Hi, everyone. Welcome. My name is Luka Kachukhashvili. I'm an associate here on the healthcare IB team. Logistically, we'll go through the presentation, and then I'll open it up for Q&A. My pleasure to introduce Jason Lettmann, ALX Oncology CEO.
Great. Thanks, Luka. Thanks to JPM for having us. I have the ALX team with me here with Alan Sandler, who's our Chief Medical Officer, Ally Dillon, who's our Chief Business Officer, and then Jaume Pons, who's our founder, CSO, and president. So thrilled to be here. It's been a great meeting for us, and thanks to you all for your interest in our company. We're going to make some forward-looking statements here today. As part of our. Oops, let me go back one. So one of the things we've been working on is how we tell this story. We picked Starlings because we are nature lovers, and one of the things we're trying to do at ALX is harness the power of the immune system, and specifically in macrophage biology.
Starlings, as you know, move in packs, and one of the things we've been working on is using Evorpacept to drive macrophages to the right place. We're very excited about what we've accomplished on that. We are developing Evorpacept, as I mentioned. It's a novel, first-in-class, we believe best-in-class approach to cancer treatment. We are operating in the CD47 space, and importantly, in what we're going to touch on today is the validation that we have. We've been executing the program now for almost a decade, and we are the first and only CD47 to have validated randomized data in phase two in gastric cancer, which we'll talk about. The safety and tolerability has been consistent.
We've now dosed over 700 patients and have shown an ability to treat cancer in a way that is safe, particularly when compared to the conventional approaches that came before us. We have applicability across solid and heme, which we'll talk to. We're able to dose very high, and again, this is a unique approach to activating the immune system. We're running several trials, as we'll get into today, across head and neck, gastric, breast, bladder, et cetera, and we are in a great spot. We have a ton of catalysts coming this year. We're coming off significant readouts last year and are looking forward to the next year and the next six months in particular. So as we'll get into, we're developing a novel IO approach. Again, have dosed over 700 patients to date.
We are the only CD47 to show ORR, as well as overall efficacy relative to the class, and it dates back to the mechanism. From the early days when Jaume and the scientific team founded the company off of a Nature article in 2014, this dead Fc approach to approaching the target is truly, truly differentiated. And the good news is that early work has now translated into the clinic, where we have multiple positive readouts to support the thesis. We are testing the drug across three major classes. We have three major shots on goal here: first with anticancer antibodies, second with checkpoint inhibitors, and then last but not least with ADCs. We've had the benefit of several great partners: Merck, Lilly, Sanofi to help support us, and we have a strong balance sheet to be able to play these milestones through over the next year.
We'll talk a little bit about the data to date. We're coming off good data at San Antonio in December in combination with Zani, which really validates this approach in breast cancer, and we have an oral presentation coming up a week from tomorrow at ASCO GI, where we're going to share updated data in our gastric study, ASPEN-06, so as I mentioned, here's where we are in terms of the pipeline. Again, we've been really testing this molecule across a wide range of indications, so ASPEN-06 on the top there is what we're pursuing within gastric cancer, and we'll talk about that. Within head and neck, we're pursuing ASPEN-03 and ASPEN-04, which are frontline head and neck studies in combination with Keytruda or in combination with Keytruda plus chemo.
Across those two studies, we have over 300 patients enrolled, and we are going to be reporting data from that in the first half of the year as well. We're also exploring ADC combinations, so one with Padcev, the second with Enhertu. We believe that Evorpacept should be able to be combined with both, and then we also have, as I mentioned, a collaboration with Sanofi to look at the combination with Sarclisa. So mechanistically, and we've just redid our graphics here to try to simplify the mechanism, the first approach is to unmask cancer. So CD47 is one of the primary modes in which cancer evades the immune system. So the first thing we do is unmask cancer. The second thing we do, in combining with an anticancer antibody, is to unleash and drive the immune system against it.
So as you can see here in the graphic, we're able to do so both with a macrophage. So when we combine with an anticancer antibody, we drive ADCP, and we're also - we do it with dendritic cell signaling. So that's how the drug works. Importantly, we've built this to do this in a safe way. So we have the highest CD47 blockade among the class. We have a dead Fc, which is very important, and we have a low molecular weight to drive, sorry, excuse me, to drive increased solid tumor penetration. We also have antibody-like PK, which enables us to do so. This is how we compare with others, and again, I think it's really important to look at what's been done in the class. So we have successfully differentiated the molecule from the beginning via the dead Fc.
So we have clinically validated now in an inactive way, sorry, I'm losing my breath here. I may have you take over for a minute, Alan, on this section. Do you want to talk about differentiation?
Yeah.
Sure. Thanks.
Okay. Yeah, so let me see where we're at here. So again, demonstrated again tolerability and clinical activity, and we're looking at the concept of the inactive Fc domain. The purpose for that is to avoid collateral damage and toxicities, and requiring then a partner antibody to have the active Fc domain to sort of drive the therapeutic effect for the immune system, avoiding then the collateral damage and toxicity. This will therefore allow for a broader therapeutic window and higher CD47 affinity, again, because of the fact that you can concentrate solely on that CD47 without worrying about its effects collaterally outside of the tumor with what the other generation of active Fc domain. Change here. All right, so again, this mechanism, as I've mentioned, enhances that therapeutic activity. Three potentially different modalities across both hematologic and solid tumors. Two potential first-in-class mechanisms of action.
Again, you have the don't-eat-me signal and then the don't-activate for T cells. The opportunities can be combined. Therefore, you have the dead Fc. You need another partner to direct it for its therapeutic effect. Those are three different choices that are done here. You have anticancer antibodies, which would have that active Fc component, and this can be done. We've got the phase two study in gastric and GEJ cancer, and we also have it in multiple myeloma with Sarclisa, non-Hodgkin's lymphoma, and a recent breast cancer study that was presented at San Antonio with zanidatamab. In addition, you can combine with antibody-drug conjugates. We have a urothelial carcinoma study with Padcev, a 1b study, and also we're in the midst of a study with I-SPY and IST looking at a combination with Enhertu.
In addition, another aspect is to combine with checkpoint inhibitors, and we have several studies looking at this with Keytruda in head and neck cancer, both with and without chemotherapy, an ovarian cancer study with Keytruda with chemotherapy, and then we also have a neoadjuvant study with human papillomavirus in oropharynx cancer, again with Keytruda in this particular setting. So the breadth of the clinical data supporting Evorpacept's potential to deliver is again shown here with the various study types. Strong activity that's been observed across six different clinical trials to date. There are now 10 ongoing studies across nine tumor types. This includes some ISTs as well. And Evorpacept is the only CD47 blocker that's been able to demonstrate activity across both hematologic and solid tumor cancers.
Importantly, and I think this is something that we'll be seeing coming up later this year, but Evorpacept is the only CD47 that's demonstrated positive data in large randomized phase two study. We've talked about the gastric cancer data and head and neck cancer will be forthcoming. Let's see.
Yeah, I'm happy to. Thanks. So as Alan mentioned, the key thing is we're testing this across three combinations. Here we're going to walk through the mechanism within gastric cancer and combining with Herceptin. I think the key points here to look at in the cartoon is that when we combine with Herceptin, of course, we need HER2-directed therapy. We need a HER2 target in order to drive ADCP. So here is the demographics of the study. Again, it was a global randomized study. We enrolled patients across 10 countries in a robust study to look and isolate the power of Evorpacept in this combination. Importantly, HER2 expression is highly variable in gastric cancer in particular.
It's a heterogeneous tumor type, so the ability to detect HER2 expression is challenging from the beginning, and we know over time that HER2 expression is lost, and we'll get into why this is important, but again, our mechanism requires HER2 expression in order to work. This is how the study was designed. Again, 127 patients randomized. Importantly, we had 48 patients of the 127 with fresh biopsy. Those patients are indicative of patients with strong HER2 expression, and that was an important part of our primary analysis to look at that patient group. We are looking at improvements in ORR, both versus historical control, as well as our control arm. This is the safety.
Again, I think as we've highlighted, we have a very differentiated safety profile, and here what you can see when comparing the results across the two arms, the eTRP arm and the TRP arm, we have not seen any significant safety signal, which again is differentiated in the class. This is what we reported in July in terms of top-line results. Again, very pleased to see an over 40% ORR rate on the treatment arm versus 26.6% on control, and I think one of the elements we were most excited about is to see the durability. So here we had a median DOR of 15.7 months versus 7.6 months on control, which again is far and above both what we saw in the control arm as well as historically what we've seen with both Enhertu and RamPac.
As I mentioned, we need HER2 expression in order for our drug to work and work best, and so when we looked at the fresh population, this is where we saw the strongest signal of almost a 55% ORR versus a 23% on control, and as we mentioned, both of these data sets compare favorably with historical benchmarks. From a tumor shrinkage perspective, again, we've seen consistent shrinkage across the data set, which really tells you something about the depth of the response. So in sum, this was the first randomized study in the space to show positive data. Again, this opens the door for us to combine with multiple cancer antibodies and sets the stage for where we go from here as it relates to combining with anticancer antibodies.
As we mentioned, we have data coming a week from tomorrow at ASCO GI, which will give more detail as to how this study has matured. We've talked about where we go and what this opens up to, and one of the studies that we also reported on recently is in breast cancer with zanidatamab. zanidatamab is an Fc-active bispecific, and the reason to run this study was again to show can we do the same thing with another Fc-active antibody in a large indication like breast cancer. We reported this data at San Antonio in December, as I mentioned.
I think the important thing to note from a baseline perspective is that we've treated patients here that have seen a lot of HER2-directed therapy, so on average, these patients have seen five to six prior lines of HER2 therapy, and importantly, in cohort one, all of the patients had been exposed and progressed Enhertu . Here, what we demonstrated was in cohort one, we saw a very strong signal, and the strongest signal again was in the patients that were confirmed HER2 positive by central lab, and in those patients, we saw a response of five out of nine or over 55%, which again, in a patient population that has seen a lot of HER2-directed therapy, certainly over and above what would be expected.
Waterfall plots again are really encouraging as we saw significant lesion reduction across both cohorts, and cohort two here is a HER2 low cohort, so again, a very consistent signal. Same with swimmer plots. The swimmers here, I think, are impressive in that we had eight patients that were on treatment for more than six months and four beyond a year, which again is encouraging and I think indicative of an IO agent. So lining up the two, and I think what we're excited about here is the story within gastric. HER2 positive gastric is very similar to what we've seen with HER2 positive breast.
So again, strong activity and the strongest activity when we have a biomarker at work, and we've had a very well-tolerated agent, and again, in patients that have progressed on prior HER2-directed therapy, which really builds our conviction as to what we're doing and that we're doing something over and beyond what you'd expect with a HER2-directed therapy alone. So the last part of this, we'll talk about where we're going beyond just anticancer antibodies. So we are also looking at combinations with checkpoint inhibitors. Again, CD47 also signals via dendritic cell signaling to prime T cells, and so in this way, we're able to take a different approach to the same mechanism, which is what this highlights. Again, mechanistically, by blocking the CD47 signal via the dendritic cell, we're able to better cross prime T cells and in a way release another brake.
So when combining with Pembro, it's in essence releasing two breaks. So to test this, we're doing two large randomized studies in front line, head and neck. Across these two studies, we have over 300 patients that we have enrolled, and we're going to be reporting on this data also first half. So excited about this. Again, this will be one of the largest data sets to report in front line, head and neck in a while and potentially could form the basis for an accelerated approval. This highlights how we got here. We first ran a phase 1b study to deliver the proof of concept, and here what we showed is a 40% ORR in patients with Evorpacept plus Keytruda.
Again, the benchmark in the KEYNOTE studies was 20%, so we saw an encouraging ORR gain, and I think most encouraging was what we saw on the OS side, where we had a 12-month OS of north of 80% and a median OS of not reached in the front line and then over two years in the second line setting. Again, I think this was a strong proof of concept for us and provide the basis for the two large phase two studies that we're running. Again, these are the benchmarks. I think if you look at KEYNOTE-0 48, importantly, Pembro showed between a 19% and then a 36% ORR with chemo, and what really drove the approval here was not ORR or PFS, which was essentially on par with control, but what they ultimately showed in terms of OS.
And I think for us, mechanistically, when you're again combining another IO agent, we would expect results to be similar and improve on what KEYNOTE-048 demonstrated. So the next couple slides just touch on the third leg of the stool. As I mentioned before, we have three large shots on goal with antibodies, checkpoints, and ADCs. We're running two ADC studies, one with Padcev and the other with Enhertu, and mechanistically, it's similar but different. An ADC, of course, is an antibody with a payload. By combining with an ADC, we think we can bring a different mechanism to the table through driving macrophage activation against cancer, and that's why we initiated these two studies. There's a strong preclinical foundation for this.
We've looked at combining Evorpacept with Enhertu and CDX models and have shown that the effect is additive and over and above what you'd expect with Enhertu alone, and we've shown that this effect we believe is largely driven through ADCP, and again, when we've looked at Padcev or with Enhertu, we're able to drive additional ADCP. So those are the two studies we're running. One is ASPEN-0 7 with Padcev. We shared data at ASCO last year, which was the first data to combine Evorpacept with an ADC or a CD47 broadly with an ADC, and excited about updating that, and then we also are in the midst of running a study with I-SPY with Enhertu, and I think that'll provide another proof of concept data point for us on the ADC story. So before I wrap up, we're excited about the team. I've introduced the folks here.
We've been building and adding to the team. Alan Sandler, our CMO, just joined us recently, formerly at Mirati and Zai Lab, and then Ally Dillon joined us about six months ago, formerly at Calithera, and have continued to strengthen and add to the team as we go into the year. So it's a big vision. Again, three big shots on goal for us here, testing nine different combinations. We think this drug across either of the three could represent a major franchise from a commercial perspective, and the combinations we've been running are in very important and large markets with drugs that obviously you all know with Herceptin and Rituxan and HER2 and Keytruda. So the foundation here is strong, and I think the commercial opportunity is significant. So as we mentioned, we have data coming on the gastric front next week, so please tune into that.
That'll be an oral presentation on Thursday. We have ASPEN-03 and ASPEN-04 reading out first half of the year, and then we're going to be sharing additional data on the ADC front with both the data from ASPEN-07 with Padcev coming as well as with Enhertu. And then last but not least, I wanted to mention we're having an R&D day in February, which is really going to lay out the path to registration here. We've been in a very data-rich mode the last year, and the goal for us at this event will be to tie that together and show the street where we're headed from a development perspective and are working on, have been working on that the last few months. Last but certainly not least, in this environment, we're well capitalized.
We have about $160 million on the balance sheet as of last quarter, which gets us through Q1 of 2026. So with that, I will open it up to questions, but thank you all.
Thank you very much, Jason and team. I guess I can kick off Q&A. I was just wondering your thoughts on just investor sentiment on the CD space. I know there's been some negative sentiment there and just what do you think investors are missing there?
Yeah, sure. I mean, CD47 certainly has had its share of failures, I think as many of you know. I think where we have a lot of conviction is, A, there's no question that this pathway is incredibly important. It is a primary mode of evasion for the immune system, and I think interestingly here, we are the only company taking the approach with the dead Fc. Starting with 47 and then Trillium and others, with those two large acquisitions, much of the field followed there with an active Fc, and our dead Fc approach is very different. It's fundamentally a different mechanism.
I think what we're seeing now is that translates into having five positive clinical trials with anticancer antibodies is really validating, and I think when we've got this combination right and we've had the success in the clinic, so for us, I think the clinical data really speaks volumes as to how we're different.
Super helpful. Thank you.
Hi, very good presentation, Parag Mahanti. You mentioned in one of the slides you're doing neoadjuvant therapy with Keytruda in HPV positive head and neck cancer, but I didn't see any data on that one. So what's the inclusion criteria for those patients? Because the HPV positive head and neck cancer patients generally tend to do fairly all right, so just wondering what's the rationale behind it and is there any data on that? Are you in phase two on that one or?
Yeah, it's a great question. So within ASPEN-03 and ASPEN-04, we're enrolling both HPV positive and negative, which is a key differentiator for our drug. We think we should be able to work in both despite the prognosis across the two being different. So it is, of course, as you guessed, a stratification factor in the study, but we're looking forward to looking at the data when we have it here first half of the year across both of those populations.
Right, but you mentioned here on the HPV positive population, so this is a population that gets radiation as a definitive treatment after neoadjuvant or they get other surgical candidates included as well in HPV positive?
Yeah, well, there are. I'm trying to think if there's surgical candidates included, Alan. I don't know if you know the answer to that, but we have.
Yeah.
Go ahead.
Just wondering if you're referring to the oropharynx?
Yeah.
Right, that was the IST.
Okay, right.
Which we don't have a lot of information on yet, but of course, it's not a study run by us right now. So just to clarify that that was an IST that's going, it's not an ALX run study.
Right, and you are doing HPV negative as well neoadjuvant study right now, right?
In ASPEN-03 and ASPEN-04, correct.
Thank you.
Yeah, those are not neoadjuvant studies 3 and 4. Those are first line. So Aspen.
ASPEN-03/04 is exactly.
Right.
Okay, metastatic front line.
Yeah.
Thank you. For me, I was wondering, I know you're going to be releasing ASPEN-06 data next week. Is there a kind of a 100-foot view you can give us, any teasers ahead of that?
Yeah, no, I think it's, you know, when we shared the data in July, certainly excited about what we were seeing. I think it was still maturing at the time. So one of the questions from the street has been, you know, what more can you say on PFS? So we're going to report PFS both across the ITT populations as well as in the FISH population. I think the other big question has been, you know, this HER2 expression story is interesting. What other methods have you used to look at HER2 expression? So have you looked at ctDNA, for example, and is this phenomenon the same with a circulating read? So for patients that are HER2 positive via liquid biopsy, is it the same story as patients that have a FISH biopsy?
So we're going to be sharing data from all patients where we have ctDNA data, and again, I think it's very important for us because it's on mechanism and allows us to have a really powerful tool in which to select the right patients.
Thank you. Any questions from the audience? If not, I think we can call it. Thank you so much, Jason and team, and best of luck in the future.
Sounds good. Thank you. Appreciate it.