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

Welcome to the Allogene Therapeutics webinar to discuss initial results from our Phase I UNIVERSAL study of ALLO-715 in relapsed/refractory multiple myeloma presented today at the American Society of Hematology. We're looking forward to discussing data from our second program that highlights progress towards our goal of making AlloCAR T therapy a reality for patients. Today's call is being webcast on our website and will be available for replay. Before the start of this webinar, I'd like to note that we issued a press release that provides the details of this data. We've also posted the materials that will be presented during the webinar on our website at www.allogene.com under the Investor Relations section. After our formal presentation, I will open up the call for questions. On the call today will -- are Dr. David Chang and Dr. Rafael Amado. We're also pleased to have Dr. Parameswaran Hari from the Medical College of Wisconsin joining us today. During today's call, we'll be making certain forward-looking statements. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, and the company disclaims any obligation to update such statements. I'll now turn the call over to Dr. David Chang.

Good morning. Thank you for joining us on our webinar. As Christine mentioned, we will be reviewing the initial results from Phase I UNIVERSAL study of ALLO-715 in patients with relapsed and refractory multiple myeloma, and we are delighted to have Dr. Hari join us. Phase I UNIVERSAL study represents the first step of clinical data of allogeneic CAR T study targeting BCMA in multiple myeloma. We believe that the safety and efficacy data highlighted in the oral presentation this morning paves the path forward for ALLO-715. And we will put this initial data in the context of Allogene's pursuit of multiple myeloma indication. Let me first spend next few minutes talking about where Allogene stands. Since the founding 12.5 years ago, we have been working with a singular focus of advancing AlloCAR T therapy. Many of you are familiar with the potential benefit of AlloCAR T therapy: access, potential to treat all eligible patients; cost, scalable and efficient manufacturing; speed and reliability, off-the-shelf for demand therapy; and innovation, being able to do multiple gene editing and engineering. I'm very proud of what the team at Allogene has been able to achieve in a short time to set the course to make AlloCAR T therapy a reality for patient. Our manufacturing team has delivered uninterrupted supply for all our clinical trials while building internal manufacturing capability at our Newark facility, which is on track to begin production of AlloCAR T cells in 2021. Our development team worked relentlessly to advance clinical programs. Now having treated over 15 -- 50 patients across 2 clinical programs targeting CD19 and BCMA, I believe we have an unmatched expertise in allogeneic CAR T trials. In doing so, we steadily advanced science and unraveled the hurdles of allogeneic cell therapy, controlling graft-versus-host disease and addressing other important safety issues such as cytokine release syndrome and neurotoxicity, or ICANS; and utilizing ALLO-647, our own anti-CD52 antibody, to create and optimize a window of cell persistence. We have demonstrated deep responses in indications we are pursuing, non-Hodgkin's lymphoma and multiple myeloma, and continuing to utilize ongoing Phase I studies to optimize the clinical benefits of allogeneic CAR T therapy. All these efforts are setting the stage for pipeline advances we have in plan for 2021: 5 clinical trials, including first pivotal trial, first solid tumor trial, first combination trial and first next-generation TurboCAR trial. Next slide illustrates our rich AlloCAR T pipeline covering both heme malignancies and solid tumors. ALLO-501 and 501A targeting CD19 for the treatment of non-Hodgkin's lymphoma and other CD19 expressing malignancies; re-BCMA targeting approaches in multiple myeloma, which I will further elaborate shortly; ALLO-316 and ALLO-819 in AML; and AlloCAR T programs in solid tumor. I am pleased to note that we have received the FDA clearance to proceed with a Phase I study of ALLO-316 in renal cell carcinoma. DLL3 represents our next target of interest, along with over 10 additional targets in solid tumors that are in various stages of preclinical development. It is worth reminding ourselves why allogeneic cell therapy matters in multiple myeloma. Multiple myeloma is a progressive disease with known non-curative therapy, and the prognosis for patient worsens over time. The speed of disease progression in later lines of therapy poses a clinical challenge for patients waiting for autologous CAR T therapy who often require bridging therapy to control the disease at the risk of potentially increasing cumulative or synergistic toxicities. Time is of essence for patients with rapidly progressing disease, and allogeneic CAR T therapy offers a potential solution. Earlier this year, we rolled out our multi-pronged approach to bring AlloCAR T therapy to patients with multiple myeloma. This is with the intent of maximizing what allogeneic CAR T therapy can offer, either as a monotherapy in a combination setting or as a next-generation approach. We are successfully executing in all 3 fronts: ALLO-715 monotherapy, which was presented today; the planned IND submission before year-end and start of trial initiation of ALLO-715 and nirogacestat combination study; and the planned IND submission in the first half and trial initiation in 2021 of ALLO-605. Now let me invite Rafael Amado, our Executive Vice President of R&D and Chief Medical Officer, to provide the overview of UNIVERSAL study. Rafael? Rafael, you're on mute.

Thank you, David. Sorry about the mute moment. I will introduce the UNIVERSAL trial in -- during my talk, and then I will ask Dr. Parameswaran Hari to walk us through the interim results, following which I will make a few comments, and we will move on to Q&A. Today, BCMA T cell therapy has shown remarkable efficacy, but several logistical challenges may limit access. Allogenic cells has several advantages, including minimal delays and the potential to treat all eligible patients without need for bridging therapy. Manufacturing is scalable, and there is less product variability. They can be engineered to carry not just CARs but other genetic elements that can enhance antitumor activity and lend themselves to repeat dosing. Shown here is the CAR construct that is used in ALLO-715. It includes a human scFv and a 4-1BB costimulatory domain. And in order to eliminate GvHD, we knock out the expression of the TCR alpha constant region by gene editing using TALEN nuclease. Our approach to preventing early rejection consists of gene inactivation of the CD52 receptor, also using TALEN technology to allow selective lymphodepletion with ALLO-647, which is an anti-CD52 monoclonal antibody, which depletes CD52 cells in patients, while the donor cells remain protected to expand and kill malignant cells. Next slide, please. The UNIVERSAL trial is a Phase I 3 plus 3 dose escalation study being conducted in 11 centers in the United States. To enter the study, patients must have either relapsed or refractory myeloma; two, proteasome inhibitors, IMiDs and anti-CD38 therapy. All patients must be refractory to the last line of therapy. Bridging therapy is not permitted. Patients must have an ECOG of 0 or 1 and lack antibodies against donor HLA antigens, among other entry criteria that you can see on the slide. The primary end point is safety and tolerability of ALLO-715 and ALLO-647. The secondary end points include ascertainment of a recommended Phase II dose and lymphodepletion regimen, antitumor activity, ALLO-715 cellular kinetics, a serum -- and serum ALLO-647 concentration. Patients received escalated doses of ALLO-715, as you see in the slide, at 40 million, 160 million, 320 million and 480 million CAR T cells at fixed doses after conditioning with fludarabine and cyclophosphamide at 90 and 900 milligrams per meter square, respectively, and ALLO-647 at either high dose or low dose, defined as 39 or 90 milligrams, also fixed dose. Lymphodepletion is given in 3 divided doses, and cells are infused on the 6th day post initiation of lymphodepletion. Next slide, please. The UNIVERSAL study is a pilot trial and the first to report data with the BCMA CAR in the allogeneic setting. Our original goal was to understand whether the process was even feasible and safe and whether allogeneic T cells transduced with an anti-BCMA CAR could exert antitumor activity. As with our ALLO-501 CD19 CAR, the key questions we had at the outset were: Can ALLO-715 be successfully manufacture? Can it be safely administered without causing graft-versus-host disease? Can ALLO-647, together with fludarabine and cyclophosphamide, allow a sufficient window of lymphodepletion that permits ALLO-715 to expand and persist? Can we see meaningful responses in our refractory population? And lastly, can we enhance the responses on their durability with future dosing and scheduling optimization? Next slide. So to answer these questions, it is my pleasure to ask Dr. Parameswaran Hari to walk us through the interim trial results. Dr. Hari is a Professor of Hematology and Section Head of Hematological Malignancies and Adult Bone Marrow Transplant Program at the Medical College of Wisconsin, and he's an investigator in the UNIVERSAL trial as well as multiple other BCMA directed therapy trials. Dr. Hari?

Thank you very much. Thank you for the opportunity. So as mentioned earlier, this is preliminary results of the anti-BCMA ALLO-715 CAR T cell therapy in the UNIVERSAL study. Next slide, please. So these results were recently presented a few hours ago at the ASH meeting. So the most important point to recognize is that's the Phase I study. It enrolled 35 patients, and the time from enrollment to the start of treatment with this allogeneic off-the-shelf product was 5 days. So the safety population was 31 patients as 4 of these patients who became ineligible could not be treated. Anybody who got lymphodepletion was considered in the safety population, and the efficacy population is 26 people. Multiple doses of CAR T cells were examined in the study, going from 40 million cells as a fixed dose, up -- all the way up to 480 million cells. And also, lymphodepletion was compared predominantly, the dosing of ALLO-647, which is an anti-CD52 monoclonal antibody, and also a regimen that did not have fludarabine or CA. The standard regimen included fludarabine, cyclophosphamide in the conventional fashion and the ALLO-647 antibody. Overall median follow-up time was 3 months with a longest follow-up about 6 months. So the population is quite typical for CAR T studies in myeloma, but in some ways, a little bit more advanced in that these patients were enrolled and treated in a very short interval, which means that people with a rapid pace of disease evolution could be treated on this study. The patients were -- age was 65, the oldest being 76. 50% of these patients had high-risk cytogenetics. There were 1/4 with extramedullary disease, 23%. And the time from initial diagnosis to this treatment was a median of 5.4 months. And the number of prior regimens range from 3 to 11 with a median of 5. 94% of these patients were prior auto transplanted, and 94% were penta-exposed, meaning they had exposure to the 5 major classes of drugs in multiple myeloma. And the patients also had to be refractory to their last line of treatment. Next slide, please. So being a Phase I study, the safety profile is of great interest. There are 2 classic CAR T-related side effects that are common to all CAR T products so far. These are cytokine release syndrome and ICANs or the neurotoxicity of CAR T. As you can see, cytokine release syndrome was quite manageable in that nobody got grade 3 or above cytokine release syndrome. And the majority of them were -- all of them were grade 1 and 2. And the total was 45%. No patient experienced ICANs or CAR-specific neurotoxicity. More importantly, graft-versus-host disease, which is a theoretical concern, whenever you give allogeneic T cells to a human, you have the potential of these allogeneic T cells causing graft-versus-host disease that was not observed at all. Infusion reactions to the ALLO-647, which is the monoclonal antibody, was also quite manageable at grade 1 and 2 and only occurring in 1/4 of the patients, 23% of these patients. Infection, which is again another risk in both the myeloma setting as well as the CAR setting, was 42%, with one patient having succumbing to an infection very soon after the treatment. And the majority of infections were, again, grade 1 and 2. 13% were grade 3. The one single grade 5 event related to rapidly progressive myeloma in a patient who was on the CA cohort and passed away very quickly after receiving treatment from a fungal pneumonia. Next slide. Here is the response element or the efficacy element. As you can see, we are showing the overall response here in this slide of ALLO-647 at various doses as well as in the population at dose level 3 and 4 wherein patients received 320 million or 480 million cells. As you can see, the overall response rate achieving a partial response or better was in 60% of the patients, with 40% achieving a VGPR, a very good partial response or higher in the 320 million cell dose group. 5 of the 6 VGPR+ patients overall have been assessed for minimal residual disease status, and all of them were negative. Next slide. This swimmers plot actually shows the longevity of these responses. Here, again, just to orient people, the green bars are complete responses, stringent complete responses and a VGPR response. The bluish green bars are the partial responses, and progressive disease is in red. You can see patients are continuing -- the top 2 patients, for example, in the 480 million have a very short follow-up there and minimal response or stable disease but not progressing. Coming down to people with further follow-up in the 320 million and the 480 million cohort, you can see patients achieving partial response and converting, patients achieving rapid complete response of VGPR and staying in response, and at least one patient, towards the upper half there, having had a minimal response then progressing at about 3.5 months. The longest response is a complete response down below, where patients have actually exceeded 6 months now and staying in response at the 320 million dose. There are many other -- 2 other patients in the 320 million, which are showing the arrow with ongoing responses. And another one which we normally see for agent myeloma would be the patient with MR then progressing to a PR and then progressing to a VGPR+ response and then continuing to respond, that's the patient about the middle of the slide with our 3 colors there. So these are quite typical for an agent with single-agent efficacy, and that's the only takeaway I would take from this -- for this slide. Here is a representative patient. Again, we can see that the CAR T copies, as measured by the vector copy number, expand -- suggesting that the primary requirement that we have for a cell infusion, which is that the cells need to expand, does happen. The expansion is highest -- for highest cell doses at 320 million cells. And that, again, is a -- in the purple color there with the highest expansion going from up to 10,000 copies per microgram of total DNA. At lower cell doses, expansion was not as high or as sustained. At the 320 million dose, you can see that CAR persistence is up -- all the way up to 4 months or 120 days. Next slide, please. Here is another way of looking at this. This is a 71-year-old patient with a rapidly progressive myeloma who had already seen a prior autologous transplant and a prior experimental BCMA-targeted therapy and was also progressing on the last line of such therapy. So essentially, a highly advanced patient with 9 previous lines of therapy. The patient received FCA with low-dose ALLO-647 and received 320 million, which we are showing in this slide here as the ALLO-715 dose here. And the patient experienced grade 1 CRS with symptoms of fever and tachycardia and were treated with acetaminophen. Patient achieved a VGPR on day 14, which then continued and went to a stringent complete response by day 28. Here is the ALLO-715 shown as a flow cytometry plot, with 91% of the patient's lymphocytes showing CAR expression by day 14, registering that the most of the expanded T cells in the patient at that time point were CAR positive. So they -- essentially, this shows that the lymphodepletion was effective. And in the lymphodepleted environment, the ALLO-715 cells form the majority of T cells in this particular patient at that time. Next slide, please. This slide is attempting to show that the T cell recovery and CAR expansion over time in the particular patient, as you can see again, by day 7 to 14, there was CAR expansion. Kappa free light chains in this particular patient declined rapidly by day 14, correlating with the expansion of CAR in that day 7 to 14 period. Patient achieved VGPR by day 14 and a stringent complete response, which was sustained by day 28, which then still continues at month 6 on this patient. Next slide. So in summary, as a physician in this myeloma environment, I would say that this is -- these are early results. UNIVERSAL trial is the first allogeneic BCMA CAR T trial that has been presented. Approximately 90% of the patients were treated within 5 days of study enrollment, making this an exciting option for patients with rapidly progressive disease who really cannot wait to get CAR T cells. Bridging therapy was not required, not allowed on this study prior to the ALLO-715 dosing, which, again, suggests that the single-agent efficacy of this particular CAR T is what we are seeing in this slide set. ALLO-715 and ALLO-647 regimens were tolerated across the dose levels explored in this study. Graft-versus-host disease or neurotoxicity were not seen, and cytokine release syndrome was manageable at grade 1 or 2. Infection rate is similar to what is expected in advanced multiple myeloma. There was one death. Dose-dependent ALLO-715 activity was observed in heavily pretreated and refractory patients, patients being refractory to the last treatment they were receiving at the time of study entry. Expansion and persistence of ALLO-715 cells were observed, and they were persistent through month 4 as well as we can see from the slide. 320 million cell dose with an FCA conditioning regimen or lymphodepletion regimen was associated with a 60% overall response rate. 5 of the 6 VGPR or higher responder patients who were assessed for MRD status, all of them were negative. Ongoing enrollment and further maturation of this data will allow us to evaluate this for the broader myeloma community in the future. Thank you.

Thank you, Dr. Hari, for a great summary of the UNIVERSAL data to date. Next slide, please. So we started this study fully knowing that this was pioneering work that would require optimization of cells and lymphodepletion, doses and schedule. We have accomplished our objectives of manufacturing the product, being able to administer it safely, observing expansion and long persistence, which is dose dependent. And importantly, we have also observed, as Dr. Hari just show you, those dependent meaningful response rate, which in dose level 300 million or 320 million cells is 60% overall response, with 40% of patients attaining a VGPR or better. This is definitely a strong data showing important antitumor activity seen for the first time in an allogeneic trial. We obviously have more work to do as we optimize key parameters and follow these patients longer, particularly those treated more recently with higher doses. The study continues to explore doses of 480 million cells using standard doses of flu/cy and higher doses of ALLO-647. And as David mentioned, we expect to start our nirogacestat combination in the first half of the next year as part of our comprehensive BCMA program, which also includes ALLO-605. Next slide. We believe that ALLO-715 access and logistics are key differentiators from autologous therapies. Although apparently, product could be manufactured for patients enrolled in autologous trial where this data was reported, up to 19% of patients were not treated presumably because of progressive disease precluding treatment. A large proportion of patients require bridging therapy while awaiting treatment in autologous trials, whereas it's not allowed in the UNIVERSAL study. Indeed, the waiting period can be as long as 4 to 6 weeks in some of these autologous trials, whereas it is off-the-shelf, and therefore, about 5 days or so in UNIVERSAL. Although 11% of patients not treated may not seem very different from 17% or 19%, there are differences between the timing of counting to study entry. For instance, counting from time to enrollment or from time to apheresis. So there's no uniformity as to when this parameter is measured. In addition, retreatment and re-dosing is feasible with ALLO-715 as it is an off-the-shelf product, whereas it may require remanufacturing, it would require remanufacturing and it would be impractical in the autologous setting. Next slide. Here, we contrast the toxicity rates of UNIVERSAL with other commonly reported autologous BCMA studies. Treatment in UNIVERSAL was very well tolerated. ALLO-715 was associated with a starkly lower grade of toxicity across all categories, including CRS, neurotoxicity and neutropenia. There was no GVHD. And importantly, the rates of infection in UNIVERSAL were no different than that of other cell therapy studies. The rate of grade 3 or higher infection was 16%, and all the events occur in patients today with a low dose of ALLO-647. Likewise, the overall mortality rate attributed to adverse events was similar to Ide-Cel in the KarMMa study, Orva-Cel in the EVOLVE study at 3%, and more than double was the figure in the Cilta-Cel product in the CARTITUDE trial, which was a death start of 97 patients due to AEs plus some due to disease progression, which has been reported in an ASH abstract, which is being presented today. Next slide. Here, we contrast this efficacy results of the UNIVERSAL trial at 320 million cells with those of autologous trials, not to do inferential comparisons but to see how our results are tracking on efficacy and safety relative to autologous therapy, which may become the initial future standard. When contrasting the response rate of the higher-dose patients in UNIVERSAL, we can see that the response rate in UNIVERSAL is high as 60% in the higher cell dose cohort, which is impressive in this first-in-human study. Likewise, rates of VGPR or better responses were lower in UNIVERSAL but overall impressive in such refractory patients. When interpreting these results, it is important to acknowledge a few factors. First, the sample size is very small still in the DL 3 subset, and a single responder can increase the response rate by 10%. So this number is still very unstable. Second, the UNIVERSAL study is a pilot study and the optimal lymphodepletion regimen and ALLO-715 dose, including potential re-dosing, have not yet been completed. Thirdly, in the UNIVERSAL trial, a higher number of patients enrolled in the study received cells than in the other trials, and therefore, a possible selection bias may occur by eliminating more patients who progress in the autologous trial during the waiting period even after apheresis. And lastly, patients in the UNIVERSAL study demonstrated a significantly better safety profile than the rest of the trials, as was shown previously. So I believe this is my last slide. Thank you for your attention. But prior to going to Q&A, I wanted to invite Dr. Hari, who lives and breathes this field and has participated, as I said before, in all these autologous trials and UNIVERSAL, to make a few comments. So if I could ask you, Dr. Hari, how do you compare your experience of treating patients in the UNIVERSAL study with the experience in autologous studies?

So the pro and the highest biggest pro for an ALLO approach in the ALLO CAR world for multiple myeloma would be the off-the-shelf nature of this product and the fact that the ability to infuse the CAR is a confidence for the treating physician. When one tries to enroll a patient onto an autologous CAR T study, there is always the possibility that the pace of disease is rapid. And in the 6 weeks or so from the time of intending to treat the patient, getting them on study, getting an apheresis state, and then the 4 weeks to 4 weeks plus, the median is about 4 weeks for the cell product to come back, you actually do not know if the product is going to be made. The manufacturing success is a question. But generally, it is successful. But that time period is critical for the patient, and it is critical for the physician to keep the patient going during that time, at which time we necessarily need bridging. And also toxicity can happen from the bridging, sometimes from the disease, such as renal failure, et cetera, which leads to nontreatment. So it's a little bit more of a challenge, whether on, a, will you be able to treat this patient with CAR? Will you be able to get the patient -- the CAR at an appropriate dose? Being an off-the-shelf product with a defined dose, it is much more feasible that the patient will get treated. But on the other hand, in the study setting, there is also a more aggressive patient who can get on an ALLO off-the-shelf study. And there is a selection bias which eliminates the worst patients from getting onto auto studies at the -- because of that inbuilt delay. So the -- I appreciate the ability to treat the patient off-the-shelf in -- especially the sickest to the sick patients. So that's what I would like to say about the time to treatment aspect.

Thank you very much, Dr. Hari, for those insights. And with that, I would like to turn it over to Q&A.

Thank you, Rafael. Thank you, Dr. Hari. [Operator Instructions] First question will be coming from Marc Frahm from Cowen.

Congrats on the data. I just want to kind of dig on the persistence aspect of the cells. And like there's one patient who showed deepening of response at 3 months. And then you also have a couple of few people who have relapsed, which is seen with the autologous products as well. In those patients where the status is changing, are the cells still there and appear to be active and so maybe the relapse mechanisms are the same as you're seeing in autologous? Or is there a chance that it's because you're losing the cells and then on the efficacy side, do you think they're still active at that 3-month time period?

Marc, this is Dave Chang. Let me take that question. And also, I may ask Dr. Hari to comment on the cell persistence. I mean what we are seeing across different studies is a common theme on the translational science aspect. I mean lymphodepletion matters, and that includes the depth of T cell suppression and the time before T cell starts coming back. And I think we have a distinctive advantage of being able to use ALLO-647 to really tightly control the T cell suppression as well as T cell recovery. And this is what we are calling as a window of persistence during which we expect the cells to expand and persist for a period of time. We're dealing with relatively small set of data coming from 501 as well as 715. So that's our non-Hodgkin's lymphoma and multiple myeloma program. And the theme of the data is highly consistent, I mean the focus on the cell expansion and the correlation between the cell expansion and response. And exactly the question that you are asking, whether the evolution of the response depends on persistence of the cells, I mean, I think we are talking about relatively few data points at this point. So we are not really able to make a meaningful comment on that, but this is something that we are following very closely. Having said that, as sort of the data set that we have showed in the presentation, what we are seeing is that when we increase the lymphodepletion, also in this case, in the 715 study, when we increase the cell dose, we see much better cell expansion, and our cell expansion goes up to -- as Dr. Hari presented, up to about 4 months. So I think this is pretty remarkable in terms of what we can do in the allogeneic setting. Dr. Hari, any comments, any thoughts on this?

Yes. So I can address in a broad perspective, so -- as many people here on this panel have studied the data. Even in the auto setting and even in other CAR T settings, you don't necessarily need persistence for long-term disease control. Really, that is the key question. How long will these responses last? Are they going to be comparable to the other agents that we have, et cetera? So in that regard, if you get a really deep MRD-negative response, you may not need persistence. If you have persistent cells, small emerging clones may be eliminated. And we actually don't have, from the myeloma world, much data on that, as you can -- as you know from the other presentations at ASH today. As a myeloma physician, our group, we believe that there are 3 aspects in terms of myeloma recurrence after CAR T. One is the CAR T cells have disappeared and the clone is emerging. Number two, the myeloma clone has acquired resistance to the CAR T, even if the CAR T is persistent, by losing BCMA expression. Sometimes it's a biallelic DCMA deletion. Sometimes, it's a change in the epigenetics of BCMA expression, et cetera. And number three, tumor microenvironment can create a situation where both the antigen is present and the T cell is present, but they are not able to have an effect. So persistence is one aspect of relapse, and persistence definitely is something that is desirable for that 1/3 of people who relapse. But there are other mechanisms by which myeloma cells that we already know to escape even persistent CAR T. On the other hand, one advantage I see for off-the-shelf products is that re-dosing and the ability to re-treat may offer a different way of approaching lack of persistence or even emergent clones that may still have BCMA expression. So it's a little complicated subject, and as a treater, I really don't know where we are headed with that persistence aspect.

Our next question comes from Salveen Richter from Goldman Sachs.

So on the efficacy front with the multiple myeloma program, do you think with additional optimization here, be it higher doses or the lymphodepletion regimen or repeat dosing, that you could achieve similar data to what we're seeing with autologous CAR Ts? And as you look at the breadth of your programs to date, I guess, I'd be curious if there's something unique here with multiple myeloma versus lymphoma that could limit the efficacy.

Yes, Salveen, a great question. We are still early in the UNIVERSAL study and continuing to enroll to get additional experience at high cell dose as well as using high lymphodepletion. I mean the way that we think about optimizing the benefit risk of AlloCAR T therapy is really -- hinges around cell dose lymphodepletion and also, as Dr. Hari mentioned, potential to re-dose. And that's just in the monotherapy setting alone. And also, we are -- as we have covered, we'll be moving forward with a combination study as well as using the next-generation technology of BCMA CAR. So I think we have a lot of different levers that we are pulling with the goal of providing the best benefit/risk profile of a product that we can advance in the multiple myeloma indication.

Our next question comes from Tyler Van Buren from Piper Sandler.

Thanks very much for the presentation. It's encouraging to see that everything is moving in the right direction with respect to cell dose and 647 as you look to increase both of those. I had a question, a follow-up on cell expansion and persistence. If you compare the cell expansion and persistence of the 320 million cell dose to the earlier -- or to the Ide-Cel presentation in the same session at 450 million cells, you guys are going above 10 to the fourth, whereas Ide-Cel is going above 10 to the fifth, and you guys are persisting up to 4 months as opposed to Ide-Cel going up to 6 months. So -- but then Dr. Hari just said that you don't necessarily need persistence for long-term disease control. So my question is as you increase doses, are you more focused on getting the cell expansion higher maybe to above that 10 to the fifth threshold? Or do you view them both equally important?

Tyler, as usual, you're asking very sophisticated question, and I really appreciate that. I think trying to make a trial comparison about the magnitude of cell expansion, I think that's a little bit of a challenge because everyone is using a slight different assay. So obviously, we do pay attention to that, but that's not really the only gauge that we are looking for. We were really trying to see internal consistency, both coming from the lymphodepletion, cell expansion and the dose dependence of that cell expansion and ultimately, benefit/risk profile of the therapy. So I mean that's what we are doing. And trying to really dissect this early on, especially given our data set is still relatively limited and emerging, I think is premature. Rafael, any further thoughts on that?

No. I mean, I think it's been shown before in that very trial also that there's a dose response, whether -- and we didn't actually see such a stark dose response in lymphoma, for instance, and it's been seen in other studies in myeloma. So it may be that this initial antitumor response is important. I think the role of persistence is really unknown. But as seen -- I fully agree with Dr. Hari that if you can achieve a CR, particularly a stringent CR with a high MRD negativity, you may not need long persistence. So I think it's to be defined as we continue to dose escalate and to increase lymphodepletion. And I think that's going to give us the answer.

Our next question comes from John Newman from Canaccord.

Just wondering, in terms of the high dose for ALLO-647, which you included today, curious if you saw higher sale expansion at the 320 million cell dose and also if you saw some hints of better curability there.

Okay. I'm going to ask Rafael to comment on those aspects. Mind you that at high dose, we are still early, and we don't have complete translational data set yet.

Yes. I mean we treated 4 patients with a high dose, as you saw. Three of the patients responded. We did see higher lymphodepletion, as David mentioned before, both in terms of the [indiscernible] as well as the durability of the lymphodepletion. We also saw one complete response in that group. And the data continues to mature, and we are now treating at 480 million with 60 milligrams with a higher dose at 90 milligrams. So the question is going to be what happens when we treat more patients. But our view continues to be that the higher lymphodepletion leads to more expansion and clinical outcomes improve. So we fully expect that, that will play out as we treat more patients.

Our next question comes from Mark Breidenbach from Oppenheimer.

Thanks for taking my question, which is probably directed toward Dr. Hari. We've seen some data suggesting free light chain normalization within the first month after CAR T infusion may correlate with the PFS benefit. Are you generally seeing free light chain responses in patients who are achieving objective responses with this treatment beyond the single patient that you highlighted in your presentation?

So from my -- our own experience here, I have to say that free light chain responses are very quick in CAR T treated patients, irrespective of the modality of CAR T, whether this CAR T or another CAR T. I'm definitely involved with many other CAR Ts. On -- but the data that you do show that the free light chain response is maybe correlated with the duration of response, I'm not -- I'm a little skeptical about that data because, essentially, the free light chain, if anything that's going to be correlated, I would think it's going to be MRD negative day rates and the rapidity of getting such MRD negativity. The free light chain generally is a poor surrogate compared to MRD, et cetera, mainly because it is -- the free light chain is a measure of the light chain producing myeloma cells. In this particular population with highly refractory/relapsed patients, there's multiple subclones. There is a tremendous subclonal heterogeneity. And the clones that tend to come back, especially after T cell-mediated therapies, are the more anaplastic clones or the more primitive clones, which don't even make in. So I really -- I'm a little bit skeptic about the free light chain data. But to the specific question you asked, yes, we do see the rapid free light chain reductions in this CAR T as well as some of the other CAR Ts.

And Mark, in our data, as Dr. Hari covered during the presentation, the patients who are tested for the MRD all tested MRD negative.

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

Congrats on the data. Can you -- maybe just starting off, can you clarify, I guess, the differences between sCR, CR, VGPR? They all tend to be grouped together. Is there any sort of a dose response that you might be seeing in terms of the higher doses getting more CRs and sCRs versus VGPRs? Or should we even care?

Well, I think this is the question that Dr. Hari would -- you'll be in the best position to sort of distinguish the fine nuance of how multiple myeloma disease assessment is done.

So a quick 2 to 1 second primer is that myeloma has a disease marker. And in clinical trials of myeloma as opposed to the real world, we only enroll patients who have the -- such disease markers. And these disease markers are secreted M proteins in the blood or urine or light chains. VGPR is a 90% reduction in the total disease burden. A complete response is where there's 100% reduction in the disease burden, which means you cannot measure it anymore and associated with the less than 5% myeloma cell burden in the [ net ] bone marrow. And the stringent CR is that less than 5% in the bone marrow becomes 0% by flow cytometry or other methods -- similar methods. So that into -- again, what the modern myeloma world in the last 2 years has shown us is that VGPR, CR and stringent CR essentially can be lumped into one entity as long as you are measuring MRD as well. There was another presentation today in the biology session, which is very exciting, which showed that if you get to a VGPR and you're MRD negative, it doesn't really matter if you're in a CR or a stringent CR. So a VGPR with MRD negativity is as good as it gets.

And if I can add just, Ren, all the CRs were observed at the highest dose level of DL 3 at 320 million, so to your point of dose relationship.

Our next question comes from Luca Issi from RBC.

Congrats on all the data. Just wondering, it looks like in lymphoma, your response rate is CD52 dose-dependent but was pretty agnostic to the number of cells that you were actually using versus multiple myeloma. Looks like you need both, a high dose of anti-CD52 as well as high doses of cells. So wondering if you have any thoughts or comments on that.

So look, let me take on that question. I mean you are making very astute observation, and this is something that we have seen in other programs as well. And I think this -- the cell dose response that sometimes you see, sometimes you don't, I think it really depends on where you are starting in the dose response relationship. Dose response relationship is never linear. It plateaus out at some point. So if you're starting doses already nearing the plateau, you're not going to see much cell dose response. On the other hand, if you're starting doses in a linear phase as we believe is occurring in the 715 study in multiple myeloma, you will definitely see the cell dose response. So I think this is really somewhat context dependent on the cell potency as well as indications. But the concept that really underlies this, the dose response relationship curve.

Your next question will come from Jason Gerberry from BofA.

Mindful that it might be a little early, but I'll still ask anyway. With autologous CAR Ts, we see deepening of responses at later time points with PRs converting to CRs, call it, 3 to 6 months post infusion. And would you expect to see similar conversions on ALLO-715? Or do you think that complete responses will tend to occur within 1 month post infusion?

So Jason, let me sort of start, and then, Rafael, maybe you can expand on this. I mean, definitely, even in the data presentation that Dr. Hari covered, we saw some responses that got better over a period of time. And whether this is going to be the period during which that occurs, is it just a matter of 2- to 3-month window, or is it going to be longer window, we don't know because we don't have the data set. I mean, Rafael, you are following the data a lot more closely. Any thoughts on this?

I mean, I think that's been seen definitely in the autologous setting. We have seen some examples of patients that even start with stable disease and then go on to the PRs. And then 3 months later, they get a CR, and that is sustained. So I mean it's still a very short time. The median follow-up is less than 4 months. So it's premature to say that, that's going to occur in all the PR patients, but we definitely are hopeful that these responses can deepen as time goes on.

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

Congratulations on the update, and thank you for making the presentation, taking our questions. So the conversation that's occurred in this -- it goes back to the auto CAR T setting probably back 2 years now. How's been -- how the landscape's evolved in the later lines? You obviously have Blenrep as an option. You also alternately have a non-BCMA agent, selinexor. You have tocilizumab in development right now with really promising-looking response rates that will be updated later today. Then you also have, as you pointed out, really great outcomes with auto BCMA CAR T., but obviously, the issue with rapid progressors, that's well -- as seen in the clinical community, probably within 30% of their patients. Dr. Hari, how does this kind of fit in? And Dr. Chang, how does this fit into how you think the clinical use could hold up? And what, for this type of product, is, in your view, the ORR hurdle and the MDOR hurdle? Obviously, this is speculative, but when you're putting out this program and you keep optimizing how you're doing either combined with the GSI or conditioning agents, you probably have something in your head of what you think need to get there clinically.

Dane, great question, and I'm so delighted to hand back to Hari because as a treating physician, I think he will be most well positioned to respond to your question, and I'll follow up with some additional comments.

Thanks. So we, in the myeloma community, are very excited about the drugs that you mentioned, especially the new agents, tocilizumab is a BCMA bispecific. There are several other bispecifics being presented at the meeting. There are also a couple of new bispecifics with newer targets, GPCR5D (sic) [ GPRC5D ] and FcR5H, et cetera, being presented at the meeting. So very excited about those off-the-shelf products for relapsed/refractory myeloma. Autologous CAR Ts have matured and have more duration of response data, but it is very clear to everyone in the myeloma community that autologous CAR Ts are also associated with a relapse and very limited re-dosing ability with essentially no responses to re-dosing. So that being said, a CAR T approach that is more universally applicable and a CAR T approach which is off-the-shelf, and if the safety data holds up over time, you do not need an apheresis center. You necessarily do not need a big transplant center to be doing an allogenic off-the-shelf CAR T. So some of those things make it a real-world option that may be amenable for an allogeneic CAR T to enter into the treatment space as far as I can see it. Obviously, the more number of agents that we have, which, for myeloma patients, it is really exciting for all of us in the myeloma world. And we are actually thinking about what works in sequence and what works synergistically. So essentially, as, again, everyone on this call knows, the treatment of myeloma, even when we have a target -- when a single target with multi-modality approach to that target, which is happening in the BCMA situation, many of us have patients who have experienced one BCMA-targeted agent and then go -- not responded or responded then failed, and then go on to another BCMA-targeted agent and responded and had a long response. The patient that was in the slide set was a similar one. And the one thing I like about this trial, which I congratulate the company on, is that they do allow patients with prior BCMA exposure to come onto the trial, which is basically a bold approach, and that is something that was not tested in the autologous CAR T setting. So in the real world, as you mentioned, there is an ADC, Blenrep, that's already available and many patients may get exposed. Some of those patients are not going to be eligible to some of the autologous CAR Ts that are in development right now. So this way, it is a moving space, and I, as a myeloma physician, welcome more and more agents to come in.

Exactly. I think this is a great time if there is any great time for anyone with cancer. But for multiple myeloma with different treatment coming up, I think this is really an exciting time where we can really affect the disease course of the patients with multiple myeloma. I mean the way that we see this is especially in refractory setting, we are really going for the efficacy and also, at the same time, trying to leverage the convenience of the allogeneic that comes with the AlloCAR T therapy. From the efficacy perspective, when we look at the data that's coming up in the cell therapy, you're talking about the CAR T BCMA versus BCMA bispecific and then BCMA ADC, there is a trend that's becoming more and more solidified where efficacy really follows from the cell therapy and then bispecific and then ADC. So we believe in the cell therapy. And by making this an off-the-shelf, I think we have a winning solution that can potentially really help the patients out there.

Our next question comes from Matthew Holt from JPMorgan.

So I want to ask you about the patients that progressed prior to treatment with 715, and I appreciate the context for how this compares to auto BCMA CAR T. So the question is, do you think these rapidly progressing patients are a treatable patient population? And how does this result change how you think about the value proposition of allogeneic CAR T in multiple myeloma?

Maybe, Rafael, you can comment on the experience that we have. And Dr. Hari, I mean, I think this is really a clinical decision, maybe you can further expand on that. Rafael?

Yes. We have 4 patients that progressed too quickly, really, within a week, to meet inclusion criteria. So in the context of a trial, obviously, we cannot allow the patient at the time of entry if any of the laboratories are off. So one patient, for instance, developed pneumonia. One patient developed C. difficile colitis. One -- and a couple of patients developed acute renal failure, which is common, unfortunately, in myeloma. So these were patients, again, with very advanced disease. And obviously, one can look at it from the other side of the coin, which is if we can even make this even shorter, it is 5 days, the value proposition of off-the-shelf therapy then really becomes very obvious because we could potentially treat these patients even sooner. So obviously, there are going to be patients that are way too sick to be treated with these agents, but we believe that comparative to the autologous setting, we are able to treat many more patients than the autologous trials can. And Dr. Hari, you can comment on that.

Yes. In addition to the comments that were just made, what I would like to say is that the real world is quite different from the artificial or the virtual world of clinical trials. For example, one of these patients, which I know about, was a patient who went into kidney failure and reversible kidney failure related to the myeloma right as he was about to get into a lymphodepletion. And that particular patient could not go on trial and the window of going on the trial closed for him because he got something else, which then made him ineligible, his platelet counts were low, all that. Because in a trial, we have specific eligible criteria. If your creatinine clearance is 39, you're not going on study. If you are 40, you can go and stay. When we have a product that emanates from a clinical trial and it's commercially available, whatever that product may be, then we end up using it in patients like this. So essentially, even in a rapidly progressing setting, in the real world, we would end up using a product that's off-the-shelf more likely than a product that -- where we have to wait for. And this applies also to the auto people, too. They will also get to use -- we will end up using their products too much easier. And this will also apply to the ALLO product in that some of the patients who had, for example, an infection that prevented them from getting on trial in a limited amount of time, especially a Phase I trial, where the cohorts are 3 and 3 and 3. Your third cohort is gone. Another center has gotten the cohort, another patient has gotten the cohort, our center will not get the cohort. So that's the real -- that's the world of trials. In the clinical world, these patients essentially will end up on treatment. And every agent that we have tested in myeloma, whether it's a drug or a cell or whether it's an autologous or allogeneic, more patients will get it in the real world than can get on trial.

Our next question comes from Raj Prasad from William Blair.

Curious to know, on the response rate in the subset of patients with EMD and high-risk cytogenetics, did you see any VGPR pluses in those patients? And just kind of a 1b question. We know kind of from the auto space the importance of the stem cell phenotype population. Any color you can give us on kind of the stem cell phenotype population of your cell product?

Rafael, do you want to take on that question? Raj, you're asking very complicated questions.

Yes. I mean to the first question, I would say that the responses, including the very good responses and CRs, were independent of prognostic factors. So there were patients with prognostic factors that attained them. So that's the first question. On the second question, generally, our cell preparations have a really high proportion of stem cell, memory cells and central memory cells. So they're young cells and immunophenotype also [indiscernible] between CD4 and CD8 equal ratio. So I can -- that's about what I can tell you that we select for very healthy cells that have an early memory phenotype.

Our next question comes from Tony Butler at ROTH.

Rafael or David, the presenter earlier in the day had made -- when I asked, had made reference to the most ideal dose being 320 million -- perhaps being between 320 million and 480 million. And I'm curious if you concur with that. I only say it because it still looks like 480 million may be a more optimal dose above, either in between or that for 320 million. And I appreciate your comments.

Tony, great question. I think we can speculate about what the optimal cell dose is. But let's have a more meaningful discussion as we have more data on the higher cell dose. I mean, I think your point is about 320 million, 480 million or higher. I mean, I think all this is something that we can only speculate at this point. But we are generating additional data as we continue to enroll patients at higher cell dose.

And our last question will come from Ben Burnett with Stifel.

He may be muted.

I think he is. All right. Well, we can -- I don't think Ben is able to unmute. So we will conclude this. So thank you for your participation in today's webinar. It will conclude the program, and you may all now disconnect. Thank you.

Well, thank you very much, and have a great day.