Good morning, everyone. Welcome to Jefferies London Healthcare Conference 2025. My name is Roger Song, one of the senior analysts covering SIMCA Biotech in the U.S.. It is my pleasure to have a fireside chat with the next company, ALX Oncology. Welcome, Jason and Harish.
Thanks for having us.
Excellent. All right. Maybe, Jason, why not you start with some overview of ALX and then given the recent strategic kind of pivoting and then now focusing solely on very two high-value programs and then give us some high level and then we can go into.
Yeah, great. Thanks for having us. Appreciate it. It was a good meeting. At ALX, as I think many of you know, we were founded as a CD47 company about 10 years ago. That is our lead evorpacept, which is a very differentiated CD47. In the class, there's been multiple failures over the years with an Fc active approach. We have a dead Fc, and as we can talk about, that's really made all the difference. That's the mechanism that we were founded around, and that's the mechanism that's now played out in the clinic and is working. The second program we have now in the clinic is ALX2004, which is a novel EGFR targeted ADC.
As a company, we made the decision back in 2021 to really diversify our efforts. As part of that, brought in a platform that we'll also talk about, and it was the result of that effort that led to ALX2004. Excited about that program, excited to have it in the clinic, and been pleased by what we're seeing so far. As you mentioned, two programs, two very different programs, and that's what we're focused on now.
Yeah, I like that. For the CD47, obviously, we're going to talk about that. This is more focused on certain indications in which you see some promising data in that population, biomarker-driven, right? Obviously, EGFR ADC is a high-interest kind of space in a very diversified program. Maybe we stick with, we start with the CD47, which is a very differentiated CD47 program. You just recently, I think a couple of weeks ago for the early and then during the call, and then you released some new data and then also CC. Looking at the CD47 high population, in particular in the gastric cancer, how do you think about that data and then how we can make some research or translation to your planned breast cancer data?
Yeah, sure. Just taking a step back mechanistically, CD47 again is one of the most primary ways in which our healthy cells communicate to the immune system. It's fundamental and it's highly conserved, and it's also been a really challenging target, as I mentioned. The beauty of our design is separating the don't eat me signal. Evorpacept provides full blockade of CD47, and then we utilize the Fc activity of an antibody or a bispecific, whether that's Herceptin, zanidatamab, et cetera. It's the combination of those two things working together that then causes a macrophage to eat to drive ADCP. If you think about our mechanism, we need both of those targets at work.
What we've seen in our data in gastric, for example, is a really compelling result on an ITT basis and an even more compelling result when we look at patients that are truly HER2- positive. What we think is a transformational benefit for patients that both have HER2 positivity as well as CD47 high. That's what we saw in our data. Again, the clinical data tracks, the ITT data looked good. The patient population where it was confirmed HER2 positivity looked even better. Again, to see both of those mechanisms at play is where we saw a really strong result. To your question, that then forms our program now going forward.
Given the data you've shown in the CD47 high population, it is very dramatic in terms of the high versus low. Just give us some of your view on the translation for the tissue from different organ and then also the cut-off for you. I think seems you're, as long as you reach certain threshold, it doesn't matter with the two granular kind of cut-off.
Yeah, exactly. I think that's what's been really compelling about this data set. It was a predefined analysis, of course, done retrospectively, but what was really compelling for us is that it didn't matter what expression, what level of expression we chose. The response was strong, whether it was IHC3, IHC23, et cetera. We showed four different cutoffs in our poster at SITC, and it didn't matter. I think that really speaks to the strength of the mechanism. For us, we've now demonstrated in two positive HER2 cancers with our gastric data that we've been talking about here, as well as in breast with our partners at Jazz, combining evorpacept with zanidatamab also showed a really impressive signal. I think for us, that's where we're focused is HER2-positive cancer going forward. I think this should really translate because CD47 is so fundamental.
We know it's expressed on, overexpressed on just about every tumor type across both solid and heme. I think that's, yeah, that's what's been really de-risking for us in the program.
Got it. Yeah. In terms of the HER2 breast cancer study, yes, you showed that if you confirm the HER2, the effect size is definitely more dramatic than the ITT. How do you think about the CD47? If or when you will release that data, will it further de-risk the opportunity for breast cancer?
Yeah, I think what we're excited about now is, again, I think in IO, one of the biggest challenges has been targeted IO, right? Of course, PD-1, PD-L1 is the ultimate targeted checkpoints. We do think CD47 has similarities to that. When we saw the data in gastric and saw such a profound effect in the CD47 high patient population, that is leading us to look at all of our data sets. You mentioned the study with Jazz at breast, we're actively looking at that. We have a collaboration with Sanofi with multiple myeloma. We're looking at that. All of our data, I think, is now on the table, if you will, and it's important for us to continue to validate this biomarker across other data sets. We think the story and the biology is really strong to support that.
Yeah, absolutely. Investors want to keep looking at the de-risking events. I think just highlight this will be another next de-risking event as you start to see more CD47 high biomarkers.
Right. Yeah, and I think that's a great question. I think the bet on us right now is given our focus is on HER2-positive breast post and HER2, where we see a massive opportunity as HER2 moves to the front line. The bet's really, can we do it for a third time? I think as you talk to clinicians, they would tell you that HER2 cancer is HER2 cancer. Most drugs that work in one work in another. We've now done it in HER2-positive gastric. We've shown it in HER2-positive breast with zanidatamab. Can we do it a third time in this study? I think, again, we're confident. We're biased, of course, but we're confident that that'll be the case and that'll then really lead us to run the registration.
We need the confidence from the company, right? Otherwise, how are we going to do it?
That's a better way to put it. Not bias, confidence.
Yeah, confidence. Yes. You are running the phase II, right? As the chemo and then the combination. You say you will have the intern data next year, 3Q. What do you want to see from there? What will be the decision-making process to move forward potentially in the pivot?
Yeah, Harish is our CFO, but he's also subbing in as our CMO.
Oh, okay.
That's a great answer.
That's a rare combination.
Yeah, that's a good one.
Be careful there. I don't know if that's a good one. No, I mean, one thing I think that we talked about the opportunity post and HER2 setting, right? In terms of if you look at the second line plus response rates that you've seen has been, I would say in prior trials, larger trials like SOPHIA's study has been fairly established. You've seen about 20% response rate is what we've seen. What we haven't now in a truly in a clinical trial setting is post and HER2, what response rate we've seen. Recently at ASMO, if you look at the real-world data study that looked at post and HER2 setting, over 600 patients where response rate were probably close to 15%. We wonder given we know it's in CD47 as an immune evasion mechanism, so it's possible that it's even lower than that for a CD47 high.
Clearly, when you look at our double positive patients, obviously we want to make sure we see a signal. We see a similar signal. We think something like, let's say, 35% or more in those double positives would, I think, would kind of validate and would be consistent with what we've seen in the past. That's number one. Another thing we're looking at, obviously in this study, is besides validation, understanding the cutoff points. Again, what we had laid out was the cutoff points in gastric, but we wanted to know what that would look like. Right now, that's something that we've been looking at to determine. Because once we've learned that, that'll inform kind of where we take the study forward.
Pretty good answer.
It's great. I think I can keep spending.
You don't need to spend, yeah, you don't need to spend that money on the CM. I think this is a pretty clear benchmark, SOPHIA, and then the recent ASMO, the real world, it seems the 15%-20%, you want to double that and 35%-40%. That's totally reasonable. How validated the CD47 biomarker to say, so in this trial, how different you will compare to the gastric? When you go into the meeting with the FDA with this intern, assuming you will do that, maybe correct me if I'm wrong, how are you going to propose the cutoff, different cutoff, different way to measure the CD47?
Yeah, I think we've had FDA interaction already to date on this study design, and I think understanding the cutoff is really important. And to Harish's point, there hasn't been much magic needed. It's worked across a range of different expression profiles. I think going into a registrational study, certainly history would tell you that you need to have that right. We are going to do that. I think that's why we're taking the extra step to have the phase, to do the phase II to be able to really inform that. Again, we're not asking clinicians here to change practice, to change care. This data is all based off of the original biopsy that's taken at the time of diagnosis. It's really just another test. Again, it's IHC driven, so should be relatively easy to implement it for them to adopt.
Now this IHC assay, how validated that is? If you find the right cutoff, can you propose to FDA, say, okay, this is the assay and the measure we want to do for the pivotal?
Yeah, I mean, right now it's your standard test assay. We're going to, of course, need to invest and put the effort into designing and building the companion diagnostic, and we'll do so with a partner. That'll come again, I think, just like any targeted play, you need to do that and invest as you get closer to the registrational phase and that effort.
Post this interim, maybe I ask to clarify, would you go to the FDA to talk about the pivotal design? Should we expect the next step will be the pivotal after the interim data?
Yeah, I mean, this is an open label study, and again, we're just looking for validation yet again. I think that's where there's an open question for us. How many patients will we need? The study's designed as an 80-patient study. I think that will give us more than enough. What will be important is comparing the high versus low population in that data set. We've guided the interim data in Q3. I think if we see 40-50 patients even that are trending in line with what we've seen to date, again, if you think about the bar, as Harish pointed out, 15%-20% ORR versus what we're seeing, we just want to see that again.
The minute that we see that, I think we'll be on our front foot getting into our registrational phase, working with FDA to confirm the design and moving forward as quickly as possible.
Excellent. Okay, great. It's not far from the pivotal pass. That's very critical.
It's not, right.
Okay. Understanding this setting is post-HER2, which makes sense because everyone knows most of people will become the standard of care. How do you think about potentially can move earlier line or is that matching this mechanism into the CD47? Is it pretty orthogonal?
Yeah. No, I think it's a great question, Roger. I mean, for us, what's been so encouraging and perhaps we've understated this some is just the strength of our safety. Historically in CD47, it's been challenging. Significant grade three and above heme-related tox have ultimately led to the demise of the Fc active programs. Because of our dead Fc, we are not seeing that. We've seen it now in almost 800 patients that we've dosed. That does allow us to go earlier, whether it's in the adjuvant or neoadjuvant setting. Again, those are bigger studies, will take more capital, but I think that's an option for us. It's interesting if you look at the work being done with our drug at MD Anderson, they're currently dosing patients in first line NHL, which as we know is one of the healthiest populations in all of cancer.
I think that tells you something about our safety. The study that we're running with Herceptin could easily then, I think, translate up into earlier lines and breast.
Got it. Okay, great. Okay, so I understand this is your lead program and has been foundation since inception, but you do bring another angle of the pipeline and then the ADC platform. Maybe can you just give us a couple of minutes on the platform, how that differentiates from other ADC because we have kind of the ADC out there.
Right.
You also think this can be very unique.
Yeah. Yeah, no, this is the best ADC.
Okay. All right. That's a confidence.
I think it's, no, there's certainly a lot of activity, a lot of great drugs coming and certainly approved ADCs. I think for us, back in 2021, we made the decision to diversify the pipeline. The strength of our company has been our science. And our founder, Jaume Pons, is really a world-renowned expert in ADCs. He assembled a team in Palo Alto back in 2021 to begin our effort with ADCs. We acquired a company, company in quotes, a very small company called Scalmi that had about a dozen really strong protein engineers, chemists, and ADC experts. At the time, they were looking at some really interesting linker payload constructs, a shield, some novel toxin work. That work provided the basis for what we're doing today. From 2021 up until earlier this summer, we largely didn't disclose the program.
Part of it was just understanding how competitive, to your point, Roger, ADCs are and the desire to keep this under wraps. Part of it also was that the focus of the company had been on CD47 and investor focus was there, not on what we were doing in the pipeline. We made the decision to not disclose that program until we were about to dose our first patient. That is what we did. Early in the summer, we disclosed ALX2004. It is an EGFR targeted ADC with a really unique linker payload construct as well as a unique epitope. That program is now in the clinic. We dosed our first patient in August, announced at earnings last week that we cleared our first dose level. We were starting at one mg per kg, which is a relatively high dose.
Pleased to be able to get through that and get through that quickly without DLTs. Early days, but excited about the potential. Certainly, EGFR is a well-validated target. If we can hit that target in a safe manner, I think it's going to be a major catalyst for us.
Yeah, the industry has tried the EGFR ADC a couple of times, including some of my covered companies. How do you think you can be different or better, superior to them? You mentioned your unique linker payload. What is that and what's the DAR and then also the epitope, why you think you need a unique epitope for the EGFR?
Yeah, I mean, I think it goes back to what we did internally. We synthesized probably over 60 ADC different linker payload constructs and really benchmarked off of ENHERTU and tried to optimize the on-target delivery as well as the bystander effect. We shared data over the summer that supports that. We're using Topo- I. It's a DAR- 8, as you asked that. I think it really takes advantage, I'd say, of modern ADC principles. Some of the ADCs that have failed have used different payloads, different constructs. We know that Topo- I has been the most validated. The other piece is the epitope. I'd say the other learning for the ADC field is that the epitope matters. Our epitope is unique. The competitors in the space are using cetuximab and panitumumab. Those are the approved EGFR antibodies. Those antibodies have significant on-target skin tox.
This has been a challenge for the EGFR class since the early days of ERBITUX. We made a conscious decision to look back into what big pharma had done to solve that program. We chose an antibody that was specifically designed with unique binding. We tweaked the affinity as well to essentially remove the on-target skin tox. We saw that. We saw that translate into the primate work that we did. We did not see skin-related tox, which is important. We also did not see ILD, which is important given what is known about Topo-based ADCs. It is really that foundation that I think is what is different about our program.
Yeah, I definitely heard the notion not all the Topo- I is the same, right? I think you have some of them, they have ILD, some of them, but the ILD may be related to Topo, but also the EGFR related to the skin. You want to make sure you are finding balance, not hitting those kind of tox and widening the therapy window. The other thing is that do you use any masking technology because it may complicate the whole engineering?
We did not. I think it's interesting because we do have in-house expertise and have a shield we've worked on over the years. What we found is that the design here was so good that there was no need. I think that translated in vivo, where we saw good activity across probably over a dozen models at different range of EGFR expression, we saw great activity. As I mentioned, in terms of the NHP work, saw translate there as well.
You think you're not seeing those EGFR-mediated tox because EGFR is widely kind of expressed across even healthy tissue because the epitope you find is not expressed in those healthy?
Yeah, I mean, we know from our work in house that it's different binding. It's a different binding motif, which I think matters. We know that affinity matters. By doing those, tuning down the affinity as well as the unique binding, that's what does it. I think the challenge has been in EGFR is if you think about just the tox with the naked antibodies and now putting a payload on top of that, it's very challenging to get the TI right, as you said. Early days with the program, but so far so good. We know that these skin-related issues with EGFR are seen very acutely, very quickly after dosing. So far so good.
How about the internalization and then the bystander effect? Because when you tune this affinity and then epitope binding, so would that impact the internalization?
Yeah, I mean, the internalization right now is on par with ENHERTU, et cetera. We know it's well internalized. The bystander effect was something that the team spent a lot of time optimizing, so really concentrating on the linker itself to enable that. We do think based off of our work that any benchmark it versus ENHERTU, which we use as our reference point, that we're seeing improved bystander effect as well.
Good. All right. You are in clinical, and then we're about to see some clinical data next year as well. Just tell us what's your expectation, how you're going to make decision if you see something.
Yeah, I'll let our CMO answer.
Okay, yes. Here we go, Harish.
No, I think we guided to seeing our first safety data in the first half where we initiated our phase I dose escalation phase is ongoing. I think Jason mentioned about, I think we're glad to see where FDA granted us an ability to start with a healthier dose. One mg per kg was the first cohort that we cleared. We are now dosing two mg per kg cohort patients. Of course, the primary goal for it would be to look at safety, AEs, PK profile. I mean, those are stuff that you would is what we want to make sure we're on the clear. Number two, I mean, we are, I mean, the one thing that we're doing is we're going after more EGFR or expressed in tumors. Focusing on lung, CRC, head and neck, and esophageal.
Which gives us the potential to look at early efficacy signal. I mean, I would say safety is the primary one. Given this, otherwise it's a validated target, which is kind of where the safety has been a bar, which is what I know we've been, as investors, and we've been headed to clear that, but it's also hoping to see some early efficacy.
I think you designed the phase I with some dose exploration and then dose expansion. With the safety data first half, would you be able to make decision to move to the next stage or how should we think about the next?
Yeah, I think that's our goal. I mean, to Harish's point, we pick four tumor types where you would expect to see activity once we get to the right dose. I think in ADCs today, it's very important to quickly pick where you're going to go early. We are doing that actively in-house. Our goal would be potentially even as part of dose escalation to continue to stack the right patients into that study so we can quickly then move into the indications where we ultimately want to play. I do think that's really important. You mentioned the competition in ADCs. I think speed and time to get to the right indication to the right patients is what's important. That's kind of our overall philosophy of the effort.
Excellent. Now the real CFO question. How's the balance here?
Yeah, it's other hats.
Another hat, yes. Change. How's the balance sheet? How does that support both program? I think you have very meaningful data next year. How does DM move forward?
Our cash runway gets into early Q1 2027. What we're focusing on primarily, almost, I would say, our priority score is on these two clinical trials. We just took by the phase II breast and the ALX2004 phase I study. The safety in the first half would be a milestone that we'd be looking forward to. Q3 is when we'll have something to break out, which is what we're trying to cover. No, we feel good with kind of where and looking forward to these two catalysts. That may be a good trigger point to keep up the balance sheet at that point.
Good. All righty. Thank you for the time with us this morning. Thank you, everyone.
Appreciate everybody.