Good afternoon. Thank you all for joining us here today. My name is Henry Jiang. I'm with the banking team here at J.P. Morgan, and it's my pleasure to be introducing ALX Oncology today. Joining us on stage and presenting today will be Jason Lettmann, CEO, as well as Barbara Klencke, Chief Medical Officer. Just a reminder that we'll have time for questions at the end of the session, so please wait until then for any questions, and we'll get you a microphone. But without further ado, I'll pass it over to you, Jason.
Great. Thanks, Henry. Thanks for having us, and thanks to JPMorgan for the week. And appreciate you all spending some time. We heard that Thursday is the new Monday at JPMorgan, so thank you all. Here are our forward-looking statements. So really excited to be here. We've had a really exciting week, I think, for ALX. We're coming off an incredible year for the company, a year in which we had seven different data sets read out, and I think we clearly understand a lot about both of our programs. So as a quick reminder, we're developing Evorpacept and ALX 2004, both clinical-stage programs, both highly differentiated in their class, and both have made very strong progress. So on the Evo front, we were founded as a CD47 company back in 2015. And the story with Evo is one of a target that is incredibly important to the immune system.
It's incredibly important in oncology, and it's been a very difficult target to crack. The story with us is our mechanism dating back from the Series A to the day is unchanged, and we've watched that mechanism play through in the clinic and is now well validated in the clinic, and we'll walk through and have Barb walk through some of our data. We're now laser-focused on advancing the program in breast and in multiple myeloma, and both of those studies are ongoing and progressing well. On ALX 2004, this is a highly differentiated EGFR-targeted ADC. This is an internally developed asset that we've been working on through 2021, and it's now in the clinic. We'll talk through what makes this ADC so unique and why we think it has the potential to be a first-in-class EGFR-targeted ADC.
Again, great progress in the clinic, and as we shared last week ahead of this meeting, we are now in phase I. We've cleared the first two dose cohorts and are making really strong progress on that program as well. As a reminder, we're coming off 2025, which was really a data-intensive year for the company. First and foremost, we presented at SITC just in November updated Aspen-06 data from our randomized study in gastric. What is so exciting and I think really interesting for this program is we know that Evo is an active agent, we know it's a safe agent, and we now know exactly where to target the drug as CD47 is also an incredibly strong predictive biomarker. Barb will walk through this more, but we really have shared transformational data in terms of this targeted approach and are excited about where that's headed.
We also shared data from our collaborations with Jazz and Sanofi. Both have been great partners for us. These studies further validate what Evo can do not only with antibodies but with bispecifics like Zanidatamab. This story for us is not limited to solid tumors. Importantly, we shared data out of MD Anderson and our study with R-squared, and there again in NHL we showed a strong data set. Certainly not last but not least, we've advanced ALX 2004 into the clinic last year. This program has been in dose escalation and really progressing well as well. So this is a quick snapshot of our programs. We are laser-focused on Aspen breast. We see an incredible opportunity post-HER2 in the HER2-positive space. As we announced last week, we're now enrolling patients. We have an incredible amount of enthusiasm from our sites, and that's been going well.
Also continuing to work with Sanofi, we now have our combination with Sarclisa into dose optimization, and that's also progressing well. We shared data from Aspen-06 as well as from our study with Zanni over the last year, and that really forms the foundation for what we're now doing in breast. And then, as I mentioned on 2004, that study has now clicked through the first two dose cohorts. We're on to 4 mg/kg, which is really encouraging because safety has been an issue in the EGFR ADC class. So again, just as a reminder, and this is what makes us different on the CD47 front, there's no doubt it's been tough and there's been challenges, but we continue and have been the only company developing a CD47 in this way. Our mechanism is fundamentally different in that we bifurcate the eat-me signal from the don't-eat-me signal.
Our drug, Evorpacept, as you can see in the red, blocks the don't-eat-me signal, blocks CD47, and then the uniqueness of our mechanism is using an Fc-active antibody, whether that's a traditional anticancer antibody or a bispecific, to provide the eat-me signal, and these two things working together is what has been proven in the clinic to be effective, and again, when we have the presence of these two antigens, if you will, that's when we're seeing the strongest response. This is very different than what's been tried in the past, and this cartoon depicts what happens with red blood cells. CD47 is expressed in almost every cell in the body, and because of that, it's very difficult to target with a conventional Fc-active antibody.
That's what you see on the left here, and what ended up happening with those programs is an impossible therapeutic window challenge, where they were not able to dose high enough without having significant on-target toxicities. Our program on the right, due to how we work, does not activate macrophages against red blood cells. Therefore, we've been able to dose much higher, and we have not had the therapeutic window challenges that others have observed. This has played out. This thesis that we had dating back to the Series A has now played out in the clinic. What you see on the top is a series of different combinations that we've run: Herceptin, Zanni, Rituximab. This combination now has been validated across a number of different clinical studies, and there's no question that we're seeing consistent activity and safety that's differentiated versus the others.
In terms of the active approaches, at one point there were nearly 20 of these. Now there's essentially a very small number, and the reason why I-Mab, Trillium, Magro, etc., have failed or been discontinued is due to the approach of having an active Fc, which we now know doesn't work. And this differentiation for us has been critical, and I'll now turn it over to Barb to walk through some of the data that we've seen in the clinic.
Thank you, Jason, and good afternoon. I will be really focusing for this first part of my talk on just going deeper into the data that Jason has just alluded to. There we go. CD47, incredibly important for cancer cells. It is one of the main ways that cancer evades the immune system. There are just a wealth of data looking at CD47 as a negative prognostic biomarker, meta-analysis that we display here in 38 cohorts across 17 published studies, 7,000 patients, all with the conclusion that CD47 overexpression correlates with low survival. You can see all of the tumor types on the right there where this has been shown just in this meta-analysis alone. Going into the clinical data, here, I'm going to tell you a little bit more about five different data sets.
These are the first two, and in fact, I'll come back and talk deeper about these, but the gastric study on the left, which we've already mentioned, Aspen-06, this is a randomized phase II, relatively large study, allows us to look at subsets, including a very important subset of patients who overexpress CD47 as well as being confirmed as retaining HER2 positivity. In that population, the response rate is 65%, nearly a 40% delta from the control arm. On the right, we have a smaller study, but again, we're seeing this remarkable response rate. This is a late-line patient population, nine patients with Zanidatamab that were confirmed centrally as being HER2 positive. The control here is a standard published benchmark, but at best, you're not going to see a late-line population receiving anything better than about a 20% response rate.
And all of these nine patients happen to have also had Enhertu. Three studies in a row have shown Rituxan plus Evorpacept, again showing an unbelievably high response rate. These are complete response rates. It's either a Rituxan combo or a Rituxan/Revlimid so R-squared. The first one was our own work in a phase I study in relapsed refractory indolent lymphoma. The second one in the middle there is an MD Anderson second-line indolent lymphoma, CR rate of 83%. And now in the first-line setting, and this was just at ASH last month, 92% complete response rate in the first-line setting. So coming back, as I said, I would come back to some of these data sets to go deeper. This shows the trial design of Aspen-06, the gastric cancer study Enhertu -positive patients. These are second- and third-line patients. They all must have had prior HER2-targeted therapy.
We enrolled 127 patients, and you see the randomization there. TRP is trastuzumab, ramucirumab, and paclitaxel, either alone or with Evorpacept. Out of the patients that were enrolled, 75% or 95 patients were confirmed as having retained HER2 status. This was determined either on fresh biopsy following their prior HER2-targeted therapy or on ctDNA. Out of those patients, we performed a pre-specified, pre-planned analysis based on CD47, and that's the data that I will really be focused on in the next couple of slides. So this shows you the first subset is the retained HER2-positive patients. These are 95 patients, and you see a nice response rate of 49% versus 25%. But when we further subset by CD47 overexpression or lack of evidence of CD47, we see further enrichment in the CD47 high group, and this is the data that I showed you before.
This, once again, on the far left, is the response rate, same patient population, but now we're seeing the durability, 25-and-a-half-month duration of response when you combine Evorpacept with the trastuzumab-based therapy. This translates obviously into a good PFS and OS. The hazard ratio for PFS is 0.39, and you can see the hazard for survival 0.63. Safety, we've looked at safety across all of our studies, of course, and what we see is a very consistent profile across 750 or more patients now treated with Evorpacept. This is just a tornado plot just from the 06 study. It shows, it demonstrates that the rate by grade of adverse events due to any cause is comparable across the two arms. So in general, our treatment is characterized by a generally manageable and reversible adverse event profile.
I'm going to focus now on how this data supports moving forward in further studies in breast cancer. So this is the Zanidatamab trial. We've stated it a couple of times now. The patients who were centrally confirmed as HER2-positive are shown in the middle there, 56% response rate. So this is pretty remarkable because these are sixth-line patients. They happen to be, they must have had at least three lines. These patients had a median of six. They all had Enhertu . And the duration of response isn't mentioned on the slide. The duration median was not reached, but the range was from five-and-a-half to 26 months, and the PFS was seven-and-a-half months. So this trial, published about a year ago, gives us further support. Now, interestingly, we're also looking this quarter at the CD47 to understand whether CD47 might be a predictive biomarker in this patient population.
I don't have the data for you today, but we will be presenting that at a congress in the first half of this year. So then just what is the unmet medical need? There are a lot of agents approved for HER2-positive breast cancer. Obviously, also the Enhertu has been a spectacular addition to the armamentarium, and that is moving up. There is now a first-line label a couple of years ago, a second-line label. So this is an amazingly good opportunity for patients. However, what do you do after that? It's really somewhat uncharted territory. There are a lot of active agents, but how well do things work post-Enhertu ? And what generally is being seen is things are not working quite as well as you would like. No good optimal sequencing of treatment has been described. And some of this data comes from real-world evidence.
There was a 600-patient trial, real-world evidence report out of ESMO from Japan. Response rates were in the 15% to less than 20% range. In the US, there have been a couple of large real-world evidence studies, short time to next treatment, short time for PFS of four or five months at best, and some like SG producing even lower rates. So what we are excited about is if we can replicate anything like what we saw in the gastric HER2 setting or in the Zanidatamab HER2 combination, this will become a very important regimen for patients. We are currently active in this protocol. This is an 80-patient single-arm trial of HER2-positive patients. They must have had prior HER2-targeted therapy, including Enhertu. 100% of patients will have had Enhertu. Response rate is our primary endpoint.
Importantly, just like in gastric, we're targeting what is the response rate in patients who retain HER2 positivity. We'll be assessing that through ctDNA. And then our key secondary endpoint is what is the response rate in patients who are determined to have overexpression of CD47 in this setting. This study is enrolling. We've predicted interim data in Q3 of this year. The addressable patient population is also large. So here we show that 20,000 patients are in this patient population by our estimates. This is a $2-$4 billion market opportunity. We get there through thinking about in the U.S., 48,000 HER2-positive patients, the majority of whom will retain HER2 positivity. We've assumed here 60%-80%, and half or more of those patients should be overexpressing CD47. So with that, I'm going to turn this over to Jason for an introduction to ALX 2004.
Great. Thanks, Barb. So the quick history with ALX 2004, back in 2021, we as a company made the decision to continue to expand our pipeline and brought together a group of really world-class protein engineers, chemists, scientists in Palo Alto to do so. And then from 2021 up until this past summer, did not disclose the program by intent. We certainly felt that the competitive nature made it better, frankly, to keep it under wraps. So that's what we did and made the decision to wait until we were close to the clinic. And I think the opportunity that we really saw is if you look at the validated targets in oncology, there are very few that don't have approved products or late-stage trials that will clearly define standard of care. EGFR has been challenging.
It's been challenging because of the target itself, but also we think because of the design of the prior ADCs. And here with 2004, what we've done is really spent an incredible amount of time and effort in the lab designing this ADC. So I think what's been demonstrated in ADCs is that the epitope selection matters, the antibody matters. And that's been the case with EGFR ADCs. And here we chose a unique epitope, Matuzumab, and we are the only ADC in development with this antibody. And what makes it unique is a big pharma-developed antibody that was designed specifically to devoid the on-target tox associated with the EGFR antibodies. So this antibody continues to have great binding and activity against EGFR without having the known toxicities. Importantly, the second part of what we did is to really spend a lot of time optimizing the linker payload.
Barb will walk through some of our preclinical data, but our goal was to use the most validated payload, which is Topo 1, and spend time optimizing the linker payload, and through that, we were able to improve the on-target delivery as well as have superior bystander effect relative to Enhertu, so that design, that approach then carried through our preclinical work, which we'll give you a very quick snapshot of today, but in a range of models, you'll see a dozen models here quickly, we showed dose-dependent activity irrespective of EGFR expression, which was really important. That carried through into the work we did with CRC-derived model and CRC models and patient-derived models where we showed both in homogeneous and heterogeneous tumors great activity as well.
Importantly, on the safety front, in our NHP work, we did not see the typical EGFR-related tox that you'd expect, which we think is indicative both of the affinity here as well as the epitope, and we also did not see evidence of ILD, which is important as that's been a known safety issue with the Topo class, so quickly, just in terms of the competitive setup and where we see the opportunity, in ADCs, what's been successful is targeting a single target. That's been the simplest approach. That's been what's been easiest to optimize, and that's our approach here. We've taken, again, the most validated payload, which is Topo 1, spent a lot of time optimizing the construct with Topo 1.
We know we're going against a validated target, and as a singular target versus a bispecific ADC, we know exactly how to optimize that, which I think enables better targeting as well as potentially better patient selection because we can use EGFR as a way to select patients. Certainly, last but not least, our antibody has been optimized, and it's different. Most of the ADCs and bispecific ADCs out there are using Cetuximab or Panitumumab, and our differentiation with Matuzumab is really key here. So with that, I'll turn it over to Barb to walk through some of the preclinical data.
All right. So yeah, again, I'm going to show three or four slides that really demonstrate the proof behind the statements that we are expecting. We designed a molecule that should have better target delivery, better bystander effect, lower toxicity, and better efficacy. So this slide really shows you how by stabilizing the linker payload deconjugation, we minimize linker payload release in circulation. This is a study of non-human primates, non-human primate studies, PK study, and it really shows how the linker was designed to deliver more payload to the tumor and not to the periphery, and thus reducing exposure to normal healthy tissues. This study here, there's a few studies on this. These are CDX mice models.
The first three parallel bars there are showing how the rigorous linker payload selection strategy process really matches or exceeds the activity of a DXd linker payload in these models, both in terms of direct killing and on the right, the bystander effect, so these first three set of bars show several CDX models. They have varying degree of EGFR expressions, and again, what you're seeing here is the proportion of mice that have experienced complete tumor eradication, and you see better or equal results for the ALX 2004 molecule versus a comparator. On the fourth set of bars on the right, we show the effect of a bystander model. This contains a mixture of EGFR high cells and EGFR ultra low cells that you would not expect a targeted molecule to be able to target directly and would only be eradicated through a bystander effect.
So again, here, ALX 2004 outperforms the DXd comparator, really supporting the statement that we have improved bystander effect. This slide 29 really shows a snapshot of efficacy data, and we've done a very thorough evaluation. These are tumor types, EGFR expression across a wide variety of EGFR expression density on the cell. There are cells up here that contain the P53 mutation or a KRAS mutation or a BRAF mutation. And across all of these different tumor types, what we see is very remarkable tumor suppression or regression or even tumor eradication. And we're doing so, we're accomplishing this sometimes with one milligram. All of these are one milligram per kilo dosing or show a dose-dependent relationship here. But what we're seeing is either with one single dose or a dose of once weekly times three, we're seeing these types of outcomes.
This really sort of confirms the broad applicability of ALX 2004 in EGFR positive tumor types. This is the NHP summary of our toxicology results, and as you can see, we have both the NOAEL and the HNSTD described here. All findings were minimal to moderate, fully recoverable. This justified a pretty robust starting dose for our phase I study of one milligram per kilo in our first-in-human study, and speaking of that, this is my last slide. It is the study design for that first-in-human study. We've been quite pleased that we were able to start at one milligram. We doubled the dose, which we publicly announced to two milligrams, and then once again doubled the dose to four milligrams, so we are actively enrolling as of last week to the four milligram per kilo every three weeks.
Now, this is a study that includes both a dose escalation component and a dose expansion component of the trial, and it's limited to four tumor types where we feel that EGFR expression will give us a good chance of seeing efficacy over time. Those tumor types include non-small cell lung cancer, head and neck cancer, colorectal cancer, and squamous esophageal cancer, and with that, I think I will pass it back to Jason.
Great. Thanks, Barb. Just to wrap up here in terms of where we're headed, I think 2025 really was a year of data and execution, which sets us up for 2026 here where we have a number of catalysts that are going to be important for both programs. We think we have the opportunity to have two agents that can be first in class and best in class. And our goal at the end of this year is to have both heading on registrational paths. And so looking forward, key for Evo is going to be sharing the interim data in Q3, which I think will further validate this biomarker-driven story and again, set us up for a registrational study Enhertu-positive breast.
On the 2004 front, our goal is to continue to ramp dose escalation, continue to execute at pace as we have, and ultimately share data in the first half of this year to elucidate the promising safety profile that we're seeing, so a lot going on this year, very excited about what we have in front of us, and again, thank you all for the time.
Thank you, Jason. So we'll open it up to questions. If you have a question, please raise your hand and we'll get you a microphone. Otherwise, I can kick us off. So we know there's been quite a few high-profile failures in the CD47 space. What differentiates ALX's platform and why do you think Evorpacept can succeed in this space?
Yeah, I think as we talked about at the beginning, the key is our mechanism. It was different at the time of our company's founding and it remains differentiated today. It is a fundamentally different way to attack this target. The others used CD47 as a tumor-associated antigen, and ultimately that didn't work. And a lot of times in oncology, you don't learn that until the randomized studies. And I think that's what has been demonstrated. What's different for us, and again, demonstrated in a prospective randomized study, is just the strength of the activity and the differentiated safety. And I think that's what is so exciting about this biomarker story is it's right on mechanism. When we have, for example, HER2 expression and CD47 expression, our drug is working and driving transformational benefit to patients.
Great. Thank you. We have a question over here. Yeah, we'll give you a microphone real quick.
Thank you. Super presentation. I have a question mechanistically on ALX 2004. I mean, great design in the way that you've really derived that molecule in the test and the data package presented. Beyond monotherapy, what are the combination approaches that we know already EGFR agents are succeeding? For example, you mentioned KRAS and potential synergisms there. Where would you be once you have that safety established and the dose, the next steps for this agent?
I think in head and neck and lung, I think of PD-1 as a potential way to combine given its activity there. As you mentioned, a BRAF inhibitor or other things in colorectal cancer. I think what we'll do is see which tumor types we see the best activity. I think one of the exciting things about a single agent, if it's got a sufficient response rate, we can go after accelerated approval with a single agent, but then you do have to have a confirmatory trial. You're often also trying to get it up into earlier lines of therapy, and that's where the importance comes in in terms of having a strategy for combination.
I have another one. So the Aspen breast trial, this will be two-pronged. What data do you expect to or results do you expect to be read out in the third quarter of this year? And given that it is a single-arm uncontrolled trial, how will you interpret those results?
Sure. I'll take the first part, but the goal both internally and externally is to deliver meaningful data in Q3. Again, I think what's really important about the design of the study is we have both CD47 high and low, and we'll have patients that we know will be HER2 positive and some that will have not retained expression. And so that setup for us, the ability for us to compare across those groups is going to be very instructive. And if we see data, again, that even remotely approaches what we've shown in these two other studies, to me, that is a whopping success. But do you want to?
In terms of an 80-patient single-arm study, how do you interpret the results? And that's pretty much why I focused on talking about some of these real-world evidence studies. In the past, we had large data sets because breast cancer is so common, and we know that trastuzumab and chemotherapy, whether you're whichever chemotherapy backbone, your response rate is about 20%. And we are not seeing that that has gone up post Enhertu. If anything, it's going down. So I think we have a very solid benchmark of published data. And if we see good results, we'll know that we have something special.
Great. And assuming those results are robust, what are your plans after that? What else is needed to get Evorpacept to market?
We would need to do most likely. It's hard to say if we had a sky-high response rate, maybe we have an opportunity, but essentially, our assumption is it's a phase III randomized comparative trial. I would expect that to look like trastuzumab chemotherapy, dealer's choice, and compared to trastuzumab chemotherapy plus Evorpacept. We are preparing for the likelihood that it would be a CD47 selected patient population where we would expect transformational benefit, but that is really one of the main reasons to run this current 80-patient trial is to have the level of evidence that FDA would require in terms of setting the defined cut point for a patient selection strategy in a future phase III.
To the degree that you're comfortable. Your point number three on ALX 2004 being a highly differentiated ADC, I presume the linker is a key component there, and what comments might you make on why that linker strategy is proving apparently to be very successful?
Yeah, I think that's a great question, and we walked through, I think, just a real high-level snapshot of the internal work we did to optimize that, but it all comes back to the science and the work in the lab. Our team synthesized, I'd say, over 60 different linker payload constructs. We used Enhertu, we used deruxtecan as key comparators, and through that work, we were able to really hone in on this linker, and I think it's important because if we look at the failures from AbbVie, Amgen in this space, they did not have the same linker construct, we know that, and they did not have the same epitope, and I think in terms of modern ADC lessons learned, those things are really important, and there's certainly others that are focused on this.
Again, I think we've benefited from the history here to really optimize this in the lab.
Sure. Maybe one more. Could you talk a little bit more about your partnership with Sanofi for Evorpacept in combination with Sarclisa in multiple myeloma?
Sure. So I think Barb did a nice job of highlighting on one slide our data in solid tumors, but then also our data in HEME, and we have three different data sets in NHL that really validate that Evo is also very active in HEME malignancies. And if you look back to the history of CD47, it really was in HEME, and the reason why it started in HEME is because we know CD47 expression in HEME malignancies is very high, so that's what was the basis for the partnership with Sanofi. That resulted from an inbound outreach from them. They have a really interesting asset with Sarclisa. And the game in multiple myeloma right now is to develop the right combinations, so we're really excited about that study. We're part of a basket study called Umbrella.
We communicated over the summer that it met Sanofi's bar to move to the next phase, and very excited about what that could mean. We see a really large opportunity in multiple myeloma. It's an incredibly large commercial opportunity, and Sanofi's been a great partner, so we're excited about that as well.
Awesome. Thanks, Jason. And thanks, Barbara. I think that concludes our session today. Thank you all for joining us.
Thank you.