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

Very good afternoon. Thank you very much for joining us at the Goldman Sachs 2022 Healthcare Conference [indiscernible] To start the call, can you highlight the overview [indiscernible] the progress in general across the [indiscernible] portfolio [indiscernible].

Thank you, Salveen. First of all, thanks -- thank you very much for joining us here. [indiscernible] Great to see you. [indiscernible] [indiscernible] system and as for last 4 years. Finally, at the company, it's really based on taking the allogeneic assets from Pfizer [indiscernible] patient platform that's based on ALLO-647, our anti-CD52 antibody, and generating the proof of concept. The proof of concept here really is not only getting the deep responses but also demonstrating the durability of the response. So probably a highlight coming from our most advanced program, ALLO-501A, which we are planning to initiate the pivotal study. Relatively soon, that data that we have presented at last year's ASH is when you look at the 14 patients who have achieved complete responses at the time of the data cut, 10 patients were still in complete remission. And of those 10, there were 7 patients who had passed the 6-month time point. So frequently in the South therapy space, 6 months CR is considered as a good predictor of what will happen to that patient. And certainly, that is based on individual's risk of progression after being a complete remission for 6 months. It gets extremely -- exceedingly low. And what we have shown in that data presentation is that of the 7 patients who have passed the 6 months, all the complete remission was ongoing. And none of them had progressed. So from that perspective, the lead program has shown the most important proof of concept, the durability of response that one is seeking in the chimeric antigen receptor therapy treatment. We also have a second program in the BCMA, ALLO-715, which we are developing. We are taking several different approaches. But as we continue to review the data, the single infusion of ALLO-715 is beginning to shine in terms of both the response, depth of the response and just like the 501A, the durability of response. And the third program is our program that's targeting solid tumor ALLO-316. That's a CD70 target in CAR T. And we are continuing to escalate the dose in the dose escalation phase of the Phase I, and we hope to share the data sometime in the near future. So that's really the pipeline, focusing on advancing the heme malignancies but also looking at the solid tumor where the opportunities are much greater, focusing on demonstrating the important right lymphodepletion, demonstrating the durability of response. And last thing that we started talking about probably last 6 months or so is the investment that we have made in the manufacturing that's finally beginning to pay off in terms of bringing our own manufacturing facility online. And we currently estimate that from that manufacturing facility, we can produce up to about 20,000 doses a year.

So maybe to start with the CD19 program that's entering pivotal stage. How confident are you that the FDA is going to sign off here on that program starting and maybe talk about the likelihood that you -- that they'll agree to a single-arm registration study?

Yes. So that you're talking about ALLO-501A program. And by the way, last week, we announced that FDA has granted RMAT designation to our ALLO-501A. And we have had discussions with FDA about the pivotal study and starting the pivotal. And that ranges from exactly what the study design and endpoint for the main pivotal study as well as taking care of all the CMC-related issues. And then the third leg of the ALLO-501A program is we have the need to demonstrate the contribution of ALLO-647 as a lymphodepletion. So this has been discussed extensively. At this point, we're at the last phase of sort of wrapping up the CMC-related issues. And I don't want to speak for the FDA but based on all the discussions as well as recent RMAT designation, I'm very confident about our ability to start the study midyear, which is just a matter of next few weeks or next month or 2. So let's see.

Perfect. And then maybe just speak to the parameters around pivotal trial design and what you can incorporate from earlier studies such as consolidation dosing and your thoughts around that.

Yes. So what you're referring to is, in our Phase I study, we studied both a single infusion of ALLO-501A as well as trying to leverage the benefit of our lymphodepletion, where we can use the ALLO-647 alone as a lymphodepleting agent. So we started what we coined as a consolidation where we gave 501A 28 days apart in 2 or 3 infusions in succession. We have shown proof of concept that both can be used safely. And also both approach can produce a complete remission. And at the time of the data cut as presented at ASH, obviously, the follow-up on consolidation is much shorter than single infusion, which has been going on for some time. So based on additional data review, internally, we have made a decision on how to proceed forward. And the only thing that we have not done is sharing the exact study design to the external community, which I think is -- the time to do that is when we launched the study not just talking about the study design before the study launched. So that's the reason that we are holding off on the details of the study. But ALLO-501A will proceed as a single-arm study. And like any other single-arm study in hematologic malignancy indications, the primary endpoint will be the response rate, and the key secondary endpoint will be the durability of the response or the duration of response, which FDA has been asking for any single-arm study and obviously in the CAR T therapy. They are very interested in the durability of response.

And so when we -- when you disclosed the trial start, will you also give this additional data sets that have played out over time that went into the trial design?

Yes. So we haven't exactly decided about how to communicate the data. You're talking about not just a study design but the evidence supporting the choice of the approach that we are making. What we have said is year-end this year, we'll provide update on the 501A so -- as well as our entire CD19 program. So we are deciding what is the better forum for us to provide a data update versus clarifying the study design. So it will be just a matter of time.

And then maybe just going back to consolidation dosing just because there have been so many questions around that. What could be the mechanistic reason that you saw a deeper response -- like if the second response is deeper? And then maybe you could speak to how many times a patient could be redosed but then, separately, what you thought about the FDA guidelines around redosing?

Okay. So let me sort of think about the way that the last question, FDA, there is a draft guidance for the CAR T therapy. And there is a specific language about if you were to retreat and the way that I interpret that guideline is in terms of if you were to treat with a different product, okay, do you still have the cells from the first infusion? That's the level of question. I don't think it directly applies to how we are doing the consolidation. So I don't think it's a major issue. The other question about why do you think consolidation is working better, the way -- the genesis of our consolidation approach is when we look across all the people treated with CAR T, especially with the CD19. There's a good portion of the patients who achieved complete remission, but there is also a number of patients who achieved only partial response and then progress roughly quickly thereafter. So what we really wanted to preserve is with additional dose of consolidation, can you make patients with a partial response, make the response deeper to complete remission? As well as will the consolidation lead to a longer durability of the response? Those were the 2 key hypothesis. I think we have shown in the data presentation, definitely, you can convert the partial responses to complete remission. And obviously, in terms of follow-up, we feel that we need to follow up a little bit longer to see which one provides a better benefit. And also, we take that into consideration that from the convenience perspective, single infusion obviously wins out and consolidation regimen. You just give one infusion and you're done. So what we are looking for is consolidation being much better than what the single infusion is doing. If it doesn't, then obviously, the value proposition for single diffusion outweighs having to do 2 infusions.

And then you have a second pivotal trial, expand, as you talked about, that looks at ALLO-647 and the contribution there. Could you provide additional color there on the trial design? And is it designed to demonstrate superiority? And if so, what type of powering and number of patients you would need to do that?

Yes. So the powering is already done. And we believe that this study, even as a randomized study. So stepping back a little bit, we are using ALLO-647 in addition to Flu/Cy-based chemotherapy. And ALLO-647 that we are using is not approved. And there were many different reasons why we took this approach. We believe this outweighs simply using existing anti-CD52 antibody. But what we have to do is demonstrate the contribution of ALLO-647 to Flu/Cy-based regimen. Personally, based on all the data that we have coming from more than across not just the ALLO-501A program but also ALLO-715 BCMA program, we believe that without ALLO-647, you cannot provide enough window for the cells to expand and persist and provide the responses. And we think we do have enough evidence. FDA wants a little bit more, which is why we are proceeding with this randomized study. And here, we will have to show in terms of when you do a comparative study. There are different endpoints that can use. Usually, when you do a randomized study, it's a time-dependent endpoints such as progression-free survival. And those end points, we believe can be achieved with a sample size that we have talked about, which is smaller than the single-arm 501A study that I just talked about. So the level of confidence that we have on that study is even higher than the level of confidence that we have on the 501A studies.

Got it. In the case, I guess, that expand does not show a benefit, let's you say the low probability that happens, what does that mean for the portfolio moving forward?

I think then you will have to look at the totality of the data. I think there are many different scenarios. But that's just a challenge that premise, what if it doesn't show the -- that the ALLO-647 is not providing any contribution. So far, our own data as well as in our Phase I study, we have used different doses of ALLO-647, and the dose response relationship that we are seeing in that context and also, importantly, not from our own data set, but there are many other allogeneic CAR T players who are trying to use a chemotherapy-based lymphodepletion alone to get the kind of cell expansion and result that one is trying to get. And I think the approach that they have taken, and I'm not going to name individual companies, is going up on the lymphodepletion doses because the standard lymphodepletion just is not sufficient. So when you do a study, there's always a little bit of risk, but I think this is a very derisked study.

And then maybe you could talk on the commercial opportunity here. You're involved in getting the first drug approved for CD19 on the autologous side. Maybe you could walk through here how do you think about where an anti-CD19 allogeneic therapy would fit in?

Yes. I mean this is a lot of debate. And I think many of you have listened to key opinion leader conversations about how the CAR T and other therapies in non-Hodgkin's lymphoma space will work out. With the efficacy that the CAR T has shown autologous CAR T, if any off-the-shelf shows that level of efficacy, I think you will definitely be a significant threat to any autologous CAR T. But more importantly, let's look at the entire landscape of non-Hodgkin's lymphoma. There is an initial induction therapy. It is our chop. And with the recent European approval of CD79B ADC Polivy, I think they will get some traction between [indiscernible] plus Polivy. So then what happens if somebody fails, so it progresses after induction chemotherapy. Traditionally, it has been a bone marrow transplantation. But both Kite Pharma as well as BMS have shown that the CAR T treatment is superior to bone marrow transplant. So I think this is where the CAR T will really play out in the second-line setting. And then when somebody progresses after CAR T, then all the options are open, including potentially using bispecific T cell engagers as well as other chemotherapies that is out there. So that's more, in a much bigger way, how we think about the competitive landscape in the non-Hodgkin's lymphoma when you think about the second line, I mean, that's a very big indication. And I think there's enough evidence there for the CAR T to be successful and get a lot of traction.

What happens -- I guess, just given your studies are focused on patients who haven't had autologous CAR Ts, what happens if those drugs move to second line, how do you think about your commercial ability?

Yes. I mean, there is really -- we are not just thinking about a third-line setting. One thing that we are planning on is conduct a study in the second-line study. So we do feel it is important not only generate the data for the third-line setting but move quickly to the second line. And because of the off-the-shelf nature as well as the supply issues, we believe that we can get those studies up and running pretty quick. But right now, our focus is really starting the initial pivotal study and their additional study plans.

Maybe pivoting over to the BCMA program, where we're going to see data at ASH, I believe.

Or at year-end.

Year-end. Could you start by recapping the highlights of the data we've seen to date? And then talking about where you see similarities versus Abecma and J&J Legend, particularly coming out of ASCO, we've seen extremely high bar on the latter. So how do you think about where you'll fit?

Yes. J&J's [indiscernible], the long-term follow-up data, that was very impressive. And I didn't think it would happen in multiple myeloma. But for those who are in the CAR T therapy, much of the discussion like 3, 4 years ago was CAR T therapy multiple myeloma does not provide the durability. And thanks to Legend and J&J, they prove everybody wrong. And even multiple myeloma physicians, just like about 7, 8 years ago, talking about potential cure of multiple myeloma, which is a fantastic time. What we have shown with our ALLO-715 program is we can get very high rate of response. The sample size is small, but we're talking about 80% overall response rate. And we are seeing the improvement of the response from the initial response to very good partial response or better, including the complete remission. And in our study, patients who get very good partial response or better, the MRD response rate amongst those patients is almost 90%. So I think what we have shown is with a 715 program, we can get very good response rate and also very deep response rate. And when we presented the data, which is still ongoing in terms of follow-up, we had a durability of response that's getting close to 9 months. And this is the durability that will continue to get longer as we follow the patients. So now the least to the most important question in the cell therapy space, you have Abecma. That's a BMS product. And also, you have [indiscernible], which appears to be superior to Abecma in efficacy. Where do you need to come in with the allogeneic CAR T to have a play? Our current view is if we are at Abecma or better, and I personally believe that we can be better than Abecma, we are in play, especially taking care of all the logistical challenges as well as manufacturing the bottleneck that the [indiscernible] therapy is experiencing right now. We believe that there is a lot of opportunities in multiple myeloma with allogeneic CAR T therapy.

And when we see this data later this year, and I believe it's including combination arm data with nirogacestat and TurboCAR, what exactly can we expect? And can you maybe frame for us how many patients we'll see, the follow-up time, just an understanding of how much of a picture we will get here?

Yes. I think for those who have been following us, because potentially multiple myeloma, we have taken a multipronged approach 715 single infusion, which is the study that we've been carrying out the longest and where we believe that we have an extremely competitive data. The second one was testing 715 in combination with the gamma CPTs inhibitor. Here, we completed dose escalation, and we're just following the patients with the durability of the response. The third one was testing the next-generation ALLO-605, which is a TurboCAR, which is essentially designed to enhance the potency of the CAR T cells as well as persistence, let's say, in the clinical trial. And the last and the fourth arm is the concept of consolidation, which we believe needs to be tested. So those studies are all ongoing. Probably for the year-end, given the evolving landscape and competitive landscape, I think the more important question is whether we are in a position to start talking about the pivotal study. So back to your question about patient number and all that, let's just wait. In the current environment, I think if you think about today's market in the XVI, it's not one of the happiest state by a lot of people, I mean, we definitely feel the urgency to prioritize and focus with the speed more than just trying to do broadly. So there is some thinking in terms of strategic involvement about how we're approaching this. But ultimately, what we are trying to get to is do we have an approach that gives sufficient benefit/risk profile that will allow us both to the pivotal study. I mean, I think that is the most important question to us right now.

And you talked about what would be a positive signal for durability with CD19. Is it analogous with multiple myeloma? As well if you have CR rates at 3 to 6 months, how do you think about durability?

Yes. I think that durability, I think, with the ALLO-501A program, I mean, we are already there. We presented at ASH last year, 14 patients who achieved the complete responses. At the time of the data cut, 10 patients had still ongoing complete remission. And of those 10, 7 of them had already passed the 6-month landmark time frame. And none of those 7 patients progressed. I mean they continue to be in complete remission after the 6 months. This is exactly what we saw when we are conducting the pivotal study of the YESCARTA. And also, it makes a lot of biologic sense. Non-Hodgkin's lymphoma, especially aggressive non-Hodgkin's lymphoma, is a fast-growing tumor. If you were able to keep the patient in complete remission for 6 months, the risk of such patient progressing after 6 months goes down significantly. And I think that's why we saw with YESCARTA earlier days. And now there's a much longer follow-up, we know that to be true, and exactly that's what we are seeing with the ALLO-501A program. So that's why we think from the ALLO-501A program, the probability of successful pivotal program is very high based on all the data that we have. And multiple myeloma, what is the right durability? I think current standard is durability of response ranging between around 10 months to now about 20-month plus 10 months for Abecma and 20-month plus for [indiscernible] roughly speaking, I think that's the range that would be, in my view, acceptable.

And as you look to CD70, given the work you've done with these other 2 targets, and I believe we saw some data from CRISPR at EHA over the weekend. What are you thinking the likelihood is that you can get an optimized program to work there in both blood cancers and solid tumors?

Yes. So CD70, the way that we are focusing that program is trying to generate a proof of concept that the CAR T can work in solid tumor. And as we're doing, I think there is a growing evidence. If you were to ask me about 3 years ago, whether CAR T was -- would work in solid tumor? At that time, I would have said, you know what, we just haven't done enough experiments. But now there are very interesting targets that seem to be working quite well. How they make [indiscernible] is one. CD70 is another one and also DLL3. So I think this is really a very interesting time for chimeric antigen receptor and solid tumor, where we are beginning to see some light at the end of the tunnel. And once that happens, these programs can expand pretty quickly. So CD70, we've been doing dose escalation study in renal cell cancer. And CRISPR has been doing both renal cell as well as in hematologic cancer, especially key cell leukemia and lymphoma, and they presented the data at EHA. I think it is very encouraging and worthwhile data to note. Mainly, from the safety profile perspective, there doesn't seem to be any on target [indiscernible] adverse event. So CD70 is a safe target to go after with the primary antigen receptor. I think they have shown that. And certainly, from our ongoing renal cell cancer center, cancer -- renal cell cancer study, we agree with their conclusion. And the kind of efficacy that they're seeing, the durability, I think, still needs some improvement, but it's very exciting, and they are still trying to optimize their cell dose and lymphodepletion, and we are trying to optimize the cell dose in the renal cell. I think, at the end, setting aside about who's ahead and others, CD70 is becoming a very interesting target with a lot of potential in solid tumors as well as heme malignancies that are not touched by BCMA CARs or CD19 CARs mainly T-cell leukemia and lymphoma.

Could we see data this year?

We already have. We already committing a lot in this current environment. I mean the study is moving along well. But in terms when we will release the data, we're going to have to sort of take it into the context of how much data set do we have so that when we present the data, there is a very little question.

Got it. Maybe just manufacturing here. So you've invested a lot in manufacturing in CMC. Maybe you could speak to how you feel you're differentiated versus your competitors. As we know, manufacturing is such a key ingredient here in cell therapy. But then, secondly, when you think about multiple myeloma, for example, you have J&J saying that they'll be able to supply the whole market soon. But then you look at where Gilead is today with supply and so forth. So how likely do you think it is that one player could supply the whole multiple myeloma market?

Yes. I wish I could ask that question to Christi Shaw. What took us so long when Janssen -- J&J is talking about they can do it within a year. Obviously, 2 will have a different view. But let me not get into those details because I cannot speak for J&J, but bringing up the manufacturing takes a lot of time. It's not just building the facility. It's validating the manufacturing facility. There are many layers of validation that needs to be done. And then you have to show the comparability of product manufactured from the new facility versus old facility, and then it needs to get -- undergo FDA inspection and approval. So this is not something that can be done quickly in general. So I don't know what secret sauce that J&J has to feel confident that they can increase the manufacturing capacity to meet the demand, which I think, in multiple myeloma, you're talking about 10,000-plus patients, which is not exactly where Kite is even after 7 years. On the other hand, as I've said, with allogeneic, and this is really the power of the allogeneic manufacturing, from a single facility on an annual basis, we believe that we can generate more than 20,000 cell doses. So that is probably one of the secret source that we have at Allogene. And this is also an activity that takes a long time. And this also differentiates us from many of the new entrants in the CAR T space, where they may have an interesting data, but they still have to take care of the manufacturing, which is very time -- it takes time and also is very cost-intensive. So let's see.

Are there any questions from the audience?

Yes. So the question is gamma secretase inhibitor, the combination study that we're doing with the 715. In view of the recent release of ASCO where the brand wrap, this is BCMA ADC in combination of gamma secretase inhibitor, I think if there was any signal of the combination providing benefit in that study. If it's there, it's very hard to see. And whether it has any read-through to what we are doing with the CAR T therapy? Obviously, there is some read-through for me to say there's no read-through will be far from true. So we definitely noted the data, and we're just waiting for our data to mature more. I mean what we have said is that we completed dose escalation, and at this point, we're just following the patient.

Could you just remind me what your dose escalation program showed for 501?

Yes. So dose escalation in the 501 study, we tested 3 different doses, starting with 40 million cells, went up to 120 and then went up to 360. And at this point, the dose that we are going forward is 120 million cells. And we use not weight-based but fixed cell dose regardless of patient's weight unless this is a very small patient. So the trade-off, what do we see in the dose escalation? We saw responses at all dose levels. Certainly, when we compared 120 and 360, we did not see much benefit of using 3x more cells. But compared to 40, 120 provided much better profile. So that's how we settle. So there is a little bit of dose response relationship, but I think we are already started with -- on the extreme where the dose response relationship was relatively quick.

Great. Well, with that, thank you very much, David.

Well, Salveen. Thank you very much for having me here, and I look forward to announcing at some point about the start of the pivotal study.

Great.