Okay, why don't we go ahead and get started with our next session? My name is Chris Raymond. I'm a senior biotech analyst here at Piper Sandler. It's my pleasure to introduce our next company, which is ALX Oncology. Today, joining us, we have CEO Jason Lettmann. Just to go over the format for everyone, we'll have just a couple of minutes of presentation just to level set for everybody the story on ALX that Jason will provide, and then we'll jump in with a fireside chat format Q&A. This is meant to be participatory, so if anybody has any questions, just raise your hands and I'll make sure your question gets asked and answered. But without further delay, Jason, take it away.
Yeah, great. Thanks for having us. Appreciate it. Always a good meeting, so appreciate you having us. I'm happy to give the overview. ALX is an immuno-oncology company, I think as most of you know. Our lead drug is evorpacept, which is the leader in CD47. By way of background, CD47 is one of the most important ways in which our immune system signals to cancer to be left alone, or it's known as the "don't eat me" signal. The company was founded in 2015, and at the time there were two really differing schools of thought on how to take on CD47. One was the conventional way, which is we know that cancer uses CD47 to evade tumors, so can you use CD47 as a tumor-associated antigen and drive an antibody against that?
Our school of thought was that it was going to be difficult to do because CD47 is so ubiquitous. It'll be very difficult to target just CD47 that's expressed on cancer. So we took a different approach, a combination approach. So we use evorpacept to block the CD47 signal, block the "don't eat me" signal, and then we combine it with an Fc-active antibody to drive the "eat me" signal. And those two things working together are what drive ADCP or drive activation against tumor.
Okay. So maybe just a general CD47 question. This comes up constantly, and I know Jason, you hear it probably from investors as well. Obviously, it's been with some of your predecessors and other participants in the field, it's not been exactly 100% success, a lot of setbacks. Why, I guess, are you still so enthused about CD47 as a target? Why should investors be willing?
Yeah, I mean, I think there's no question dating back now over 10 years that it is a very important pathway and a very important checkpoint. I think the way that history played out, and is often the case in drug development, is a bit unpredictable in some ways to see a company like Forty Seven first get acquired by Gilead for $5 billion. Shortly thereafter, Pfizer acquires Trillium for $2 billion. A lot of interest in the space. We certainly benefited from that. And both of those companies and then the companies that followed them all took the approach of the first school of thought I mentioned. So let's use CD47 as a tumor-associated antigen. There was good reason to believe at the time that that would work. And then long story short, in the clinic, that's not how it played out.
In fact, what we've seen is with magrolimab and the other CD47 agents, it's very difficult to target CD47 and not have tox. That's dose limiting. It limits what you can do in a solid tumor setting. Ultimately, randomized data speaks. In the big studies with magrolimab, that's what we saw. Meanwhile, we were plugging along. We do not have single-agent activity by design, and that takes a while.
What we're seeing now and what we shared last year with the first randomized data in the space in gastric cancer is that our approach is working. It's safe, it's effective, and I think most importantly, we now know exactly what patients it's working in. There's no question there's a bit of an overhang with CD47 and in IO in general. But again, this is drug development and it takes patience and time for it to play out, and we're really excited and have a lot of conviction in our molecule.
Great. And so as you mentioned, by design, this is a combo agent, and you took a different path from others. And so you're pursuing essentially three combinations, right? Anti-cancer antibodies, ADCs, and then checkpoint inhibitors. Maybe give us a quick overview of those approaches and sort of remind us of the confidence and the mechanism with each of those.
Yeah, sure. So overall, if you look at resistance broadly defined, whether it's to an antibody like Herceptin, an ADC like Enhertu, or a checkpoint like Pembro, CD47 blockade is at work, hampering the ability for those agents to work. So each of those combination modalities for us is slightly different. And I think that's what's exciting about this program. We have three big shots on goal. There's no question we have the most data to support how we would combine with a naked antibody like Herceptin, but we're also running studies with ADCs. Our two ongoing clinical studies are with Enhertu and Padcev, obviously two very successful ADCs. And then we'll talk about the checkpoint story, but we're running two large randomized studies in frontline head and neck in combination with Pembro, which we'll read out first half next year.
And so you got the three main sort of combination approaches, but there's an awful lot of cancer drugs out there that fall into those categories. Just maybe talk about the process that you guys go through to decide which agents you feel gives you the best shot.
Yeah, it's starting with those three buckets. And I think what's so interesting about this molecule, and again, it goes back to the science, is that, again, CD47 signaling is everywhere. And there's been a consistent drumbeat of the importance of it, and so what we look at is where have we de-risked each of those the most, if you will, and how do we push forward. And so on the antibody front, we now have five different clinical studies, and we'll talk about them some today, that show that signal.
When we've combined with an Fc-active antibody, this drug has worked. And I think that gives us a lot of confidence then to look into other combinations beyond what we're doing today. I think on the checkpoint side, I'd say we have less clinical data there, but certainly a strong story there as well. As we get data from ASPEN-03 and ASPEN-04, that will help build our confidence. The ADC, the third big shot on goal, is definitely emerging. We shared the data at ASCO last year on the bladder study with Padcev and are excited to share more there as well. Three big shots on goal. We do not need all three to work here to have a very meaningful drug, but we are excited about what we have across all three at the moment.
Excellent. Okay. Let's jump into some of the indications here and maybe start with NHL. So the investigator-sponsored phase I trial in B-cell NHL that was at AACR, for getting into that data, maybe give us an overview of B-cell NHL, the R-squared standard of care treatment regimen, and why evorpacept may have utility in this indication, the underlying sort of premise around the whole.
Yeah, sure. I mean, again, we know in heme malignancies and a lot of the roots of CD47 were within heme that CD47 is expressing as a mode of evasion. And our data in NHL now across two clinical studies, our phase I-B study and the MD Anderson study with Dr. Strati has been very strong. And I think we know now with certainty that when we combine with Rituximab, again, Rituximab provides the positive signal that we are driving efficacy.
In our phase I-B study, when we combined with just Ritux alone, we had a roughly 65% ORR, which is more than double what you'd expect with just Ritux. And then as we shared at AACR earlier this year, we had a close to 90% overall response rate in relapse refractory NHL, which again, that's well more than double what you'd expect with the R-squared backbone alone. So two different studies, both very strong signal, and again, it makes sense mechanistically given the biology at work with NHL.
Great. So tell us what's next in NHL based on these two important data points?
Yeah, so right now I think what we're doing with Dr. Strati is he's now enrolling patients in frontline NHL. He's been pushing forward in that at MD Anderson. Again, frontline NHL relative to other cancer patients are some of the healthiest out there. So it says a lot about our safety, and we're looking to that dataset to see yet another signal. And as we watch that data as well as the second line data, I think that's going to give us a real sense of how the data is maturing in terms of PFS and survival, and that then will drive a decision. I think NHL for us is interesting. We just have a lot of other things on our plate at the moment that are where we're focused.
Okay. And maybe let's get into that then. So bladder cancer, you had a fairly important data readout at ASCO back in June. That was ASPEN-07. Just again to orient everyone, give us a background of this program and why evorpacept in combination with Padcev was chosen and sort of where that program stands?
Yeah. I mean, when we combine with an ADC, ADCs are just an antibody with a payload, right? And if you have an Fc-active ADC like Padcev, we should be able to drive ADCP in a different way than what Padcev alone should do. So in this study, we were looking at second line bladder. Padcev has now, of course, moved frontline in bladder, but it was a second line study combining our drug Evo plus Padcev. The benchmark in that setting is the EV-301 study, which is around 40% ORR.
What we shared at ASCO was an ORR of north of 60%. I think the asterisk on that data was it was early days. We were still actively enrolling the study and had a mix of both confirmed and unconfirmed responses. And so that data has since been maturing. We've now completed enrollment on the entire cohort, and we're looking forward to sharing an update on that front as well. But the importance of that data is it's really the first dataset to combine CD47 blockade with an ADC. And again, novel mechanism, novel approach, and so to see a signal, even though an early signal, I think is exciting for us.
So before we get into other programs, I guess maybe to take a step back, I have a dosing question maybe for Jason. So with NHL, you guys assess 30 mg per kg and 60 mg per kg. Aspen-07 in bladder looks at 20 and 30 mg per kg. How do you guys decide which dose to use? And I guess maybe a more broad question is how do you think, when do you think you'll get a better idea about the dose response and the optimal dose?
Yeah, I think the good news on dose is that we essentially are using the same dose. As a non-scientist, the way I think about it is we dose at 15 mg a week. The time in which we do that varies to match our combination rate regimen. So when we use 30, it's because our combination agent is dosed every other week. But the 30 mg per kg every other week is basically what we've done across the board.
We know the dose, and we have yet to reach DLT with our drug. And we know that that dose relative with magrolimab and some of the others is significantly higher. And yeah, so in the Padcev study, again, same dose that we've used in 06 with gastric, et cetera. We tested 30 and 20 in that study, but again, 20 versus 30 should make no difference given our half-life is beyond 30 days. So both should be active doses.
You made a comment about the overall safety profile of evorpacept that's been fairly clear through the data that it's differentiated on the safety front from other CD47s. Maybe just a question though, on the Aspen-07 trial, the profile was pretty similar to what we've seen, but there were a few grade 4 AEs that were related to evorpacept. Can maybe comment on these cases and is there an update as to how these patients are doing?
Yeah, I mean, I think safety continues to be consistent, really well tolerated. Even in follow-up beyond the ASCO update, we have seen nothing of concern in that patient population, nor have we seen it across the 500 plus patients that we've treated to date. So I think it can be underappreciated at times, but relative to magrolimab and the other Fc-active approaches to CD47, we just haven't seen these same issues. And again, it goes back to how we're taking on this target. And I think it's encouraging because when we think about developing a combination agent, the safety part of the equation is super important.
Yeah, so there was a little bit of, I guess, confusion or question on the actual efficacy readout from ASCO, and I wanted to maybe see if there was an update there. Just to maybe level set, you had eight confirmed responses in that 26 patients study and eight unconfirmed responses, so if you just add those, that's really impressive, 62% response rate, but four of those unconfirmed responders dropped out, and we're all trying to do math here with small numbers, so I get that it's splitting hairs in some ways, but I know you guys said before the Padcev phase III experience, which is about a 40% or so ORR was sort of the bar. Where do things stand now, at least in terms of that program and that effort, and when's the next sort of update? So we'll get a good sense of what the response rate is.
Yeah. I mean, that again, early dataset, so had a mix of confirmed and unconfirmed. I mean, we can talk over beers if that's a good time to share data or not, but we went ahead and did it just because I think it's important. It was the first data to combine with an ADC. What we're going to share first half of next year here is updated data. So we'll have all patients, 30 or so patients with confirmed scans. And then importantly, we're going to see how those patients are doing over time.
One of the things I think we were most encouraged by was the spider plot and seeing patients do well for an extended period of time. And frankly, you just would not expect that in second-line bladder with Padcev alone. We think it's indicative of an IO agent, and we are cognizant of the fact that what we've shared so far has been really early. So we're going to let that data mature and then, yeah, first half of next year come out and be able to say a lot more on where we are in an ORR rate perspective as well as hopefully more to share on the kind of DOR durability of those responses.
Yeah. Maybe another conversation for the bar or over beers, but on the spider plot.
We starting that now or do you want to wait?
So you did share an early spider plot. We got a lot of investor questions on if response deepening over time? How should we think about that?
I mean, I love that spider plot just because I think with Padcev you see kind of a view, right? You see patients that are responding and then they lose it, and I think what we saw over time was some real deepening of responses, which again, in second-line bladder, when we talk to clinicians, you wouldn't expect, so I think, again, there was early days, so there was a lot of start to the line, if you will, and the spider plot, but so far with what we're seeing, we were really excited about it because again, a slow deepening response is just not what you'd expect, but when you engage the immune system, it is what you'd expect, and so we do think there's something different and unique there.
Good. Okay. And then just on the next steps, you alluded to more patients having an update with only confirmed responses. Is this an ASCO type of timing or is there some other venue that we?
Definitely first half.
Okay. First half. Love that. Okay. Makes sense. Okay. And then just what's the development path for bladder cancer writ large?
Yeah. I mean, I think for us is let's show what our drug can do with an ADC, right? And that's the point. And again, I think that's the importance of this data because then it unlocks not only future studies with Padcev, but within HER2 or frankly any ADC. And there are so many ADCs in development that I think bringing something to the table that can essentially allow an ADC to work in a different way is exciting. So for us, bladder, I think looking at a first line opportunity with Padcev now that we have demonstrated what we can do with Padcev would make sense. Certainly a big swing and a big study. But for us, it's more broad than that and let's look at ADCs and see where we can best play there.
All right. So let's maybe pivot to gastric GEJ as the sort of next sort of tumor type that you've been looking at. So you had Aspen 06 data this year in combo with a triplet known as TRP as trastuzumab, ramucirumab, and paclitaxel. It's hard to get all that out, but just give us a background of this program.
TRP.
Yeah. And why utilize evorpacept really? What's the utility here in this indication?
Yeah. Again, we're looking at a second-line gastric patient population that have all largely progressed on Herceptin. Every single patient had seen a HER2-directed therapy and progressed. So the question that we're seeking to answer is, can we combine with TRAZ, give patients TRAZ again, and do something new and different to allow those patients to see a response? And we need TRAZ again, right? We need Herceptin to provide the positive signal. And this was the first randomized study in solid tumors in CD47, right? I mean, this space has lacked RCTs and that's what this provided. So we were really excited to see the delta that we shared in July. We had a roughly 41% ORR on treatment versus around 26% on control.
I think what we were most excited about is that for patients that had fresh biopsies, meaning indicative of high HER2 expression, those patients did phenomenally well. We know in gastric that patients lose HER2 expression. We know it's heterogeneous, and we know our drug needs HER2 expression in order to work. So for those patients that had fresh HER2 biopsies, we had over 30% delta versus control.
That was a pre-specified analysis. It was an on mechanism for us. I think the street has asked, well, why not just enroll patients that have fresh biopsy? That's what Daiichi is doing in their HER2 study. I think we could certainly do that. But what we've now learned, and I'm a big believer that learning is really important with a new mechanism, is we know exactly where we can drive the most effect. And that's in patients that have progressed on a HER2 agent and have strong HER2 expression. And there are a lot of those patients. And so that was what was really exciting for us about the data.
Yep, so to that point, you're ready to embark now on the phase III portion. Just maybe give it a little bit of an overview. You gave a little taste there with patient types, but just an overview of the design of the phase III portion.
Yeah. So right now our study is comparing versus TRP, TRAZ, RAMPAC. The phase III is versus RAMPAC because that is an approved regimen in the standard of care, global standard of care in second- and third-line gastric. So that would be the phase III. I think before we embark on that, we're going to go back to FDA with the full story now. We have more to say on PFS, which we will soon. I think at the time of the July readout, it was early days.
I think what got a little lost was that we essentially completed enrollment of Q1 of this year. So when we reported the update in July, it was early days. And I think, yeah, we're going to have more to share here soon as it relates to how that data has matured. We're going to be looking deeper at this HER2 expression piece, both how did these fresh patients do as well as looking at CT DNA to take another swing at looking at HER2 expression. I think looking at those two groups will give us even more data as to where our drug is working best.
So we got about a minute here, and I wanted to maybe spend some time talking about the upcoming catalysts. Obviously, you've got a lot going on next week, San Antonio Breast Cancer Conference. You have a combo with HER2 bispecific. You've got ASPEN-03 and ASPEN-04 updates, I-SPY data coming. Is there any one particular?
I mean, yeah, it's the breast data coming later this month, the ASPEN-06 data that I just mentioned, which will be, I think, really important for the company and a lot of focus on that. And then Aspen-03 and Aspen-04, which we're running in combination with Pembro. These are front line head and neck studies. We're going to be reporting on over 300 patients randomized. Really excited about that.
Certainly, there's a lot of investor enthusiasm around Merus and Bicara, rightfully so, who have put up good single arm data. We're going to be bringing a very large randomized data set of over 300 patients. Both of those studies were designed for registrational intent. And we've been at these studies for a long time. We started them in early 2022. Again, we're developing an IO agent. So seeing the tail, if you will, is really important. And we think that those studies, again, assuming success, can be really, really disruptive. And excited about that too.
Great. All right. Lots to look forward to. We're out of time though. Thank you.
Sounds good. Thank you. Appreciate it. Thanks.