Ready to start. Hi, everyone. My name is Perry Mayo-Malasky. I'm one of the analysts here at Bank of America on Jason Gerberry's team who covers SMID Biotech and Specialty Pharma. I'm pleased to introduce our next guest, Allogene Therapeutics. I'm here with CFO, Eric Schmidt. Eric, welcome.
Perry, thanks so much for having us here. I remember last year this was sort of the first coming out party on Wall Street post-COVID. Today, you know, it's just been a pleasure to see, the activity in the hallways and elevator banks and feel like really the world is back to life. Terrific, terrific opportunity for us.
Yeah, absolutely. It's great to be here in person. I wanted to start with the upcoming CD19 phase 1 update at ASCO. You know, mindful, you know, there isn't much you can say specifically about the data readout, but I know that the company has been talking about durability of clinical benefit of 501A. You know, I guess I'm just wanting to know what incremental you could learn at ASCO, specifically, you know, the number of patients that you're gonna have with a 6-month follow-up and 12-month follow-up, and then in the Alloy-treated patients, and then more specifically in the 12 patients who were Alloy-treated FCA 90 lymphodepletion subgroup, which is applicable to the ongoing pivotal trial.
Yeah. A lot of questions there. Let me try and unpack that and make sure I start at a high level so I don't lose anyone who might be a little less familiar than you are with our programs. First, ALLO-501A, the construct you mentioned, that is our lead program. It does target CD19, and it's in a couple of pivotal studies right now. We call them ALPHA2 and EXPAND. Those trials kicked off starting last fall and are in full effect right now. We're enrolling patients in each, and we're targeting completion of enrollment and data toward the end of next year. We're excited to have the first off-the-shelf allogeneic product in pivotal studies.
We obviously are trying to replicate the tremendous benefit the autologous products have brought to patients with large B-cell lymphoma. This is a third-line indication that we're going after initially. We think that if we can replicate that safety and efficacy by virtue of also bringing an on-demand therapeutic, something that can be produced at scale, something that can be dosed within days, not weeks, we can really treat a lot more patients and impact a lot more lives. That's our mission statement at Allogene. Specifically, you alluded to the phase 1 update that we're expecting to show at ASCO in a couple weeks' time. Specifically that cohort will focus on phase 1 patients who are treated with Alloy product materials.
Obviously the Phase 1 experience is a dose-ranging experience where we're optimizing the cell dose, optimizing the lymphodepletion, which in an allogeneic setting is absolutely crucial to demonstrating activity. Also in an allogeneic setting, you have an opportunity to optimize manufacturing. That's honestly not something you can do in an autologous setting. An autologous setting where each patient is his or her own manufactured material and is idiosyncratic to that product. You can't really tweak and iterate the manufacturing parameters. We took a long time to do that with our Alloy product material. We've treated now over 175 patients in the clinic across our pipeline and platform. Through this iterative approach, we really were able to refine and narrow down what we believe are optimized process development parameters, optimized manufacturing conditions for Alloy.
We now are deploying Alloy in our pivotal studies. Of course, when we show the updated Phase 1 data sets, we're keen to zero in on those patients who got the optimal process. Yes, we'll be talking about Alloy again at ASCO. The second parameter that we've optimized is lymphodepletion. FCA refers to flu, cy, plus ALLO-647 at 90 milligrams. FCA90 is 90 milligrams of ALLO-647. That anti-CD52 antibody is in our hands, again, critical for performance of our product. If you aren't using a lymphodepleting regimen that includes the antibody, nobody's been able to optimize the lymphodepletion window in a way that allows for optimal cell expansion and persistence.
We've identified through a series of dose-ranging experiments, 90 milligrams is the optimal dose. We've again optimized the process we call Alloy, and the ASCO presentation will focus on that optimized cohort that we're moving into phase 2. You know, most interesting at ASCO, I think, will be the updated durability data. It does seem like we're head and shoulders above the field in terms of our ability to generate not only complete responses, but also responses that are durable. We, of course, at our showcase event last year, had a previous update where we were showing activity in line with the autologous therapies that have been approved. Certainly safety that's very consistent with those datasets, if not potentially a little bit better tolerated.
We'll be providing the updated dataset at ASCO, and in particular, this will be the first time we're showing these data in a medical form for some time. Whereas investors have had a little bit of a preview of these results, we think that the results at ASCO can really help inform the clinical community, get people excited about our ongoing pivotal trials, and better showcase Allogene in a scientific form.
Okay. It sounds like the upcoming readout, the phase 1 readout, will maybe give some additional information on, potentially on 6-month durability, you know, potentially 12-month durability in the Alloy manufacturing process to really, you know, solidify, some of the previous data that you've shown where you're, you know, competitive with your autologous, counterparts on those points.
Yeah, I mean, that's a really good point. In general, in our hands and certainly in the autologous hands, if a patient is able to get into complete response at six months, what we call a six-month CR, those responses tend to be quite durable beyond six months. That's something that we had showed at the showcase event. We'll be further following up that cohort of patients that's in response for, you know, another five, six, seven months, whatever the interval is between data cuts. We would certainly hope to see continued persistence of response for those patients who have achieved a six-month CR. I think those data continue to be informative and continue to compare, as you suggested, very favorably with the autologous experience.
Okay. I guess, what do you view as the bogey in terms of the 12-month CR rate compared to autologous CAR Ts on a modified intention to treat basis? I'm wondering if you could speak more broadly about ITT versus MITT and, you know, which ultimately you view as the more important parameter.
Yeah, also great question. Let me start with six-month CR rates because, again, those tend to be most predictive of durability. If you get a patient into a CR at six months, they tend to have a very good prognosis. If you look at the autologous data sets on a six-month modified intent to treat basis, the six-month CR rates are somewhere between 30% and 40%. Certainly that's the bogey we'd be shooting for, and we hope we can do as well as those game-changing therapies which have provided so much treatment benefit in this population. There's a modest diminution of effect after six months. If you'd look at 12-month CR rates, they'd be moderately below that 30%-40%. You see only a few...
A falloff of a few percentage points between six and 12 months in the autologous realm. Again, we would hope for something similar out of our allogeneic therapy. The other question you had, I'm sorry, remind me.
It was on intention to treat versus modified intention to treat.
Intended to treat versus modified intent to treat. That's obviously an area where an off-the-shelf product could bring meaningful benefit. The data sets that generally I just spoke to and have generally been circulated across the autologous products are modified intent to treat. By that, the data sets are restricted to those patients who are not just enrolled but also got to therapy. If you look at how many patients were intended to treat but never got to therapy, depending on the autologous product, that's between 10% and 30% of patients. Those patients in the databases that have been reported have simply been ignored.
Obviously, in an allogeneic setting, we think we can treat a far greater number of intent to treat patients, and we would expect on an ITT basis to be even superior to the autologous products. On an MITT basis, you know, certainly we're shooting to be at least as good.
Understood. Understood. You know, in terms of Alloy, I realize that you've, you know, kept the Alloy manufacturing updates, perhaps close to the company, based on, you know, potentially based on competitive dynamics. Could you maybe speak more broadly about the different levers you can pull in manufacturing that would drive the kind of material step-up you're seeing in your phase 1 data set?
That's another good question, we're gonna be somewhat restricted in what we can say for, you know, obvious competitive reasons. We do think we have a head start here. We do think we've treated more patients and produced more manufacturing lots probably than anyone else in the industry, maybe even as many as anyone else in the industry combined. This is, you know, cutting edge. Obviously, this is new, innovative work. Again, what this allows us to do better with an allogeneic product is this approach of scalability. If you're treating multiple patients from a single batch, you have the ability to interrogate various manufacturing parameters and determine which are best. You just simply don't have that freedom in an autologous setting where each manufacturing run can only treat a single patient.
You don't know with an individual patient whether they're failing therapy because of manufacturing or for some other reason. We've really tried to take advantage of being pioneers in the allogeneic space, and using this scalability in manufacturing to up our game. I suspect this will be a continuous process, and even though we've made great advances with Alloy, we're certainly not done yet, and we'll continue to innovate and hopefully excel. In terms of exactly what we've done, I think you can imagine that the allogeneic product production process is multifaceted, and there are several steps along the process, whether they be transfection with a lentivirus or electroporation with the TALEN mRNA or expansion and purification steps.
We've looked at each of those point processes one by one and tried to tweak the parameters that at the end of the day provide for a more potent process or a more potent product. We do have the ability to measure that product in vitro, in vivo, and now in the clinical setting to justify the improved or enhanced efficacy. You know, this is still a work in progress, but one where we've made a lot of progress and one I think where we're very well situated today.
Okay. maybe one more on lymphoma, then maybe we can switch to 316. basically the... you know, in terms of the broader auto CAR T space, you know, you have CAR T moving into second line. I guess, how do you think about that in terms of, you know, what a launch for allo CAR T looks like and how that impacts it? Are you basically fighting for, you know, with bispecifics and auto CAR T for naive patients to CAR T in the third line plus setting? Or should investors really be focused on your program moving into earlier line settings with ALPHA3?
Yeah, great question. I mean, I guess, at a high level, what you're asking about is our market opportunity, right? Today, the unfortunate fact is that only about 10% of all eligible CAR T patients are getting a CAR T, and that goes for myeloma as well as lymphoma. That's, you know, unfortunately a sorry statistic because these therapies are viewed as best in class and game-changing with their ability to transform patient outcomes. The whole mission statement at Allogene is to begin to democratize cell therapy and bring it to the masses with scalable manufacturing, on-demand delivery, a much easier treatment protocol and process. Where we're starting in third line large B-cell lymphoma, the current penetration rates of CAR T therapy in that setting is about 30% or so.
We think we can further extend the penetration in that last line setting. As you mentioned, the autologous CD19 products are already moving into second line, and we of course, have aspirations of doing the same. We provided guidance that this year we intend to be phase 3 ready for a trial in earlier line large B-cell lymphoma, and we would intend to kick off that study in the first half of 2024. We'll go where this market is. Today, the CD19 autologous CAR T-cell market is annualizing at about a $3 billion clip approximately, and it's projected to grow over the next three to 5 years to approximately $6 billion-$7 billion market.
We think if we can match the autologous profile in terms of safety and efficacy and have that added convenience and scalability, we might even be able to further grow that opportunity.
Okay. You know, on 316, maybe at a higher level, just the, you know, the Dagger approach and kinda the masking that you're doing in production, how you have the benefit of preventing fratricide and cell exhaustion for potentially higher quality product. I guess, in terms of the Dagger technology, just to understand it, the CD70 CAR has almost a dual activity where you're targeting alloreactive lymphocytes that are CD70 positive as well as, you know, the main benefit, which is targeting renal cell carcinoma with 316 at this time. Am I thinking about that correctly? What are the different components?
Perry, again, another good question. You're so familiar with our technology that I feel like I better step it up a level for those in the audience to make sure we're not losing them. ALLO-316 is our anti-CD70 candidate, and as you say, it's directed at renal cell carcinoma. It's our first move into solid tumors, and we're excited, and it's one of the first, if not first allogeneic CAR T constructs to really show good proof of concept in renal cell carcinoma. We're in the midst of a phase 1 dose escalation study with ALLO-316. We've treated now about 20 patients in total.
Specifically in that subset of renal cell carcinoma patients who have failed the first and second line therapies, generally speaking, which are checkpoint inhibition and TKIs, we're seeing quite good response rates on the order of about 30%. Early days for sure with ALLO-316, but very exciting clinical activity and something that we're keen to move forward with as fast as we can. Your question really pertains to how we've able to engineer the 316 construct and potentially enhance the activity of this moiety in a way that so far at least, no one else has been able to do with either an autologous or an allogeneic product that targets CD70. There are two maybe tricks to the trade.
The first is that, if you don't take heed, it's potential for an anti-CD70 CAR T to commit fratricide during the production process. What I mean by that is CD70 is expressed on activated T lymphocytes. As you're expanding your CAR T population, possible that without taking due measure to prevent, one CAR T-cell may attack and kill off another CAR T-cell, something that's called fratricide. As you say, we use a masking technology that prevents the CAR T-cells during the production process from attacking one another, and it allows us to get a pretty robust cell expansion and scalable production process.
The other trick is something called Dagger in our hands, and we take advantage of the property of CD70 here being expressed on activated CAR T cells to use what we call a Dagger moiety to prevent the premature rejection of the CAR T cell by host immune T cells, alloreactive T cells. We do have evidence that use of the Dagger enables very good expansion and persistence in our hands. Not only does the CD70 CAR moiety direct the CAR T cells at the renal cell carcinoma cells and allow our CAR T cells to attack and control cancer cells, but also it allows our CAR T cells to eliminate alloreactive T cells and stay around for a bit longer and go about their anticancer activity for a longer duration of time. We're really excited about this Dagger technology.
In fact, it's a moiety that can be deployed not just on CD70 CAR T-cells, but potentially other CAR T-cells that target any other cancer antigen, CD19 or BCMA, and provides for a real platform approach toward overcoming allo rejection. Very exciting technology. We've now published this property in several different scientific journals and forums, and we're keen to further explore it.
Got it. Thanks for the detail, and appreciate speaking with us today. I think that we're out of time, but we're looking forward to additional updates.
Thank you, Perry. Thanks for having us today.