Alx Oncology Holdings Inc (ALXO) September 2026 Conference Transcript

Good afternoon, and thanks for joining us to have a conversation with Jason Littman, Chief Executive Officer, and Harish Shantaram from CFO of ALX Oncology. ALX Oncology is a clinical stage immuno-oncology company advancing two internally developed programs towards multiple inflection points in 2026 and 2027. The lead program, Evroposet, is a first-class CD47 blocker designed to separate blocking the don't-eat-me signal from delivering the eat-me signal through a partner FC-Active antibody. And CD47 expression has now emerged as a predictive biomarker across both AspenO6, the gastric study, and also the HER2-positive breast cancer study. That thesis is also being tested out in ASPIN-09, a Phase II study with evapacet plus transtuzumab and physician's choice of chemotherapy in N-HER2-experienced HER2-positive breast cancer, with top-line data expected in mid-2027. So the second program, which is the more interesting program and exciting one, the novel EGFR-directed Topo-1 ADC, ALX2004, is currently in phase one dose escalation across four high EGFR-expressing tumor types with safety data and dose escalation data expected in the second half of this year. So to discuss both the CD47 as well as the EGFR ADC, let's get started with Jason and Harish.

Great. Thank you. Thanks for having us.

So for those who are new to the company, CD47 carries a lot of history. There was a $5 billion acquisition at one point.

There was a $2 billion acquisition that really didn't work. um so but why um do you think a wordpressant mechanistically is different and it's a better bet than on the same target yeah sure so i think you know cd47 like a lot of things in biotech there's been all sorts of ups and downs i think you could write a novel about the history of drug development in that space that's what makes it fun what we get to do each day is it's it's unpredictable. You know, as we like to say, it's not the target's fault, however, that things played out like they did. I think there's just been no question over the last 15 or 20 years of research that one of the fundamental ways in which cancer evades the immune system is via CD47. And it's a tough, tough target because it's also how our healthy cells signal to our our immune cells to be left alone. And because of that challenge, that fundamental challenge of expression, where you have expression on healthy and you have expression on cancer, again, that's what required a unique approach. And so if you think back to our company's founding, there was really two schools of thought. One, the conventional one was let's design an FC active antibody one antibody that will both activate drive eat me and then block don't eat me and what that ended up doing was causing all sorts of significant on-target issues because that because of the fact that cd47 is so widely expressed they had really significant on-target toxicities that really weren't apparent until after those acquisitions when they ran the randomized studies That, for us, was what we tried to solve at the company's founding. So we bifurcate the eat-me signal. We have a dead FC. So we provide full blockade of the don't-eat-me signal. And then we use an FC-active antibody like Herceptin, for example, to provide the activation. And that mechanism is the same that we're pursuing today. And it's been a beautiful thing to watch that translate in the clinic. We are far, far safer after dosing over 800 patients here. We know it's safer and, frankly, quite safe in general. And we know that the activity has been quite strong when we get that combination right as well. So one of the goals internally for you is to get both of these molecules into registration level studies in 12 months from now. so for that to happen you know in each of these programs what needs to get done you know between now and then yeah we need to be working hard as much as fun as investor meetings are arish and i get to do this but everyone else back at the office is doing the real work um i didn't mention our second program that you alluded to which is alex 2004 which is our egfr targeted adc We're super proud of that molecule. We designed it in-house by a really great group of world-class chemists and protein engineers. So since 2021, we've been pursuing that in-house. We started dosing patients about a year ago. That's been a very competitive space and also a very challenging one. Targeting EGFR with an ADC has been tough. We think we've cracked the code, as we'll get into. We have a novel epitope called Metuzumab that we're using. We think we're the only ADC in development that utilizes that backbone. And we think our linker payload architecture is quite unique, too. So, yeah, as you mentioned, our goal internally is by the time we're sitting here next year is to have both programs on the doorstep of a phase three. And I think so far, so good. Execution has been really, really quite strong across both.

So let's dig a little bit into that. 2004 program, you know, currently you're, you know, you're in the dose escalation phase and you're going to see that data later this year. So what does that update need to show, you know, for you to declare that you, you've got the right therapeutic window and can move, move this molecule forward?

Yeah. So I think the, the program's progressing quite well. We started dosing at one mg per kgs. We then doubled to two, and we've doubled to four, and now we signals over the summer that we're now beyond four, and I think that's really important for most topo-based ADCs. Four and above has been in and around the therapeutic window, so I think first things first, we want to show that we have a therapeutic window to play with, so to speak. You know, I think what's really key to remember about this study is that it is a U.S.-only site. Our sites are only in the U.S., so we are enrolling and treating patients in the top academic centers, so think Moffitt, MD Anderson, et cetera, and because of that, we're seeing late-line patients, so on average, our patients have seen three or four therapies before entering our study, so it's a great place in which to test your drug, and it's a high bar, so I think with this update, we really do want to define and I think lay out where we see the therapeutic window, but also, you know, hopefully show some signs of activity as well. Okay.

The other uniqueness about this ADC is, you know, it's an epitope that has not been tested by anybody else, originally developed by Merck-Soronel, to avoid EGFR-related toxicities, so to speak. So beyond tolerability, you know, is there anything unique about this epitope? And do you think this epitope could be used in other EGFR-driven diseases?

Yeah. I mean, I think through the development of ADCs, it's been pretty clear that the choice of epitope is really important. And our team went to school on the history of EGFR development to come to this epitope. Cetuximab and panditumumab are both great drugs. The but is they're on-target toxicity, so significant skin, blistering, derm-related toxicities that have been tough. So I think our insight was, you know, if you strap a payload to that antibody, you could really open up yourself to more on-target toxicities. Metuzumab, as you mentioned, was developed by Merck-Sorono with a unique binding pocket, with a unique domain that after a whole lot of screening, they determined did not have those issues and we think is selected to tumor in that way. You know, we did not see on target related skin toxicities in our NHP work. And that's what we're trying to show in the clinic. And you mentioned potency. I think the other really clever approach our team took was to take our linker payload, synthesize 60 different linker payloads, and then throw them up against in HER2 as our benchmark. So all of our benchmarking work preclinical was versus in HER2, and that's why we think we've also developed an incredibly potent molecule.

Okay. So the other toxicity which is normally thought of is the interstitial lung disease, which you don't see with your molecule. And also, in terms of the publicly known benchmark, there's a CSPCs molecule that says 6010, which has been escalated up to 6.4 milligrams per kilogram, but they do see some, you know, all-grade rash in there, but no ILD there. So is that the real molecule And is that the real data that, you know, you should be held to when the data comes out or that's not the right?

I should ask you what you're going to hold us to. I think for us, you know, I think it is a good benchmark. As I mentioned before, you know, rash, ILD has in the past translated. So if that's you see that in your NHP work, there's a very, very good chance you're going to see you in the clinic. And we did not see that in our NHP studies, which I think is important and a leading indicator, we hope, to the clinic. There's certainly other EGFRs in development. The CSPC molecule is one of them. You know, I think what they've demonstrated is the same as what other TELPOS have seen, which is very, very challenging to push dose beyond 6 mg per kg. So although they tested that, they ended up settling on a dose between 4.2 and 4.8. And that's typically the right window. So between four and five is where a lot of these other ADCs have settled out in terms of dose.

So, and we know that you're looking at four different tumors with this initial study. And let's say we hit the jackpot and get good data on all of the four indications.

Is that your expectation? Because I might not be doing a good job of setting expectations.

So which, you know, are there any favorites of the four kids?

I mean, I have three kids, and I've learned to not pick favorites, although all parents do have one, I'd say. No, I think what's exciting about all four, so we're going after lung, head and neck, esophageal, squamous, colorectal. And so I think of those, of course, colorectal has been very hard, and it's very hard in dose escalation because you know the bar is very low. but it's challenging, right? If you see two out of 10 patients in your colorectal cohort, is that good? It's tough. I don't know. I think for us, head and neck, lung, and esophageal are where we're most focused on at this point. And I think we've tried to think about those things in dose escalation. So we've been pretty conscious about trying to tilt more towards head and neck and lung as we enroll these patients. And we continue to feel like the the opportunity there is significant for our ADC.

Okay, so moving on to Evroposet, and especially on the 09 study. So this is a single all-comers, and you're looking at 80 to 120 patients at this point. And the expectation is to see some data in mid-2027. So can you just describe for us a little bit about the study itself, and what sort of, you know, how sure are you that this, you know, this trial could give us some data or the first set of data in mid-2027?

Yeah, sure. So, I mean, the setup for this study is a lot of clinical data. So really what informs the goal here is our two prior HER2 positive studies. The first, which was a global randomized study in gastric, where we showed an almost 40% delta in terms of orr versus control in the cd47 high population and a tail that looks like an io tail right so we had a durability of response of about 25 months and a pfs hazard ratio of 0.39 so just an incredibly strong benefit versus control and then we went on and did a study with our partners at jazz combining eva with zani also in her two positive tumor this time in breast showed a really compelling benefit there, and from there felt like breast was the right place for us to go. So now we're enrolling Aspen breast, which is focused on, again, for the third, this will be the third study in HER2 positive tumor type, looking at patients that have progressed on in HER2, so second line or greater patients. And here I think we're hoping to show similar. I mean, again, we went five for five in our first study. I don't think we're going to show 100%, so hopefully that won't be your expectation. But I think we saw a really compelling benefit. And one of the things that has really changed in our story is just the fact that CD47 is very clearly a predictive and strong biomarker for response for our drug. I think in IO, one of the biggest challenges and why there's been so many failures has been the lack of of a biomarker i mean the the pd1 story is so strong and has benefited so many patients because we know if you have a cps score of colic greater than one you're going to do great on pembro a lot of these other attempts in io have failed due to the lack of that in my opinion and i think the fact that we now know that patients that over express cd47 really have a significant at response to our drug has been a game-changing, you know, I think, insight for our program. And that's what we're focused on. So here we're going to take all comers. So we're going to have patients that are CV47 high and low. So although it's a single-arm study, we're going to have a built-in way to understand which patients do best. And with that, you know, the goal is to inform our phase three, which we hope to be, you know, pushing forward late next year. Okay.

And, you know, is there a threshold, an internal threshold that you folks have when you're looking at the study to make sure that, you know, you're embarking on the right trajectory there?

Yeah. I mean, the unfortunate thing in this patient population in metastatic breast is for patients that progress on in HER2, the prognosis is really quite poor. So at last year's ESMO, there was a really nice real-world study of about 600 women, and it looked at progression. And it's really abysmal. You know, it was about a 15% ORR, three to four-month medium PFS. So that's the bar, that's the need, that's why we're doing what we're doing. And again, I think if we can show certainly 30%, which would be a doubling of ORR, that would be fantastic. And on our last KOL call, I think Dr. Sarah Hurwitz thought, you know, six months-ish, PFS would be the number to hit. So again, not an exceedingly high bar, but there are a lot of patients out there in need, and it's a really significant population that we're trying to address.

Okay. So let's see if you can answer this question, because you haven't given the threshold on this, which is the CD47 expression cutoff, you know, do you have, you know, what's the expression cutoff that, you know, you would like to see? And, you know, how will that help you plan the next study?

Yeah, I mean, the reason we're not answering that is that we don't know. So that's, I think we do know a fair amount about how we think it should look. You know, if you look at our gastric data, One of the most pointed questions that I got from investors when we first shared it is, wow, this looks really quite cute. Nice work on your biomarker defined population. But did you just cherry pick one cutoff that looked good? And so we shared later at ESMO the fact that you could have just about picked any cutoff in terms of IHC score and the response still held. And when we got the data from Jazz with our study with Zannie, we were really quite encouraged that if you did nothing more than just look at patients that had no expression of CD47 versus patients that did, that was enough to drive the five out of five. So again, I think when you're looking at a biomarker-defined therapeutic, it's all about the spread, the magnitude of benefit. And given what we've seen in the past, if that carries through, we're going to have a lot of options when it comes to defining the specific cutoff.

And also, you know, you're working with Roche, you know, to set up the diagnostics So in terms of, you know, what sort of data do you need to see to make sure that you get to set the diagnostic in place? And do you have to have the diagnostic in place before you start the phase three study?

We do. I mean, I think we have to have the work done. And so we've been investing heavily with Roche to make that a reality, to push forward companion diagnostic. I think the good news here is that there's no magic into the test itself, right? We're looking at a target that's expressed on the surface of a tumor cell. We're using standard IHC techniques to do that. So, again, there's no magic or discovery that needs to happen. we just need to put in place the rigor of that test and then deliver more data to help support what cutoff we'll use.

So one more question on the Aspen 09. In terms of, I know you plan to talk with the FDA before you get going on the phase three study. Do you, there's also some thought about having to do with a smaller patient population because of the combination that you're going to test. So can you describe, like, what is it that makes you feel that you can, you know, do a smaller patient population than running, like, a 600 or 700 patient study?

Yeah, I think it's really one of the positive attributes of running a biomarker-driven study. You usually can end up targeting a smaller patient population. Again, it goes back to the magnitude of benefit. Like I mentioned in the gastric study, we showed a hazard ratio of 0.4 better across all those different cutoffs. And so, you know, of course, you never power a phase three at a hazard of 0.4, but it does give you, I think, the ability to run a much tighter phase three. So we'll see. Ultimately, FDA will be informative and be a big driver of that decision. But we do think if you look at the benchmarks in the history, you have an ability to run a much tighter phase 3 path.

You also talk about how Everproset can be a natural combination partner for any FC active construct. When you say that, what are you thinking about in terms of a combination?

To develop a combination product, do you need to have a partner or you can you can get started on this studies yeah i mean i think in the dare to dream scenario of what if this works right i mean the what if this works is we're sitting on the next big immune checkpoint and there's not a tumor type including in a hemoignancy that doesn't over express cd47 and so because of all the funkiness of how this played out it just so happens we're the last one standing and so when we think about the competitive setup of potentially owning and owning should be in quotes if we had a lawyer here but owning a space where we are the only cd47 game in town for patients that over express cd47 and i think our combination potential

is really endless any bispecific or fc active antibody we can play with and i think that's where yeah that's the kind of dream and vision of what we're pursuing okay so harish you know you closed the quarter with 153 million and you know what sort of a runway could you get from that and and of some of the things that jason is talking about and how much of that can be accomplished with that with what you have our cash runway guidance gets us into through the first half of 2028 we've been singularly focused on executing the two trials that jason alluded to through the phase two trial through the next major catalyst next year. And then the ALX 2004 ongoing phase from escalation study. I think these two will be, we think there's going to provide some critical data sets that will help us propel towards what you had initially started alluded to, is like getting us getting it ready for a phase pivotal study already. But we're also ensuring that we'll will be ready if the data supports it with investment in CDX and some CMC along the way as well. So we feel good with the balance sheet we have and our ability to execute the ongoing trials.

So just to close out, Jason, beyond this two molecules, is there anything in the pipeline that you would unveil in the next 12 to 18 months?

Yeah, I mean, so we, I think, again, we're really proud of the two programs, in-house developed programs, and we continue to have active research efforts. You know, I think with, as was the case with 2004, from 2021 up until last summer, we didn't disclose that program publicly, and I think we'll continue that trend. So once we get closer to IND and have things that are more advanced, we look forward to sharing it at that time.

Great. Thank you very much, Jason. Thank you.

Appreciate it.

Thank you.