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

Intend to treat versus modified intention-to-treat. So 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. And by that, the data sets are restricted to those patients who were not just enrolled but also got to therapy. And 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. And 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. But on an mITT basis, certainly, we're shooting to be at least as good.

Understood. Understood. And in terms of Alloy, I realize that you've kept the ALLO manufacturing updates perhaps close to the company based on -- potentially based on competitive dynamics. But 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 I data set?

Yes. That's another good question. And we're going to be somewhat restricted in what we can say for obvious competitive reasons. We do think we have a headstart here. We do think we've treated more patients and produce more manufacturing lots probably than anyone else in the industry, maybe even as many as anyone else in the industry combined. So this is cutting edge. Obviously, this is a new innovative work. And again, what allows 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 your best. You just simply don't have that freedom in 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. So we've really tried to take advantage of being pioneers in the allogeneic space and using the scalability, 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 production process is multifaceted. And there are several steps along the process, whether they'd be transfection with a lentivirus or electroporation with the TALEN mRNA or expansion and purification steps. When we put at each of those point processes one by one and try to tweak the parameters, at the end of the day, provide for a more potent process or a more potent product. And 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. So this is still a work in progress, but one where we made a lot of progress and one I think we're very well situated today.

Okay. And maybe one more on lymphoma and then maybe we could switch to 316. So basically, the -- in terms of the broader auto CAR T space, you have CAR T moving into second line. I guess, how do you think about that in terms of -- what a launch for ALLO CAR T looks like and how that impacts it? Are you basically fighting 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 CAR T moving your program moving into earlier line settings with ALPHA3?

Yes. Great question. I mean, I guess at a high level, what you're asking about is our market opportunity, right? And 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. And that's, unfortunately, sorry statistic because these therapies are viewed as best-in-class and game-changing with their ability transform patient outcomes. So 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. And 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. So we think we can further extend the penetration in that last line setting. But 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 III 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. So we'll go where this market is. Today, the CD19 autologous CAR T cell market is annualizing at about a $3 billion clip, approximately. It's projected to grow over the next 3 to 5 years to approximately a $6 billion or $7 billion market. And 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. So on 316, maybe at a higher level, just the Dagger approach and kind of the mask that you're doing in production, how you have the benefit of preventing fratricide and cell exhaustion for potentially high-quality product. I guess -- but in terms of the Dagger technology, so to understand it, the CD70 CAR has almost a dual activity where you're targeting alloreactive lymphocytes that are CD70 positive as well as the main benefit, which is targeting renal cell carcinoma with 316 at this time. So am I thinking about that correctly? What are the different components?

So Perry, again, another good question. You're so familiar with our technology that I feel like I better step it up a little 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 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 construct to really show good proof-of-concept in renal cell carcinoma. We're in the midst of Phase I a dose escalation study with ALLO-316. We've treated now about 20 patients in total. And specifically, in that subset of renal 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%. So 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 able to engineer the 316 construct. And potentially, enhance the activity of this where in a way that so far no one else has been able to do with either an autologous or an allogeneic product that targets CD70. So there are 2 maybe tricks of 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. And what I mean by that is CD70 is expressed on activated T lymphocytes. So as you're expanding your CAR T population, possible that without taking due measure to prevent, 1 CAR T cell may attack and kill off another CAR T cell, something's called fratricide. And 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. And we do have evidence that use of the Dagger enables very good expansion and persistence in our hands. So 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 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. So we're really excited about this Dagger technology. In fact, it's a moiety 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 rejections. So 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 I 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.