Chief Medical Officer, Dr. Barbara Klencke. Happy to pass it on to you guys now.
Great. Thank you. Thanks to TD Cowen for hosting us here. Appreciate it. Here are our forward-looking statements for your review. We are ALX. I'm Jason Lettmann, I'm the CEO. I have Barb Klencke, who is our now permanent CMO, who recently joined us. I'm gonna walk through an overview of the company, share quick highlights over the last year, talk about where we're going at a high level. Barb will share the clinical data. We will wrap up. At ALX, we're advancing two novel treatments in oncology. The first, our lead program, evorpacept, is a novel CD47. We've been working on EVO since 2015 and really have pioneered approach to the target. CD47 is one of the primary ways in which cancer evades the immune system's detection.
We have a very unique approach to that with a dead Fc, which we'll talk about. In fact, that dead Fc has made all the difference in the clinic. We have a series of combinations that we've now run, culminating in five different clinical datasets supporting EVO's activity. We're now laser-focused on a study in breast cancer. We see that as an incredible opportunity, and we also see an opportunity beyond that as again, CD47 is a fundamental target for cancer. Our second program is ALX2004. It's an EGFR-targeted ADC that we developed in-house. We disclosed this program relatively recently over the summer, and that program continues to advance very well in the clinic.
We've taken a novel approach to drugging this target with an ADC, and we'll get into why we think it's a very differentiated asset in a space that's relatively open. We're, as I mentioned, now at advancing that study in dose escalation, which is also going quite well. Again, this is our focus going forward over the next two years. We're hyper-focused on doing two things and doing two things well with these programs. First is our ASPEN breast study. There we're targeting a population post in HER2, which is a really significant need now for these patients. Patients who progress on an HER2 have very few options. We're enrolling that study and expecting top-line data from 80 patients in mid-2027. ALX2004 is also one of our primary focuses.
We are driving forward in dose escalation. That study is going well, and we're expecting safety data in the second half of this year. We also recently raised cash. We closed a financing of $150 million a few weeks ago. That funds us through the first half of 2028 and enables these milestones. Beyond breast, we have several of our studies that have been ongoing and completed. Again, we're actively enrolling our ASPEN breast study. We do have an active collaboration with Sanofi, combining EVO with Sarclisa. That program is now through dose escalation and onto dose optimization. We've completed ASPEN-06. Barb will walk through the data from this. This was the first randomized study in the CD47 space to read out positively and really set the stage for what we're doing now in HER2-positive breast.
As we'll also get into, we have a positive study with our partners at Jazz, combining EVO with Zani, which again, I think furthers the program's validation in the HER2 positive space. Last, actively enrolling ALX2004. Next, just wanna get into EVO quickly and what makes this program different and unique. Again, we are the only company using this approach to CD47, the fundamental basis and insight behind this molecule was separating the signaling. Our drug, evorpacept, provides full and complete blockade of CD47. That's what you see on the top. That EVO uses a dead Fc. In fact, EVO does not engage the Fc activity of a macrophage. It only blocks the CD47 signaling. It only blocks the don't eat me signal.
Then we combine with an anticancer antibody or bispecific, which you see on the bottom. Through that combination, we're able to both drive the eat me signal, block the don't eat me signal, and selectively target cancer via ADCP, via macrophage eating. This is fundamentally different than what's been tried in the past. The conventional CD47s have attempted to use CD47 as a tumor-associated antigen, so in essence, kill more cancer than healthy and do so relatively indiscriminately. That's what you see on the left. CD47 is widely expressed. It's widely expressed on heme cells, and it's widely expressed in red blood cells. So by doing so, they had significant on-target toxicity, where they were activating macrophages against both healthy and cancer. Our approach is different than that.
We have an inactive Fc, so when we block the signal between a red blood cell and a macrophage, there is no activation, and therefore, we avoid the on-target toxicities that others have seen. This has now played out in the clinic over the last 10 years. We've seen now whether it's a combination with Herceptin, Zanidatamab, which is a bispecific, Rituxan, Sarclisa, et cetera. Our approach using the inactive Fc has been validated now in the clinic across a number of different studies, and Barb will walk through the data here to support it. On the other hand, the conventional approaches, the active Fc approach has largely failed or been discontinued. That's been driven by on-target toxicity in a very small therapeutic window that was just impossible to overcome.
This is really the foundation and why we are so excited, why we feel EVO is so de-risked. I'll turn it over to Barb now to walk through some of the data to support that.
Good morning. All right. In the next several slides, I will go through five different datasets that have shown evorpacept's potential. The first two are in the HER2-positive breast cancer and gastric cancer settings, and I'll come back to these two trials and go into these two datasets in a little bit more depth. I'm just starting with this overview. The first study was the ASPEN-06 study that Jason already alluded to. In patients who have both retained their HER2-positive status after prior trastuzumab, as well as having overexpression of CD47, these patients had a remarkable response rate of 65% in a randomized phase 2.
The control arm in that study, patients received HER2-targeted therapy and had a response rate of only 26%, so a 40% delta. The other study shown on this slide is the study that Jas conducted. We're equal partners in that effort. This study was first presented at San Antonio in 2024. In the patients who retained HER2 positivity, we see again a very remarkable response rate of 56% when we combine evorpacept with an anticancer antibody targeting HER2, in this case, Zanidatamab. Again, I'll come back to these two studies in a little bit more depth later. Before that, I wanna go through five q uick studies, sorry, three more of the five. These are all in indolent lymphoma.
The one on the far right with a 92% complete response rate is the first one that I'll mention because this one was just presented at ASH in December of 2025. These three studies were all single-arm studies, you see very robust benchmark studies. That is, benchmark studies being published in the phase 3 setting where complete response rates with historic data were exceeded tremendously by an evorpacept containing regimen. You see a complete response rate in the relapsed refractory indolent lymphoma with EVO combined with Rituxan of 54%. In the second-line setting, EVO and Rituxan plus Revlimid, a complete response rate of 83%. Finally, in the untreated, treatment-naive indolent lymphoma, a 92% complete response rates.
All five of these studies really driving home the point that evorpacept, when combined with an anticancer antibody, can produce remarkable response rates. Let me dive a little deeper into the gastric cancer study. This was second and third-line patients. The treatment backbone therapy was trastuzumab, ramucirumab, and paclitaxel. Evorpacept was added to that in a one-to-one randomization of 127 patients. Out of the 127, we see that 95 of those patients retained HER2 positivity. This was validated either on a fresh biopsy, which was obtained in quite a few patients, in 48 patients who underwent biopsy. All patients underwent ctDNA. Through one or the other, we see retained HER2 status in 95 patients. Those patients were then further subdivided by CD47 expression.
In the patients who had a high CD47 expression, defined here as 10% or more of cells with an IHC of 3+, that's the subset where we expect the greatest benefit, that's the subset that I'll focus on in the next three slides of efficacy. Response rate, I've already shown you once, what you can see here is the response rate first in the patients retaining HER2 positivity then broken out by CD47 expression level, where both CD47 high and low did better than the control arm. On the subsequent slide, we look at duration of response, it's really only the patients who had the CD47 overexpression where you see a tremendous increase in the durability of their response.
Again, second and third-line gastric cancer patients, now we're seeing a duration of response of over two years at 25.5 months. We see this translate into a progression-free survival advantage as well. These are the 2 randomized control arms of patients in the CD47 subset, a hazard ratio of 0.39, and a median PFS in the CD47 high HER2 positive group of 18.4 months. Similarly, the survival was also somewhat better. This is a trend with a hazard ratio of 0.7. We see this type of benefit across all sorts of different cut points.
This was a pre-specified analysis, but it was certainly exploratory in terms of what the ideal or optimal cut point was. We see that whether we're looking at 5% of tumor cells expressing CD47 at high intensity or maybe a quarter of patients, we see benefit across endpoints, across ORR, PFS, and OS. These numbers of CD47 high really look at anywhere from 40% to nearly 60% of the overall population. We didn't have to cherry-pick. This was a pretty consistent result. Finally, just a word on safety. This is shown because this is a large randomized phase II of 127 patients, as I said earlier. This just shows you all adverse events by grade.
It combines the types of adverse events, it essentially is demonstrating that the rates of Grade 3, Grade 4, Grade 5 adverse events were very consistent across the two randomized arms. We've treated actually over 750 patients to date, and we're not seeing the type of toxicity that led to the discontinuation of other CD47 molecules. I'm gonna go a little deeper now into the breast cancer setting. Enhertu is a remarkably effective drug. It's in the first-line setting. Now that it's moved up to first line, there is an open question as to what the best therapy is for patients who are HER2 positive.
There's a great deal of options available, but what has been experienced recently in the past year or two since Enhertu has moved up is that a lot of these agents are not performing as well as they would have without prior Enhertu. What we're seeing is a great need for seriously effective drugs that can continue to keep patients' disease at bay after they've received Enhertu. The study that I alluded to earlier and already showed you this 56% response rate once already, this is in the post-Enhertu setting, and that's the unmet need that the patients and their physicians are looking for outcomes that can reproducibly provide benefit to patients. This was a study, again, presented at San Antonio a year and a quarter ago.
These were late-line patients, a median of six prior lines. In the patients who had confirmed HER2-positive status, 56% response rate. What's new is that we have now completed the exploratory analysis of CD47. We will be showing later this year, in May of 2026 at the ESMO Breast Cancer 2026, data that shows that responses in these patients were largely restricted to those who had CD47 overexpression, very consistent with the ASPEN-06 data. Turning now to the ASPEN-09 study, this is our current ongoing breast cancer study in the HER2-positive breast cancer setting. Like the Xani evorpacept combination, these patients will also be post-Enhertu. All patients must have had prior Enhertu. They will receive evorpacept plus trastuzumab and a chemotherapy of the physician's choice. This is a single-arm trial.
We've recently announced that we will increase the sample size from 80 to up to 120 patients, and the primary endpoint has been refined such that it's now going to report out as a primary endpoint the response rate in CD47 overexpressing subpopulation. As I've just described, this is the population where we have seen the most remarkable results. Now that we have seen it twice with the ASPEN-06 and the zanidatamab combination trials, we really have a lot more confidence that CD47 is a predictive biomarker for benefit, and that's why it's now our primary endpoint. This study began enrollment in January, and we anticipate top-line data for a bulk of the patients, 80 patients by middle of next year. Ultimately, our aim is to bring this drug to market.
The patient population is relatively large. There's approximately 20,000 addressable patients that are in the HER2-positive and CD47 overexpressing population, which represents a very large commercial market. With that, I'm going to now turn for the last few minutes to our second molecule. This is ALX2004. We talked about it briefly at the beginning. Jason introduced it. This is a very unique, well-designed molecule. We have a team of protein engineers at ALX that spent considerable effort thinking about all aspects of the molecule. The EGFR antibody was selected. EGFR is obviously a very validated target.
It's been difficult to develop into an antibody drug conjugate, so we selectively maximize the antibody choice to minimize skin toxicity and to maximize the therapeutic window. There's also a proprietary linker payload and a TOPO1 payload with drug-to-antibody ratio of eight. The activity we hope to be driven by both the EGFR and the payload, the TOPO1 inhibitor payload. The safety, we have seen very good NHP toxicity that allowed us to start the clinical trial a couple of quarters ago at a very robust 1 mg per kg dose level because of the fairly favorable safety that we saw in non-human primates. This target has been tested before by others.
We see in the first column, a lot of potential variables that should optimize the success of ALX2004. When it's been tried in the past, different payloads were utilized. We think that the TOPO1 is the optimal payload, so that's one differentiation. The other category on the end, the third column, the bispecifics, just a bit more complicated to deliver and the secondary target, less validated. With our optimal approach, we feel as though this will maximize the therapeutic window. One more point about the antibody itself. It binds distinctly to a different epitope than the epitope of cetuximab and panitumumab bind to. Why is this important?
Well, we think not only does it have a different, skin toxicity, lower skin toxicity, but I also know that one of the mechanisms of resistance to cetux and other approved EGFR antibodies are mutations in the binding domain. Those will not affect the ability of the matuzumab-based antibody to bind to EGFR, another advantage to our molecule. This slide on slide 30 shows that the linker is stable. The linker payload was really designed to deliver the payload to tumor and not to drop off into the periphery, which hopefully again addresses the therapeutic window. This slide shows a number of different things, but on the far right, it's a bystander model.
One of the effective things with in HER2 is that it has high bystander effect, and we're trying to replicate that. We've shown that in preclinical models that even tumor cells that have low EGFR expression can be quite sensitive to a supernatant that contains ALX2004, thus really confirming in preclinical models the effect of the bystander effect. Here's a variety of in vivo tumor models. These models show that with a single dose weekly 3x that you see a very nice dose-dependent tumor suppression or even complete regression across a number of models.
These models, there's a lot of detail on this slide, that describe the EGFR expression level, it describes the tumor mutational status for p53, BRAF, KRAS. What we see is, although there's some variability and sensitivity, we're seeing very, very nice regression in nearly all of these models. Then one more point about the safety. This is a summary of our GLP non-human primate toxicity studies, and the dose of 20 milligram per kilo in monkeys was a HNSTD. Again, a robust finding that allowed us to start at a 1 mg per kg dose level in the clinic.
The clinical trial has been ongoing for a couple of quarters now, and we've reported that we've been able to nicely start, and then at one, and then double to 2 mg per kg, and then double again to 4 mg per kg given once every three weeks. We're in, we announced probably one month ago that we are in dose level three. We anticipate having additional safety data reported in the second half of this year. We're in the midst of dose exploration, the study is designed to also contain dose expansion. This study is also important in that there's only four tumor types allowed. These are EGFR overexpressing tumors that include lung cancer, head and neck cancer, colorectal cancer, or esophageal squamous cell. With that, I'll hand it back to Jason.
Great. Thanks, Barb. In conclusion, again, we're driving forward towards a big next 18 months. We recently completed a financing, as I mentioned, to support all these efforts, and I think we see two programs that have the potential to change care for patients broadly. EVO, as Barb mentioned, is potentially first in class and best in class for patients that are overexpressing CD47. Again, we know that CD47 is a very important pathway, and we believe we have the drug to effectively address these patients. And doing so in the post and HER2 breast cancer setting represents a really significant opportunity to change the lives of these patients and also represents a really good place for us to start.
Again, CD47 is implicated across a range of tumors. From breast, we have the opportunity to go, you know, both into other solid as well as heme malignancies. On the 2004 front, it's a very differentiated ADC. We are the only ADC that we're aware of in development using matuzumab as our epitope, and we've spent an incredible amount of time in-house optimizing the linker payload construct. Taken together, we're very excited about what we have. Again, EGFR is a well-validated target. These patients also are in need of new options, and we think ALX 2004 can deliver for them. Again, lastly, we're coming off a very strong 2025. We reported data across seven or eight different clinical studies.
We know where evorpacept works. We know where it works the best. ALX2004 has also progressed well. That momentum carried us through into this year, allowed us to raise an oversubscribed financing of $150 million, and with the existing cash allows us to execute on both programs with the goal of having both programs pivotal-ready by the end of next year. Again, very excited, very grateful for what we have at ALX, and happy to take questions. Thank you so much. If there are questions. No? One.
What are the thoughts in terms of taking these programs forward? Would you like to sort of, take them all the way to the finish line or potentially partner with other companies?
Yeah, it's a great question. I think with the balance sheet strengthened, we certainly have opportunity now to execute, and our focus right now is on execution on both of these studies. You know, I think certainly with safety and efficacy from 2004, as well as the data from our breast study, I think that's gonna enable two pretty significant inflection points for us. We are also talking to partners. We've been successful historically with that. Our collaboration with Sanofi, for example, is a good example of what we can do. Combining with Sarclisa and multiple myeloma is a really significant opportunity. And we have the opportunity with EVO to combine both with approved antibodies, as well as emerging antibodies and bispecifics.
I think that opportunity from a BD perspective is very real and something that we will continue to explore. With ALX2004 earlier stage program, and I think what we see there is certainly a lot of inbound pharma interest as well. Our view is delivering, you know, I think safety at the right dose as well as efficacy signal is the next big inflection point. We're heads down on that program and planning to deliver data there as well. No question that we continue to advance BD conversations, but I think for us right now, it's really execution first. Great. No more questions. Thank you so much. Appreciate it.