Great. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for attending TD Cowen's 6th Annual Oncology Innovation Summit. For our next session, very excited to have a Q&A discussion with Allogene. From Allogene, it is my pleasure to introduce David Chang, Co-founder, President, and CEO. David Chang, thanks very much for joining me.
Tyler Van Buren, thank you very much for having Allogene in your healthcare conference. This is a very exciting time for us and glad to be here.
Great. Before I get started with the questions, for those of you in the audience, feel free to email me questions at Tyler.VanBuren@TDsecurities.com or Cowen.com. Once again, that's first dot last. Maybe we'll start with ALLO-316, given the upcoming update and from the dose expansion. You recently presented data in November of last year from the dose escalation. Maybe you could provide a quick review of that data and why you selected dose level two for expansion and what we should expect from the upcoming presentation.
Yeah, we are very excited to update all of ALLO-316 data. This is anti-CD70-directed Allogene CAR T program that we have been studying in renal cell carcinoma patients. We will be presenting in the ASCO, which is just in a matter of the next few days, the data coming from the phase Ib expansion cohort. Going to that, we have presented the ALLO-316 data in the past. The phase I study essentially looked at different cell doses, anywhere between 40 million cells per dose to 120 million cells. In addition, we also explored the different lymphodepletion. This is coming from the fact that CD70 has intrinsic dagger activity, and therefore the cells will expand much differently than the Allogene CAR T programs that do not have the dagger technology built into it.
With that, we decided to explore more than FCA, which is what we have been using in other programs. Another thing that we did is, given that we are going after CD70-expressing renal cell cancer, that makes perfect sense. It is a CD70-directed CAR T. We also wanted to look at the impact of CD70 expression on both safety and efficacy. After we have more or less completed various different doses and lymphodepletion, we settled on 80 million cells with a standard lymphodepletion that only has fludarabine and cyclophosphamide. That is essentially the phase Ib expansion cohort. Previously, last November at the 16 meeting, we presented the preliminary data that is based on eight patients. Out of those eight patients, six patients had CD70 expression at the target range, which is, yes, they have to express CD70 and also tumor proportion score.
This is percentage of tumors that express CD70 had to be 50% or higher. Within that patient population, which represents the majority of renal cell cancer patients, we were seeing a confirmed response rate of 33%. At the time, the durability was somewhat limited, but both patients who responded had ongoing responses at month four and second patients beyond month six. The expectation at the ASCO present, at upcoming ASCO, is we will have more patients. Obviously, with that, we'll get much more accuracy in estimating the response rate. With a longer follow-up, we will be able to say more about the durability of responses among the responders.
Okay, great. That's very helpful. Are you able to say how many more patients there will be and what the approximate amount of follow-up time will be?
Yeah, so we were targeting about 20 patients in the phase Ib cohort. That's approximately the number of patients who have been enrolled. The last patients in the phase Ib cohort were treated earlier this year. The data cut is based on when it is expected that everybody would have had at least three plus months more follow-up, and certainly some patients will have much longer follow-up.
Okay, that's great. What response rate and durability do you all believe you need to observe from ALLO-316 to warrant further pivotal development in this indication?
Yeah. That question has to be answered in the context of the patient population. In the study, we enrolled heavily pretreated patients with a median number of prior treatment of four prior treatment. With that as a caveat, I mean, generally in solid tumor, the way we think about this is we like to see responses in about 1/3 of the patients. Also, with respect to the durability, responses that go on six months or longer. That is sort of the minimum target product profile that we are looking for.
Okay. Just a standard of care, what would you expect to see from standard of care in these patients?
Yeah, so that is for the similar patient population, that information is really not there. I mean, because the patients that we are treating, not only do they have to have at least one tyrosine kinase inhibitor and checkpoint inhibitor treatment to go on the study, but when we look at the patient population, you're talking about patients who have had two prior checkpoint inhibitors, and also a majority of them had two or more tyrosine kinase inhibitors, and a growing number of patients also having treated with HIF-2α inhibitors. New treatment in that patient population, there is really limited information.
Okay.
In some ways, we rely on what the investigators are telling us, especially given the lack of information here. The investigators are consistently telling us that seeing any kind of responses in the patients that you are treating would be quite remarkable. If it's a durable response, I mean, that could be very interesting treatment options. Also, another way to think about it is renal cell cancer. I mean, essentially, there's about four different classes of medicines that are used: the checkpoint inhibitor, tyrosine kinase inhibitors, the metabolic pathway, and then the HIF-2α inhibitors. Here, CD70 targeted therapy as a cell therapy would be a new modality, which could give a lot of options to patients.
Okay. As we think about a pivotal trial for 316, maybe we're getting ahead of ourselves here ahead of seeing the data. Just maybe briefly, do you have in mind what a pivotal trial might look like? Would that be sponsored by Allogene, or would you look to potentially partner ALLO-316?
Yeah, we are trying to find what would be the appropriate next step. For us, presenting the data, getting the responses from we have sort of reactions from most KOLs, but getting the reactions from the analysts and investors. Also, another thing that we have in plan is taking the phase 1 data to the FDA to have a discussion around the next step. Obviously, when the unmet need is high, I mean, there is a single armed registration or path that could be available. That also, success of such program will be very much dependent on how you can find out the controls, which can be generated from the real-world data. Alternatively, there is a randomized control study, which is a gold standard of how we conduct clinical study in any therapeutic area. There are various different options.
What we are trying to do is we know that 316 is an active program, and we know that it works. What is the registration path and how to find a way to support the program to the next stage?
Okay, that's clear. Now let's move to cema-cel and ALPHA3. With cema-cel falling under CBER oversight, can you walk us through the ALPHA3 trial design and just any implications that there might be with Dr. Vinay Prasad's recent appointment and some of his historical comments, if you think as an easy read-through to the ALPHA3 trial?
Yeah. Let me first comment because there has been so much speculation and misconception about what may happen to FDA. The truth of the matter is nobody really knows. We just have to wait. I have to say all the initial indication coming from the FDA with the new leadership makes me feel very confident that FDA is an institution. It's never about single individuals. As an institution, which is the best in the world in terms of regulating drug development, so far, nothing has made me change my view on how FDA will embrace evidence-based approach and continue to support the drug development across various different indications. With that, now let's go to the answer to your question about the ALPHA3 design. Foremost, this is a randomized control study.
We are comparing a single infusion of cema-cel against standard care, which is watch and wait observation. That is one very important, that is a gold standard with which anybody would be conducting the clinical study. Second, patient population is pretty well defined. Essentially, we are treating patients, not everybody who undergoes the frontline treatment, but identifying those patients who are at high risk of having a disease recurrence using the state-of-the-art MRD assay. I think that is also in many ways a very efficient way to conduct any kind of clinical study. That is always viewed very positively in the regulatory bodies as well as by the clinicians. Third is the end-point that we are using. We are using event-free survival as a primary end-point, and that is the most appropriate end-point in this setting.
It also has a precedent as an end-point that has been used with autologous CAR T therapies in the second line large B-cell lymphoma setting. When I think about the study design, patient population, as well as end-points, I'm pretty confident that the ALPHA3 study itself meets all the requirement, necessary requirement to generate high-quality data that will be very evidence-based and could support the registration pending the outcome.
Okay, wonderful. Again, following up on ALPHA3, on the recent earnings call, you offered updated timelines. Maybe you could walk through some of these changes and what caused the slight delay in timelines.
Yeah. Last earnings call, we pushed out the first milestone event, the futility interim analysis, where we also intended to make the determination of the lymphodepletion from mid-2025 to the first- half of 2026. Just on the lymphodepletion, in the initial phase of the study, we are testing two different lymphodepletion. Based on the initial data, we always had made plans to eliminate one of the lymphodepletion arms and proceed as one-to-one randomization till the completion of the study. The reason for the delay is really operational issues. Coming from, one, delay in the time it took for most of the sites in the United States where we have the activated sites for them to get the necessary staffing to support the study. This is something that I had never experienced in the past.
Usually, when all the regulatory work is done, sites are more or less all ready to start screening the patients. More than once, as we activated more sites, it became a general finding that most sites now go through the second stage of finding the right study coordinator to support the study. That took additional time that we had not expected. The second is really the patient flow issue, and that is unique to the clinical study that we are doing. In our study, we identify the patients anytime during their frontline R-CHOP treatment. When we identify the patient, we consent them for the MRD testing. When they get to the MRD window, which would be at the completion of R-CHOP, that is when we can collect the samples and do the MRD testing.
Those who are MRD positive, then they can randomize the second time to go on to the ALPHA3 study. This is what we call as a patient flow from initial patient identification to actually patient going on to the ALPHA3 study, and it can take as much as four to five months. Especially if someone is identified at the beginning of R-CHOP, it takes six cycles, each cycle taking about three weeks. Altogether, about almost 20 weeks before they are eligible to have the MRD testing. Once the MRD test is done, which takes about 10 days, it takes another three to four weeks before a patient undergoes the randomization to the second process.
This is something that we should have built into the study timeline, but it sort of came to our sort of realization, yeah, you can identify the patients, but it does take some time to actually enroll the patients. Now, despite all these sort of at the end, from a company perspective, it's an explanation. Nobody likes to push out the timeline. On the other hand, we are seeing a very good momentum in this patient flow. This is how we explain that there are more than 250 patients who have consented to undergo MRD testing since the study has been opened. The majority of those patients coming in last three to four months as the momentum is building. You can think about this as a wave, initial patient consenting, and that wave will continue to MRD testing and then eventually to the randomization.
That's why we feel very optimistic about the fact that this study has sufficient momentum. In fact, we have talked about in terms of MRD testing consent. I mean, we are definitely seeing what we frequently refer to as a hockey puck effect. Eventually, that will show as a randomization. That's where we are marching towards.
Okay. Based upon everything that you've learned that you just discussed, how are you using this to decrease the time to first randomization with the newer initiated sites?
This is really the resource issues. I mean, there's very little. I mean, we can have the conversation earlier. Another thing that we are doing is also taking the study outside the United States. I mean, we initially targeted about 50 sites in the United States. We will definitely increase the number of sites as we open up the sites in Canada, which we expect to do so in the next few weeks, and then also taking into other territories as well.
Okay. All right. Okay. With the futility analysis and lymphodepletion decision now expected in the first half of next year, can you walk us all through the significance of that decision? How many patients will be included in that analysis and what you need to see between the lymphodepletion arms to select one over the other?
Yeah. The plan is to randomize and treat 36 patients altogether. There are 12 patients per arm. Looking at their safety and also surrogate for efficacy, which would be the MRD conversion. Everybody who goes on this study starts with the MRD positivity. This is using the Clarity test that we are partnering with Foresight Diagnostics. The expectation is that people who are randomized to the control arm will remain MRD positive, whereas patients who are randomized to either lymphodepletion arm and get treated with cema-cel will convert to MRD negativity. How we will be making the determination on the lymphodepletion selection will be influenced by the safety profile that we are seeing, as well as the MRD conversion rate. Obviously, the higher the MRD conversion, the more confidence it will give us.
Between the two arms, if both arms work pretty well, it becomes a little bit tricky decision. If there are some kind of differences that are very discernible, then it becomes a very clean decision.
Is it possible you could give us a glimpse into the data or what you're observing in the first half of next year?
That's a great question. I would say stay tuned. Ongoing potential registration study in a general practice is not to talk about the study result. We also have heard from during our meetings with investors as well as analysts. If we simply remain silent about what we are seeing, it may not be seen as meaningful. Whereas internally, we will have such meaningful information on the entire outcome of the ALPHA3 study. We are sort of reviewing what we can say and how much we will say. The intent is to make the announcement of initial interim analysis be meaningful to the investors.
Okay. That's helpful. We saw the recent ALPHA2 paper, which showed very encouraging efficacy with cema-cel in patients with low disease burden, which is interesting as we think about the ultimate outcome of ALPHA3. You have talked about expectations for the control arm. I guess just as we think about the interim and primary EFS analyses, how should we think about those both in terms of timing, but also what you would like to see for ALPHA3 to be successful?
Yeah. So going into the statistical assumptions, which we haven't gone into too much about how the event-free survival rates are assumed and how soon they will occur, that's all built into how we drive the patient total sample size of the ALPHA3 study, which is 240 patients. With 240 patients, I mean, the statistical finding has to be pretty with a low hazard ratio. I mean, with that, the clinical findings will be very meaningful. The outcome that we are looking for in this study is clinically meaningful event-free survival difference between the control and the treatment arm. Also, as a secondary end-point, we are looking at a slightly different end-point of progression-free survival as well as overall survival. The study is not powered for overall survival, nor the expectation in our discussions with FDA survival demonstration will be required for this study.
Okay. That's helpful. Maybe to round out the discussion here for ALPHA3, how big do you believe the post-R-CHOP MRD positive patient population is in terms of market size?
We believe that this is probably the largest indication that one can come up with in the large B-cell lymphoma. There are two things. The number of patients, our expectation around how many patients will be MRD positive is somewhere around one out of five to one out of four. That's the rough range. I mean, that already gives a much larger patient number. Another important thing about ALPHA3 study is we are trying to overcome current barriers of CAR T penetration in the large B-cell lymphoma by taking the study directly into the community-based cancer centers where the majority of the patients are cared for. What we are trying to create is take the treatment to the initial place where patients do not have to be referred. What's enabling us to do that is the fact that we are allogeneic.
We can provide drug in a vial when the patient is ready. There's no complicated logistics that's associated with CAR T delivery. All these things have gotten a lot of attractions from the community-based cancer centers. With that, we are hoping that we can create sizable commercial opportunity. Current estimate for the market opportunity globally is around $5 billion a year.
Okay. Sizable indeed. This is an oncology summit, and I know we're about up on time here, but just want to get to ALLO-329 quickly in autoimmune given the importance to the Allogene story. The CD19, CD70 dual targeting mechanism is really unique. Maybe you could just talk a little bit about the phase one study and what you kind of want to see here, as well as the autoimmune diseases and indications you all are most interested in.
Yeah. So ALLO-329 is the dual targeting. It targets CD19 and CD70 for the purpose of really addressing the underlying defect in autoimmunity. Autoimmune disorders are never a B cell disorder. In addition to B cells, where for some reason, because of CD19 CAR T data coming up, everybody thinks if you eliminate B cells, you will take care of the autoimmune disorders. What supports the B cell maturation activation is T cells and antigen-presenting cells, which CD70 can address. In addition, there are autoimmune disorders such as type 1 diabetes that are purely driven by T cells as we currently understand the underlying biology. ALLO-329 has the potential to go after T cell-driven autoimmune disorders. This is the ALLO-329 program that we are taking initially into the rheumatology indication.
The patient population that we will be studying, lupus patients, systemic sclerosis, as well as inflammatory myositis patients as a basket study. The intent of the study is leveraging the uniqueness of the ALLO-329, start testing low or lymphodepletion, which can, if we can achieve that, open up the market opportunity for what we are doing with the autoimmune programs with the CAR T. In this basket study, we will be studying the lymphodepletion with cyclophosphamide alone. We already are taking out the fludarabine. Another arm that we will be studying concurrently is one arm that has no lymphodepletion altogether. This is a dose escalation study. We expect to activate this study shortly. Our goal is to generate proof of concept data by the first half of 2026. Very exciting program.
It is a great opportunity for the autoimmune disorders where one-time treatment can potentially provide durable drug-free disease control. We are very excited about it.
Great. Really looking forward to seeing the initial ALLO-329 data. With that, we are well over time here. I think we'll go ahead and wrap up. David Chang, thank you very much for the time and the great discussion. Thanks to everyone for logging in.
Tyler Van Buren, as always, thank you very much for hosting us. It is great to be talking about allogeneic cell therapy. Now we are so close to actually getting to the finish line about making the allogeneic CAR T available for patients.
Indeed. Have a great day, everyone.
All right.