.

When you start the next dose level, the same process starts again, which means that in terms of patients who can go on the study, especially when you have multiple sites open, it can cause some logistical issues where a patient may become available, but there may not be any slots. We accommodated the site need as well as the patients who were eligible to receive the treatment by putting those patients in those levels that had already been cleared. I would say this is a very standard practice in any phase I dose escalation study just to ensure that the patient and site needs are met during the study. That is how we carried out the phase I study. Your second question around the safety and others, these are some of the questions that we get asked.

Let me reiterate that the phase I study, the purpose of the phase I study was to evaluate the safety of our cell as well as the lymphodepletion regimen, as well as really testing different lymphodepletion regimen to make sure that we can allow enough window for the cells to expand and carry out anti-tumor effect. Very important question, but we are so close to the ASCO presentation coming up later this month. At this point, with all due respect, I would defer some of your questions around the safety and any other things to the actual presentation.

Speaker 6

Okay. If I could have maybe a follow-up on ALPHA2, which is supposed to start imminently, what learnings have you been able to incorporate from the ALPHA study? On cell dose and lymphodepletion, I guess, has that informed your design for ALPHA2? I guess, are you able to, through translational data, better identify donors for ALPHA2 where you can optimize cell product?

Speaker 7

501A, just to remind everybody, the one difference between 501 and 501A is the removal of the rituximab switch, which allows the 501A to be potentially used in a much wider patient population in the lymphoma indication. From that perspective, the sequence of the CAR itself hasn't really changed. Essentially, that nature of the construct, as well as all the preclinical studies that we have done before we cleared IND, indicates that these two products, 501 and 501A, should behave in almost identical ways. However, as you know, what we find in the preclinical studies and what we find in the clinical situation may be a little bit different. As part of the normal well-controlled study conduct, we just want to confirm what we saw in the 501 in the 501A program. We have previously said that we will conduct an abbreviated phase I.

Just adding to that, we have also said that in the 501, we tested the cell doses from 40-360 million cells. At that time, we also said that we do not see the need to test any other cell doses outside the bookend range from 40-360 that we have tested. That is more or less the range. Certainly, as the 501A study gets activated this quarter, we will provide more details on the study design. Let me just stop there. I just want to sort of be cognizant of timing and release of the information and not being a little bit ahead of it. Byron, can you just remind me the second question that you asked?

Speaker 6

Yeah. Whether on translational data from the ALPHA patients that were treated, whether you're able to better identify the donors or optimize cell product for ALPHA2?

Speaker 7

Yes. That is an ongoing effort. The question really is that I think we and others, and this is probably some time ago, definitely have noticed that between different donors, there was some variability in how cells expand during the manufacturing process. That is understandable. Everyone's cells are slightly different, and there can be some differences. Our fundamental approach towards that kind of variability is trying to understand some of the characteristics so that we can adjust the manufacturing process so the manufacturing process itself addresses the variability that comes from the different donors. That is more or less how we are approaching it. This kind of analysis, as you may have guessed, requires more than a few samples. I mean, you are looking at the trend of very complex differences in individuals.

I mean, you're talking about potentially age of the donor, the sex of the donor, and whether the person may have had infections that anybody would normally get before they donated cells. I think all these things factor in. It is an effort that will take time, but we are well underway characterizing each of these parameters at the manufacturing process. It is not a simple endeavor to really point out what leads to some differences that we see.

Speaker 6

Okay. Great. Thanks for taking my questions.

Speaker 5

Thank you. Our next question comes from Cory Kassimov with JPMorgan. Your line is now open.

Hey, guys. Thanks for taking my questions. This is Matthew for Cory. I guess in regard to the ALPHA trial, I understand that you can't say much about the details of the upcoming readout, but how should we be thinking about how different NHL subtypes enrolled into the study might affect the interpretation of the initial results?

Speaker 7

Matt, thanks for that question. I think your question underlies in the fact that within the large cell lymphoma or so-called aggressive non-Hodgkin's lymphoma, there are two sort of differences. One, patients who have early progression after transplantation or patients who are refractory to the last line of chemotherapy. I mean, there are some differences. I think over a period of time, we are learning that especially when it comes to the initial responses, there isn't that much difference. I should just also add that in our phase I study, given the learnings that's coming from the autologous CAR T therapy, we also included not just the relapsed refractory large cell lymphoma, but also the patients with the so-called indolent lymphoma who have relapsed after multiple lines of therapy. There will be some patients who belong in that subtypes of non-Hodgkin's lymphoma.

Keep in mind, the purpose of phase I is, as I previously said, safety, lymphodepletion, and early lines of efficacy. From that perspective, I do not think there will be much impact on the patient's tumor subtypes in terms of our ability to analyze those key information.

Great. That's super helpful. I guess in terms of the nine patients that we'll get in the abstracts, should we expect to get any redosing data?

Redosing is an amendment that we made later on the study. As we have said in the prepared statement, the data cutoff for the abstract was January. That is before the amendment came in effect. There will not be any redosing information in the abstract.

Okay. Got it. That's helpful too. I guess just maybe one last question for me, just thinking about this more from a high level, but how do you think the COVID-19 pandemic will change CAR T clinical development in the near to medium term?

Great question. First of all, we are trying to understand how the COVID-19 pandemic will play out. I mean, I think we just lived through the early phase. Essentially, you're talking about since end of February till what is now sort of early part of May. We have about, what, a little over two months of experience. Within this limited experience, I mean, we know what we can do, which is controlling our own internal activities, making sure that the supply chain is not interrupted. Fortunately, in our case, we do have the luxury of building up inventory of CAR T cells that you can use for clinical studies. From the things that we can control, I think we are in pretty good shape.

Things that we have to react to is what happens on an external environment, including how the hospital, so this is going beyond what the investigators may do, but the hospitals do to the clinical studies as they sometimes prepare for the surge of patients. There are a lot of different variables. However, if the things more or less play out the way that we have experienced over the last two months, I'm hoping, as well as this is hoping, as well as based on the information that we have, the studies that we are planning, in large part, will not be affected, will not be affected by COVID.

Great. That's helpful. Thanks for taking my questions.

Thanks, Cory. Thanks, Matt. Sorry.

Speaker 5

Thank you. Ladies and gentlemen, in the interest of time and in order to accommodate as many questions as possible, we ask that you please limit yourself to one question. Our next question comes from Mark Fromm with TD Cowen. Your line is now open.

Yes. Thanks for taking my questions. Maybe just building on one of your prior answers, David, you've mentioned over the course of this trial early on kind of some of the struggles finding patients who had been off rituximab long enough to enroll. That is kind of the driving force for Allo501A. Now COVID potentially kind of highlighting the need to move from an auto to an allo product. How should we think about kind of shifting patient populations over time, either in terms of some of the baseline disease type, like you mentioned earlier, or other baseline characteristics that do impact safety or efficacy, things like tumor burden and things like that?

Speaker 7

Let me understand the question. Are you sort of asking whether the patient population will shift because of the COVID pandemic?

Because of the pandemic or also just your initial population, should we think about those maybe being more follicular patients that might be able to be off rituximab early on, but then maybe later you're getting more very high burden, very sick patients later now as COVID is kind of impacting enrollment in the broader CAR T space?

Yes. So I mean, in phase I, our experience in terms of enrolling a very limited number of patients, it doesn't give you a much larger view of whether there will be differences in the patient population. As I've said, the benefits of autologous CAR T, I think it's becoming apparent not just in the diffuse large cell lymphoma, but also in other indolent subtypes as well. From that perspective, the shifting of the patient population, if it occurs, I don't really see that becoming an issue. This is also a topic that could be addressed by the study design. We're doing a phase I study. Obviously, in the phase I study, we want to get as much information as possible.

As we move towards more pivotal study, especially with the current plan of conducting a pivotal study as a single-arm study with a limited number of patients—that's in the range of 70-100—there will be some further refinement of patient population so we can interpret the data properly from a single-arm study.

Okay. And then maybe also on some of the comments about the interruption to the in-house manufacturing facility in Newark, the construction, just can you remind us kind of where you stand in terms of manufacturing doses for the duration of the phase I trials for both CD19 and BCMA and kind of your readiness to advance into phase II and what you need that manufacturing facility for?

Yes. We have previously sort of made it very clear that right now we are still dependent on the contract manufacturer for the clinical supply. Our plan is to shift that dependence to something that we can control by bringing in the clinical supply manufacturing in-house. That is planned to be done in Newark. The timeline that we are working towards is completing the construction. After the physical structure of the manufacturing facility is done, there is a lot of work that needs to be done. Essentially, we are working towards getting our own manufacturing facility to come online to produce clinical materials sometime in 2021. As Eric has commented, the disruption for a short period of time that occurred after the COVID pandemic, we do not expect that to significantly affect our plans to bring the site to start producing the clinical materials.

Okay. Great. Thank you.

Speaker 5

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer & Co. Your line is now open.

Hey. Good morning, guys. I'll try and break with the trend here and actually limit myself to one question. Very quick one on maybe direct to that, Rafael. I'm wondering if you're expecting substantial variability in baseline levels of rituximab in the ALPHA trial patients. Will this be a parameter that will be reported as part of the ASCO dataset? Thank you.

Speaker 7

Yeah. Hi, Mark. Thanks for the question. It has been an important question that pertains only to the 501. As you know, obviously, on 501A, that will not be an issue. We have been fortunate to get enough patients that either were not on rituximab or they have been on rituximab for greater than six to nine months. Other patients that had rituximab sooner, in those patients, if they had a level that was above three, we would allow the patient to have apheresis for a total of three aphereses. That should bring the level below one microgram per ml, which is really the allowed level. We actually have not had too many problems getting these kinds of patients. Of course, there have been patients that had rituximab two months before, and we knew that plasmapheresis was not going to bring the levels. Those patients had to wait.

Some got into therapy and then came later. Some went on to other therapies. I must say, even though this appeared to be an important hurdle, investigators were able to select the right patients. We have been able to overcome this problem. In fact, we have not had to apherese too many patients. It has been a hindrance, but a relatively mild one.

Okay. That's very helpful. Thanks for taking the question.

Speaker 5

Thank you. Our next question comes from Alexander Duncan with Piper Sandler. Your line is now open.

Hey, all. Glad to hear everyone is doing well. Thanks for the question. First, a quick follow-up on previous questions. At ASCO, will you be providing lot information on which manufacturing runs from which each ALPHA patient was treated? On the TurboCAR strategy, could you explain the thought process behind advancing the first clinical candidate in myeloma as a follow-on to 715 as opposed to Allo316 in renal or even develop a TurboCAR candidate as the lead program in RCC given the potential for this technology in solid tumors? Thanks so much.

Speaker 7

Alex, let me take the first question. I'll ask Rafael to answer the second question. In terms of lot information, I think, as I previously said, we're getting very close to ASCO. Probably it's best to refer to the actual presentation. Rafael, second question?

Yeah. I mean, we are really excited about the TurboCAR technology. What we've seen in the preclinical work really tells us that the cells can remain less exhausted or unexhausted for a long period of time. They can divide. They can proliferate upon encountering antigens. We think that it has a lot of promise. Of course, it's going to be tested first in BCMA. It may have a lot of promise in solid tumors. Indeed, we are working on the optimal TurboCARs. As you know, the technology allows us to use different cytokines, different gates, if you will, to trigger the cytokine signal. We are at the moment working on what would be the optimal one to insert into our programs, particularly CD70 and DLL3. The initial IND will be without it.

I do not expect that the one containing a cytotale will lag much behind. It will all depend, obviously, on what we find preclinically. We are pretty excited with the potential of turboCARs in solid tumors.

Speaker 5

Thank you. Our next question comes from John Newman with Canaccord. Your line is now open.

Hi there. Good morning. Thanks for taking my question. My question is regarding Allo647. I'm just curious, going forward here, will you have the opportunity to test dosing Allo647 on its own as a lymphodepletion agent, perhaps after the initial lymphodepletion in combination with chemotherapy? Just curious if that's a strategy that you're considering here going forward. Thanks.

Speaker 7

Hi, John. Good morning. Let me take that question. I mean, Allo647, as an anti-CD52 antibody, that is a great agent for lymphodepletion that is selective and also spares our own alloCAR T cells because we edit our CD52. We are certainly leveraging the strength that comes from the uniqueness of Allo647-based lymphodepletion. In terms of your question of whether 647 can do it alone, that is a great question. Certainly, that is something that we internally discuss frequently. How to do that, I think that is a stepwise process that we'll be taking. First, making sure that we get to the adequate lymphodepletion and then start testing whether the nonspecific chemotherapy is really necessary for lymphodepletion. It is in the plan. The answer will take a little time. Definitely, it's something that we are very interested in.

Great. Thank you.

Speaker 5

Our next question comes from Michael Schmidt with Guggenheim. Your line is now open.

Speaker 7

Hey, guys. Thanks for taking my question. Just one more on Allo501A. I know that the main focus here is on optimizing lymphodepletion. I guess, David, what gives you comfort that you actually have selected the right cell dose at this point and that you do not need further dosing work on that front?

Yes. In terms of lymphodepletion, I mean, one of the things that we can look at very early on is the reduction in the absolute lymphocyte count as well as time before the T cells or NK cells or B cells start coming back. I mean, that's essentially the definition of the lymphodepletion and duration of lymphodepletion or time to the cell recovery that we have been talking about. From that aspect, we can get a pretty early read on how different changes that we introduce into the lymphodepletion can actually translate into what we are looking for. In terms of how to put that into context of cell dose, that's a great question. The cell therapy is a very sort of dynamic therapy in many ways. We learned that through the conduct of autologous CAR T therapy.

Essentially, how the cells expand is a multifactorial process: the quality of the cells, the antigen density, target density, or the tumor burden in patients, as well as the lymphodepletion that allows the homeostatic changes of the cytokines and promotes the cell expansion. There are many different things that we are looking at. That is one of the reasons that we emphasize looking at the translational parameters to make this decision. This is something that we have some experiences in optimizing and deciding and moving forward. All that experience that comes from having worked on autologous CAR T will also factor in as we lock in the final two parameters, namely the lymphodepletion regimen and the cell dose. The cell dose, as I just said, the dose range has been defined between 40 and 360. Certainly, that is the range that we are playing with right now.

Okay. Thanks. And then just a high-level question about the strategy longer term in multiple myeloma. I think you now have at least three programs that you're working on: 715, the gamma secretase inhibitor combination, and then also Allo605. I guess, how should we think about the strategy here? Are you planning on moving several programs forward in parallel, or are you, for example, planning to pick one of those programs for a pivotal study after comparing phase one data across those programs?

Yeah. Great question. Rafael is very passionate about the strategy that we are taking in multiple myeloma. I'll ask Rafael to answer that question.

Thank you, David. Thank you, Michael. BCMA-directed therapies are blossoming, as you know. I had the privilege of working on belantamab at GSK. We know that there will be an advance in this field. There will be other products that are approved. As such, our job is to try to come up with a product that is going to derive the most benefit for patients. That is why we initiated a three-prong approach that is essentially the cornerstone of which is 715. The dose escalation and movement through that trial is going very well. We said that we would disclose data by the end of the year, and we're on track to doing that. We've accelerated, if you will, the Springworks collaboration with nirogacestat. That has already been submitted. We should also have some patients treated as well in the combination.

The preclinical data is stunning with that combination. We would be able to see, even though it's not a randomized trial, the differences between 715 and 715 in combination with nirogacestat. 605 will come next year. We haven't said when. We are working hard to try to understand the benefits of TurboCAR, as I said before. The reason for this three-prong approach is that even though there are a lot of anti-BCMA therapies, none of them are curative. We would like with autologous CARs, with allogeneic CARs, to be able to move the field. One of these strategies, we hope, will do so. We remain really passionate about moving the needle, if you will, with BCMA in the allogeneic setting in multiple myeloma with one of these three strategies.

Great. Thank you so much.

Speaker 5

Thank you. Our next question comes from Tony Butler with Ross Capital Partners. Your line is now open.

Thanks very much. Just two brief questions. The first, I want to stick with the same theme, please, on the notion of an inducible cytokine receptor CAR T construct. It's obviously incredibly clever. It strikes me that the goal here was really to see, could you actually fight through the TME and be able to have some durability in the tumor microenvironment? In theory, you wouldn't necessarily do that with a BCMA binder. Or am I incorrect in that assumption? Part B to that question actually is around safety. It addresses the notion of, I could see why it would be safer than simply systemically delivering cytokines. Do you think it's safer than, for example, one of the other 715 constructs? How do you think about safety there? Finally, it strikes me that you're happy with 90 milligrams for the anti-CD52 antibody or 647.

Am I correct? Or do you need to move to, say, 120 to really be satisfied that you're getting the appropriate lymphodepletion with that compound at that dose? Thanks.

Speaker 7

Yeah. Tony, good morning. I'll ask Rafael to answer the questions on the TurboCAR. Great questions. I mean, certainly, we see a lot of promise of this autonomous cytokine signaling that we introduced to TurboCAR. I mean, there are many interesting questions that you have posed. Rafael?

Yeah. Hi, Tony. Nice to hear your voice. There are a lot of clever questions, as David has mentioned. BCMA, I think, is a really interesting target in which to test TurboCARs. I realize that solid tumors may also benefit from this technology. What we are looking for is a brisker, more rapid, and robust anti-tumor effect upfront. We know this is allogeneic CAR T therapy. Eventually, the cells will be rejected. We want the cells, while they are exerting anti-tumor activity, to be fitter and younger, to replicate when they see antigen, and to do it in a manner that does not affect the surrounding cells. In terms of safety, that obviously needs to be proven. This product has never been in humans. We are doing all our preclinical toxicology work towards an IND next year.

There could be issues having to do with autonomous cell growth. We do not believe that that is going to be an issue. Other than that, as you know, there is no soluble cytokine at all with this system, which is very unique. To my knowledge, there are not any other systems where the actual cytokine is actually not released from the cell in question. In terms of the dose, I am not sure I fully understood your question. There is a chance that using turboCARs may allow us to lower the lymphodepletion or perhaps to lower the dose level. Those are hypotheticals. I do not want to go into hypotheticals much more. In theory, that is a possibility if these are much more potent cells. I hope this gives you a flavor of how we are thinking and answers your question.

Rafael, thanks very much.

Thank you.

Speaker 5

Thank you. And our final question comes from Asthika Goonewardene with Truist Securities. Your line is now open.

Hi. Good morning, guys. Thanks for squeezing me in. I want to talk a little bit more on the lymphodepletion here. Rafael, your thoughts on this, please. The data does suggest that repressing the patient's endogenous T cells in the first 14 days is key for the expansion. I just want to get your thoughts on how important do you think it is in aggressive NHL to keep the endogenous T cells suppressed for the next 14 days? I have a couple of quick follow-ups.

Speaker 7

That's an outstanding question. It is one that we are exploring in terms of our corollary studies. We follow very closely TBNK cells. All I would say at this point is that the longer we can keep the T cells suppressed, the better. Our goal is to strike a balance between the length of lymphodepletion, which obviously can lead to viral reactivation and other toxicities, and the ability for the allogeneic CAR T cells to expand. Certainly, I think the statement that you made about longer than 14 days may actually be true in that we may need to have the cells suppressed a little longer. That is in part the reason for doing a phase I study, to really look at all these parameters: cell dose, lymphodepletion, not just with Allo647, but with chemotherapy.

What role did each one of these elements play in the suppression? What happens when they come back? What happens with the pharmacokinetics of 647 with regards to T cell resurgence, to NK resurgence? We are in the midst of that and exploring the very question that you just asked and hope to have that answer by the end of the phase I study.

Excellent. I have to ask a question about the upcoming data at ASCO. I hope you do not mind. Did you guys have time to look at and then do the analysis, provide some color on the memory phenotypes of the CAR T cells on infusion and at peak expansion?

Yeah. I'll take that question. I mean, the answer is yes. It's part of the panel that we do, both in the endogenous cells as well as the cells that are administered. Obviously, at the moment, it's a phase I study with a limited number of patients. As David said before, to make conclusions in this space, one would have to test multiple grafts from multiple sources of exogenous cells to be able to make those comparisons. Certainly, it is a really important question. We just need more time and more experimentation to be able to answer it.

Got it. Finally, the backfill. Am I right in assuming that completely agreed or completely does see that it might not be driven by toxicity and just more opportunistic here? Would you have backfilled maybe the lowest dose, i.e., the 40 million? Or was that backfill more in that 160 million dose level?

I think the proximity of the ASCO presentation is such that I prefer to wait and let you see for yourself the data.

Got it. All right, guys. Thank you so much for all the color today. Appreciate it.

Speaker 5

Thank you. Ladies and gentlemen, this concludes our question and answer session. I would now like to turn the call back over to David Chang for any closing remarks.

Speaker 7

Thank you for joining us on the call today and your continued support of Allogene. What we know will be an exciting year for allogeneic cell therapy. We look forward to speaking with you again soon. We look forward ahead to ASCO. Operator, you may now disconnect.

Speaker 5

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.