ALX Oncology Holdings (NASDAQ:ALXO) Q1 2026 Earnings Call

0:01 Greetings, and welcome to the ALX Oncology First Quarter twenty twenty six Financial Results Conference and Webcast. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentation. Please note this conference is being recorded. I will now turn the conference over to your host, Jason Letman, CEO. Please go ahead, sir. Thanks, everyone, and welcome to our Q1 twenty twenty six results. Really appreciate you all spending time with us this morning and are, looking forward to sharing these updates with you. On slide two, and before we start our presentation as housekeeping, here are our forward looking statements for your review.

0:53 On slide three, here's the agenda and plan for today. We're gonna be providing an update on our key accomplishments in the first quarter of twenty twenty six. Most notably, we are very excited to share with you the dataset that was presented yesterday in Munich at ESMO Breast twenty twenty six from the analysis of our trial evaluating evaporcept and zanidatumab, which clearly showed again that c d 47 expression is a key predictive biomarker for increasing durable clinical response in heavily pretreated HER two positive patients. This further validates the results we saw with EVO and HER two positive gastric cancer from our ASPEN six trial. We are also very excited today to be joined by doctor Sarah Hervetz from the Fred Hutch Cancer Center at the University of Washington, who is a well recognized expert in metastatic breast cancer.

1:46 She will be presenting the ESMO breast data in detail and also share her views on evobracept's significant potential within the current treatment paradigm for HER two positive metastatic breast cancer. Our CMO, Barb Quincke, will then recap our findings to date with eve EVO and HER two positive cancers across now two different independent trials and indications showing that patients with high c d 47 expression derive the greatest benefit across all key efficacy markers, including overall response rates, duration of response, and PFS versus those with low expression. These results support our targeted oncology approach with EVO, notably our ongoing ASPEN nine breast cancer phase two trial.

2:33 Barb will then provide an update from our ongoing phase one trial with our novel EGFR targeted ADC, ALX two thousand four, which also continues to track the plan, and we are enthusiastic about its potential to also change care in eGFR expressing cancers. So on slide four, we continue to advance both our programs, EVO and ALX two thousand four, and are pleased with the progress on both fronts over the course of q one and remain well positioned to report on significant data readouts from these programs in the coming twelve to eighteen months. On the EVO front, c d forty seven, as you know, is incredibly important in oncology and has been a very difficult target to crack, yet it plays a fundamental role in tumor evasion and resistance.

3:20 We've been happy to see EVO's differentiated approach to this target further validated in the clinic over now five different datasets, including randomized data. Further, the new data from this week's ESMO meeting and over the last year support CD47 as a strong and predictive biomarker. These new findings further support the drug is working as designed and also enables a targeted strategy, which allows us to focus on the patients who will benefit most. On ALX two thousand four, as you know, it is a highly differentiated eGFR targeted ADC, which was developed in house by ALX and has the potential to be a first in class eGFR targeted ADC. EGFR has also been a difficult target for ADCs historically, and ALX two thousand four was designed to address this with a novel epitope and linker payload construct.

4:12 We have been pleased to see the strong preclinical data to date translate to the clinic and with the continued strong progress in dose escalation, we have been able to further increase dose. Overall, both programs remain on track and well positioned. Now on Slide four, Q1 was a quarter of continued good execution and additional positive data as well as completion of key hires and a strong financing. As you'll hear more about shortly, this week's data validate again the power of c d forty seven in a late stage patient population. Here, we observed that all patients who were confirmed HER two positive and c d forty seven high achieved a response, including one complete response. We also yet again saw the durability that one hopes to see with an IO mechanism with a median duration of response of twenty months and a median PFS of twenty two months, which is clearly far improved over the benchmarks.

5:11 While the focus for today will be on this new data set with EVO, ALX two thousand four is also progressing through dose escalation very well and remains on track for initial safety readout in the second half of this year. We remain as excited here about its potential as we do with EVO. Further, the financing from February, which was anchored by very strong investors, further strengthens the balance sheet and enables us to execute through these important data milestones. And last but certainly not least, we added Jeff Knight, who is now our chief development and chief operating officer, which really further strengthens our leadership team. Jeff, as you may know, is one of the best operators in biotech in terms of building companies at our stage through the next phase, including commercialization.

5:58 On slide six briefly, this just highlights the execution, clinical development progress, and timelines which remain on track for both programs. Our evorpocep phase two breast trial continues to progress well with strong enrollment globally and increasing site enthusiasm. Overall, clinical timelines remain on track as we're expected to read out 80 patients mid next year. ALX two thousand four, as I mentioned, is also progressing well with enrollment and dose escalation ramping and are and are on track there for an initial safety readout in the second half of this year. Our goal and vision for both of these programs also remains unchanged as we aim to have both programs ready for registrational studies by end of next year. On slide seven, on my last slide, here's also a snapshot of our clinical pipeline.

6:49 As you know, we're advancing two novel cancer treatments with key near term catalysts. And again, ASPEN breast is on track, and we continue to also be encouraged by our ongoing study with our partner Sanofi, ST, EVO, and multiple myeloma. Our two studies in HER two positive cancers have now been completed as we'll focus on today, and ALX two thousand four also remains on track. I'd like to now turn the call to Barb, who will provide a quick reminder of our MOA, which is very important as we're clearly seeing it translate to the clinic, and will then turn the call over to Doctor. Herwitz to review the new data. Barb? Thank you, Jason. These next few slides describe aborapicept's mechanism of action. What's so compelling to me is that the mechanism of action is entirely consistent with what we see in the clinical trials.

7:40 So let me just go through this. Cancer cells commonly upregulate CD47 expression to evade immune detection. Avorpicept blocks the CD47 signaling, but it does so without an active Fc domain. So if warpocet by itself does not engage the phagocytic activity of a macrophage, we need to combine a warpocet with an anticancer antibody. And then the combination together strongly augments the ADCP activity of the antibody. And that's likely what results in the efficacy that we see in the studies that we'll talk about today. Essentially, the antibody stimulates the eat me signal, and the avoricep inhibits the don't eat me signal.

8:28 Therefore, the combinations of avoricep with an antibody are selectively enhancing or augmenting macrophage phagocytosis of cells that express HER2, for example, in the case of a HER2 targeted antibody, while also blocking the don't eat me signal. On the next slide we see how this mechanism of action translates into safety. Our clinical safety database is now more than eight hundred of Orpicep treated patients. And it also the clinical safety data is also entirely consistent with this mechanism of action that we show here. If Orpicep was designed again without an active Fc domain, That's shown on the right side of the slide.

9:18 So when we block the don't eat me signal on normal healthy cells such as red blood cells, there is no macrophage activation, and we avoid on target toxicities. This isn't really fundamentally different than what's been tried in the past by conventional CD47 inhibitors, which have essentially failed in the clinic. They attempted to use CD47 as a tumor associated antigen with both an active Fc domain to activate macrophage at the same time of blocking CD47. That ended up being an indiscriminate approach because CD47 is so widely expressed on healthy cells, especially hematologic cells in particular.

10:06 And that led to the potential for significant on target toxicity. So with that description of vorapicep, its mechanism of action and its differentiation, let me now turn the conversation over to Doctor. Sarah Hurwitz. On slide 12, you can see her background here. She is a steering committee member for our ASPEN-nine Phase II study of Avorapicep in HER2 positive breast cancer patients. She was an investigator on the ovorapacep and zanidatinib trial that we'll discuss today. And she's a senior vice president, a professor of clinical research, and the director of the Clinical Research Division at the Fred Hutch Cancer Center at the University of Washington in Seattle, where she's also the head of the Division of Hematology and Oncology and the Smith Family Endowed Chair of Women's Health.

11:06 She's an expert in the management of breast cancer and in the development of novel targeted therapies for breast cancer. Sarah? Thanks, Barb. I'm really excited to be here today. There have been remarkable changes in the management of HER two positive breast cancer, especially since 2020, with new agents like trastuzumab deruxtecan and tucatinib demonstrating benefits in pretreated disease. And with the results of DESTINI Breast-nine showing benefits with TDXD in combination with pertuzumab, we have a new standard of care according to our NCCN guidelines as of this February. What we don't know is how we should be treating patients after they've received an HER2.

11:51 This remains an area of unmet need. On slide 14, you can see this graph showing the outcomes that we have from patients who've received prior INHER2 treatment with a median progression free survival of only four point one months. What we don't have are randomized prospective data telling us as clinicians how we should manage patients after TDXD, but observational and retrospective datasets are fairly consistent showing that PFS rates of under six months is what patients experience post TDXD. On the next slide, on slide 15, you can see the list of HER2 directed therapies that we have approved and in late stage development on the left side.

12:41 These include HER2 targeted antibodies and bispecifics, HER2 targeted antibody drug conjugates, and HER two targeted tyrosine kinase inhibitors as well. What we don't have are immuno oncology therapies approved or in late stage development outside of evorpocept. And so this remains an area that's very exciting to see developed now. On slide 16 you can see the range of CD47 expression in normal cells versus tumor cells. As explained before, CD47 is expressed on all cell types and is a marker of cells.

13:27 And cancer cells can take advantage of this by overexpressing CD47, allowing them to hide from the immune system. Focusing on the left there, you can see highlighted in blue breast cancer cell lines which actually do have higher expression of CD47 in tumors compared to normal, which is highlighted in black. On slide 17 you can see a meta analysis of 38 cohorts across 17 publications, which included over 7,000 patients demonstrating fairly consistently that CD47 overexpression was correlated with shorter survival in patients with cancer. So it's a negative prognostic biomarker.

14:16 On slide 18 there are data here relating to CD47 expression in breast cancer, in particular in HER2 positive breast cancer. On the left you can see that CD47 expression is higher on HER2 positive breast cancer cells versus HER2 negative on the right. High expression is denoted in the dark blue, moderate expression in green, and low expression in blue. So HER two positive breast cancer cells appear to have a lot more c d 47 expressed than CD than HER2 negative breast cancer cells. And in fact, if you look on the right side, you can see that CD47 high cells are more common in recurrent HER2 positive breast cancer, shown on the left side, compared to primary or initially diagnosed breast cancer.

15:10 And so these data provide strong rationale for us to be evaluating of Orpicep in HER2 positive recurrent or metastatic pretreated disease. On slide 19 you can see some elegant data demonstrating that TDXD treatment may actually upregulate expression of CD47, again providing strong rationale to treat HER2 positive recurrent TDXC pretreated breast cancer with Avorpaset. On slide 20 you can see the title slide for the data presented recently at ESMO breast. This is an exploratory biomarker analysis from our Phase 1btwo trial of zanidatumab, a HER2 targeted bispecific in combination with the vorpicep in patients with HER2 positive metastatic disease.

16:07 Slide 21 gives you an overview of the study design. This is a Phase 1btwo study. And we presented the safety dose escalation cohort data from three patients with HER two positive breast cancer enrolled and data from cohort one where twenty one patients with HER two positive breast cancer were enrolled who had received at least three prior regimens. The exploratory biomarker analyses focused on these twenty four patients, and it's notable that all of the HER2 positive cohort received prior TDXC and a median of five prior lines of HER two targeted therapies. This is extremely heavily treat pretreated disease.

16:56 The patients were allowed to enter the study based on prior local HER two testing of their archival tissue. However, fresh baseline biopsies were obtained in most patients and tested retrospectively for HER two status by central assessment. And we'll be reviewing outcome results based on the central assessment as well as the intent to treat population. In addition, patients' tumors were tested for CD47 expression on the fresh baseline tumor biopsies or on archival tissue if if fresh biopsies were not available. Patients were treated with sanidatumab at twelve hundred milligrams for those patients weighing less than seventy kilograms and at sixteen hundred milligrams for patients seventy kilograms or greater.

17:50 The evorpicept was given at twenty mgs per kg for these three patients enrolled in the 1A or at thirty mg per kg IV every two weeks for the rest of the patients. Going on to slide 22, we're jumping to the efficacy outcome data. What you can see here are the confirmed objective response rate on the top row based on all 24 patients, which is thirty three percent. I find personally these data to be quite impressive in patients who've received a median of five prior lines of therapy, including TDXD. If you go down to the duration of response, those patients who experienced a response had a duration of response of twenty months and a median progression free survival of three point six months.

18:47 This next column shows the outcomes for the six excuse me, for the 10 patients who had centrally confirmed HER2 positive breast cancer where the objective response rate was now sixty percent, the duration of response was twenty point two months, and the median PFS was eight point three months. These data I think are impressive as we reflect back on the fact that our retrospective and observational data suggests that patients pretreated with TDXD have a median PFS of less than six months. So I find these data to be quite compelling and exciting. Those patients who did not have centrally confirmed HER2 positive disease had a lower objective response rate of fourteen percent.

19:34 On slide 23 we can now see breakdown based on the tumor CD47 expression levels. Using a cutoff of at least twenty percent for CD47 expression, there are five patients who had both centrally confirmed HER two positive disease and CD47 positive or greater than or equal to 20% expression. All patients had an objective response in this cohort of five patients with a median DOR of twenty point two months. However, those patients whose CD47 expression was less than 20%, that's four patients, only one had an objective response.

20:20 So this is beginning to give us data that CD47 expression level may be a marker to help us select patients particularly responsive to this targeted therapy. On slide 24, you can see a Kaplan Meier curve for progression free survival based on CD47 expression levels. So the progression free survival with a CD47 expression level of at least 20%, you can see the PFS is twenty two months. For those patients less than twenty percent, the PFS is three point four months. Again, although these numbers are very small, we're talking about nine patients total, interesting and I'm excited to see them hopefully confirmed in the larger study.

21:13 On slide 25 are our conclusions. For this exploratory analysis of our Phase Ibtwo study, of Orpicep and zanidatumab showed promising antitumor activity in patients with heavily pretreated HER two positive metastatic breast cancer, median of five prior lines of therapy, all of whom received via TDXD. Greater antitumor activity was seen in patients with centrally confirmed HER2 positive disease. Durable responses were seen in this patient population and seemed to be largely observed in patients with higher CD47 expression, supporting a CD47 dependent HER2 driven biology that resulted in this prolonged progression free survival.

22:04 It's notable that most patients with essentially confirmed HER2 positive disease remained HER2 amplified at progression with TDXD, supporting the continued use of HER2 targeted therapies. And so a biomarker driven approach incorporating CD47 may optimize patient selection for this combination regimen and warrants further study. So with that, I will turn it back over to Barb. Thank you, Sarah, for that excellent presentation. As we've seen, all of the patients who were centrally assessed as HER2 positive and who overexpressed CD47 in their cancer cells achieved confirmed response to the combination of Avoropacet plus Anidatinib.

22:51 What's new on slide 27 in the table on the right side of this slide are the individual CD47 expression levels and the confirmed response assessments for each of the 10 patients with centrally assessed HER2 positive disease. An IHC assay was used to quantify the total membrane staining for CD47. A positive result was defined retrospectively as a score of 20% or higher, which we observed in the patients shown in the top five rows highlighted with deep blue. All five of these patients with CD47 expression responded, including one patient with a complete response. That patient happened to be the only patient from the dose escalation cohort that was centrally assessed as HER2 positive.

23:40 There was no evidence of CD47 over overexpression in the four patients highlighted in light gray, one of whom responded to the evorpocep and zanidatinib combination. And then in the last row in this table is a patient who was unevaluable for either response or CD47 expression level. On slide 28, I want to highlight the consistency that we see between the results of the evorpocep zanidatinib trial in HER2 positive breast cancer patients and in the previously reported HER2 positive gastric study. On the top half of the slide, you'll see the data that we've just reviewed. This includes the thirty three percent response rate in the twenty four patients enrolled based on archival HER2 status, the sixty percent response rate in the 10 patients centrally assessed as HER2 positive, and the one hundred percent response rate in the five patients who were also CD47 overexpressing.

24:41 On the bottom half of this slide, you see the data from ASPEN six. This is a randomized Phase II study of Avoricept, Trastuzumab, paclitaxel, and ramucirumab versus the TRP regimen alone. Here you see the response rate climb as we look across the slide at the same subsets. In the ITT, the response rates in patients randomized to the aborapicep arm was forty one percent. Response rate was over forty nine percent in the patients that retained HER2 positive disease. And it was sixty five percent in patients whose tumors also expressed CD47. And recall this was a large Phase II study of one hundred and twenty seven patients. As you see, the data trends here are consistent across these two independent trials of Avorapacep when combined with a HER2 targeted antibody.

25:36 On slide 29, I'm again showing the results of the EVO ZANE study on the top and the ASPEN six HER2 positive gastric study on the bottom. These graphs show the duration of response in the subset of patients who were HER2 positive and CD47 overexpressing in the two independent studies. The duration of response was remarkable in both settings at twenty point two months and twenty five point five months, respectively. On slide 30, the same consistency across the two independent studies is seen with the PFS results in the subset of HER2 positive CD47 high patients. Both studies show remarkably long PFS, especially in light of the later line settings for both indications.

26:29 On the left, we see the median PFS for these patients in the evorpocepzanidatinib study of twenty two point one months, while the median PFS for those without CD47 expression was only three point four months. And then in the gastric study shown on the right, the median PFS was eighteen point four months for the patients in the evorpocep arm, and the hazard ratio in this subset in the randomized trial was 0.39. So these data are really why we're so excited about moving forward with the development Avorpicep in HER2 positive breast cancer. Slide 31 shows our ongoing ASPEN-nine study in the HER2 positive breast cancer setting.

27:15 Like this anadaptinib of Orpicep study population, all of these patients will have had to have had prior in HER2. This a single arm study that will enroll up to a 120 patients and has a primary endpoint of response rate in the subset of patients who overexpress CD forty seven. We're making very good progress with enrollment, and we're very much on track to achieve our stated milestone of having interim top line data from approximately 80 patients by the middle of twenty twenty seven. On slide 32, we show the market opportunity. Ultimately, our aim, of course, is to bring this drug to market. We estimate that there are approximately twenty thousand addressable patients who are HER2 positive and overexpress CD47, representing a 2,000,000,000 to $4,000,000,000 market opportunity in The United States, the five major European markets, and Japan.

28:22 I'm now going to turn for the last few minutes of this talk to our second molecule. Slide 34 shows ALX2004, our EGFR antibody drug conjugate. This is actually a very unique molecule. It was designed by protein engineers and cancer biologists within ALX. EGFR is obviously a very validated target, but it's been very difficult to target eGFR in the past with an antibody drug conjugate. We selected a metuzumab derived eGFR antibody to minimize off tumor skin toxicity and to maximize the therapeutic window. Also, the epitope is distinct from that of FDA approved EGFR antibodies minimizing the likelihood of resistance to prior EGFR antibody treatment.

29:17 The proprietary linker allows for liposomal cleavage of the linker payload like other deroxycan ADCs, but the stability of the linker antibody has been enhanced to minimize systemic payload release. The molecule also contains a proprietary TOPO-one inhibitor payload. It has an antibody drug ratio of eight, and the payload has similar direct cytotoxic potency, but it has enhanced bystander activity compared to dRuxecan. On slide 35, we show the phase one design. This is an ongoing study, and the study is designed for dose escalation, dose exploration, and expansion cohorts.

30:09 The study is limited to patients who have lung cancer, head and neck cancer, colorectal cancer, or esophageal cancer as eGFR expression is higher in these indications. And in this study, we're also making very good progress with enrollment. We are certainly on track to achieve our stated milestone of reporting initial safety data within the second half of two thousand and twenty six. We pub previously publicly released information, that we, began dose escalation at one milligram. We then said we escalated to two milligrams, and then we announced that we had escalated to four milligram per kilogram dose cohort. But as we advance the enrollment and dose escalation in this trial, we are now shifting from providing granular updates to reporting initial safety data in the second half of twenty twenty six.

31:04 And I'll now turn the presentation back to Jason. Thanks, Barb. And also a big thank you to doctor Herbert for joining us today to share her views. At ALX, we're advancing two novel cancer treatments with key near term catalysts that have the potential to be both best in class and first in class in change care. And with this new data today, we have now demonstrated in two studies and two HER two positive cancers that EVO is a very active drug and that a c d forty seven targeted approach can drive transformational benefit to patients. And, again, although not the focus for today, remain as excited about the potential of our eGFR targeted ADC, which is also progressing quite well. We now have a stronger balance sheet to fully execute through key milestones over the next year to two years, and this really sets us up well for for further execution and further catalyst.

31:59 In sum, q one was a strong quarter for us in terms of new data, new leadership within our team, and a new financing. So the message for today is one of building momentum as our conviction in both programs remains high, and we're looking forward to additional updates very soon. With that, I'll turn the call back over to the operator for questions. And again, thanks again for the time this morning. Thank you. We will now be conducting a question and answer And our first question will come from Michael Yee with UBS Securities.

33:03 Hey, guys. Thanks for taking our questions. Congrats on the updates and progress. This is Kyle Yang for Michael Yi from UBS. Two for us. The first question for management. So congrats on the data today. So for your upcoming interim data readout in mid twenty in mid twenty twenty seven from your ongoing phase two Aspen breast study, What would you say is compelling results in terms of ORR and also DOR? And do you plan to put out data on MPFS? And what would be good data for MPFS? The second question for doctor Hurwitz. Could you please help us understand how do you plan to use this drug in the clinical setting if this is approved?

33:56 Do you ex do you expect to test everybody for c d forty seven expression? Thank you. Great. Thanks, Kyle. Appreciate the question. So, yeah, on the first one, and I'll let Barb weigh in as well. I think, you know, we've been very pleased with enrollment to date on our breast study. It's going quite well. Certainly, this data, which we've been able to share just over the last couple months with the investigators has has furthered that, enthusiasm. So I think as Barb, highlighted well in her comments, feel very, good about our timelines and and delivering really meaningful meaningful data mid twenty seven. But, Barb, do you wanna weigh in more on just, you know, what we hope in terms of durability and and PFS at at that time?

34:45 Yeah. Absolutely. Well, as doctor Hurwitz said, most of the available therapies are not producing very good outcomes for patients after INHER2. Much of the data suggests that the response rate may be fifteen percent if you were to receive a trastuzumab chemotherapy treatment alone without evorpicep. So a thirty percent response rate would be doubling of what we would expect to see without the evorpicep. So I think anything north of thirty percent would be a very, very good outcome with a duration of six months plus. As you've seen in the data that we reported previously, one of the things that's so compelling about evorposap is that when we see a response, we see a very good duration of response.

35:44 By middle of twenty twenty seven, I think the duration of response will be pretty preliminary. So I'm expecting that with 80 patients worth of data, that we can assess response rate pretty well. Duration of response may be somewhat truncated, but I would hope to see somewhere in the range of six months, plus with immature data. And and I would think that PFS might be too immature to report, but it really depends on the continued progress. So we'll have to see. Yeah. And doctor Hurwitz, whether you have comments on your expectations for the ASPEN nine data or in particular, the second part of the question about the role of c d forty seven testing in the clinical practice if a vorpicep is able to get to market.

36:44 Yeah. Thank you, Barb. I fully agree with your what you stated about the ASPEN o nine study. I mean, I think seeing anything around 30% objective response rate and and a PFS of six months would be pretty important in patients this heavily pretreated. So I echo your comments. In terms of the additional question regarding how we would use CD47 expression, You know, I think this is something that's really very compelling and interesting. And the ASPEN nine study is gonna allow patients, as Barb stated, with both CD47 low and high tumor expressions that we can validate these data.

37:33 We have to keep in mind it was a small number of patients. But the data were really pretty interesting and compelling. So if if c d forty seven is validated as being a predictive marker for benefit from evorpocept, then I I do think we will be probably seeing it developed as a companion diagnostic. But but it's too too little data at this point to see, you know, to make to make that statement definitively that that's how we'll be doing it using it. I I am you know, I've been treating breast cancer patients for over twenty years, and the data within HER two were were really exciting when we first saw them come out in 2019.

38:21 I feel that same flurry of excitement seeing these data because it's it's pretty tough to treat patients post t d x d now. Their their progression free survival, their their duration of response to the next line of therapy is pretty short. And so these data provide patients a lot of hope. So I'm I'm excited to see the data validated, taking into consideration that it is a small number of patients. Really helpful. Thank you, guys. Thanks, Kyle. And our next question will come from Derek Archila with Wells Fargo. Hey, good morning, and congrats on the update here. Just a few questions from us. I think, first, you alluded in the prepared remarks, but just remind us the population in ASPEN 'nine and then how it compares to some of the patients from the update today.

39:18 That would be helpful. And then just two quick ones. So I think you mentioned the twenty thousand patients c d four seven high post in HER two. So does that assume, you know, greater than twenty percent c d four seven expression? Or I just I just wanna make sure the cutoff is the same. And then with the data here and the proof of concept with the Xanny combo, I guess, you know, how do you think about further developing this? Thank you. Yeah. Sure. Those are great questions. Thanks, Derek. So I think, you know, in terms of the population that we're studying now, you know, it is this population. That that's what I think really really derisks, if you will, this this current study. You know, I think as we walk through today, this is a late line, breast population. A hundred percent of the patients in this cohort had seen prior and HER two.

40:11 You know, on average, it's seen five prior lines of HER two directed therapy, etcetera. So, you know, I think the beauty of this design that we're pursuing now is it's it's effectively the same. So I do think that definitely contributes to our confidence in in this study. Then on the second question, and I can have Barb weigh in on this. You know, I think we we do know and from the literature, we expect that the expression profiles to be will be different across different tumor types. That's certainly what we've seen when we look at breast and gastric. But, again, I think what's so encouraging is that, you know, there's just a lot of room here in terms of choosing a a cutoff, if you will.

40:58 So, Barb, do you wanna speak to that a a little more? Yeah. I think one of the most important things about what we will understand, with data from ASPEN o nine is what's the optimal cut point? Where where on the total membrane, staining, scale, would we see the greatest differential between high response rate in the c d forty seven positive versus c d forty seven low? And it's likely to be a continuum, and we're likely to be able to not see a cliff where it's crystal clear. What we've seen in both the gastric and the breast study, though, is we're seeing about half of patients overexpress CD47.

41:47 At least in our gastric study with a larger sample size, we shared at SITC in the fall of twenty twenty five a variety of different cut points that ranged from forty five to fifty seven percent. Gastric may be different than breast, though. And so with the ZANI data, we have just such a small number of patients. But what we saw in the ZANI trial, again, about fifty percent were CD 47 high. One of the biggest reasons we increased the sample size from 80 to a 100 is just so that we could get more data because this point exactly, what is the cut point? How does it differentiate response rates, and what does it do to the population in terms of potential commercial opportunity balanced against finding the best treatment effect for patients is a really important question.

42:46 So aspin o nine will help us optimize the cut point. My best guess today is it'll be somewhere in the range of fifty, sixty, seventy percent of patients could be c d forty seven overexpressing, but we'll see. What also, of course, are the two slides that doctor Hurwitz showed where the rates are higher in patients who have more advanced disease. They are higher in the cell lines post in HER two, and they are higher in patients who, are HER two positive. So it could even be higher than fifty percent. We'll, you know, we'll learn a lot from the asp one zero nine on that exact question. And I think your last question, Derek, just on on, Zany, you know, a couple comments there. I think one, really pleased with the partnership with Jazz and what we're seeing here, for patients. I think, you know, no question that very strong activity, with this combination.

43:44 You know, the second thing, and I think why it's important to to look back at our mechanism is EVO works in combination with an Fc active antibody, and it was designed, to do so. And and so I think what what's really promising about totality of the data is whether we're combining EVO with TRAS, with XANI, with Rituxan, with an anti c thirty eight like CERCLIZA. You know, we see activity, and I think that's right on mechanism. And so for us, taking the combination of EVO plus TRAZ going forward makes sense. Again, it's the exact same combination that we, utilized in our ASPEN six study, which is a randomized study, as you know. So I do think that gives us, a lot of conviction here going forward.

44:33 Incredibly helpful. Thanks again. Thanks, Derek. Moving next to Allison Brezel with Piper Sandler. Morning, team. This is Ashley on for Ally. Just two questions from us. So just curious to learn what's the latest on the companion diagnostic development. I know you guys have talked about this on previous earnings calls, so just looking for some updated thoughts there. And, also, you know, just based on the data today and this dataset, you know, it looks like the c d 47 biomarker strategy, you know, is being further validated. So does this impact the statistical powering at all for aspen o nine? Sure. Yeah. That's that's a great question. Do you wanna go on the CDX front, Barb?

45:23 Yeah. Sorry, Jason. Yes. The Ventana, laboratory is our partner. We are working right now on developing a companion diagnostic. What we want is by the time we are finishing the full dataset of aspen o nine, as I alluded to earlier, setting a cut point that could then be available for preselection of patients potentially in a phase three trial. That's our base case assumption is that our phase three would be in preselected patients. So we will have an assay available. And then if that phase three study is positive, of course, then we would work with our Ventana partner to not only bring the vorapacept to market but to ensure that the companion diagnostic were then commercially available.

46:24 In terms of statistical powering oh, go ahead. Go ahead, Jason. No. Go ahead, Barbara. I just I mean, to kick that off, I mean, I think, you know, of course, we're not gonna power the study at a 100% ORR, and that's not what we're going to do. And I think you know? But but if you look at the the beauty of a targeted approach, I think it allows and our hope is it'll allow a much more targeted phase three where we can run a tighter registrational study, with assumptions that, you know, I think are reflective of what we've seen, which has been a really strong, you know, spread, if you will, both in terms of ORR as well as DOR and PFS. But, go ahead, Barbara. Know I cut you off there.

47:09 No. No. That's exactly right. I think with a single arm trial, ASPEN o nine, the statistics are really around estimating the point estimate of a response rate and narrowing the confidence intervals with a with a larger sample size. But what o ASPEN o nine does is it allows us potentially greater precision with this larger trial of a 120 patients such that we can then have a lot of confidence walking into a phase three subsequently and really understanding the treatment effect in patients based on their c d forty seven status. Got it. This is really helpful. Thank you.

48:01 Moving next to Lee Wotzek with Banter. Hey. This is Daniel Brondor on for Lee Wotzek. Thank you for taking our questions. We have a couple, one more technical and then one regulatory. We'll start with the technical one. On the poster from ESMO breast, you have the concordance of HER two amplification by ctDNA and FISH. I was just curious how that translates into HER two positivity in IHC. And then on the regulatory front, you mentioned registrational trials a few times in your opening remarks and in the previous response as well. Does that mean you're ruling out a potential accelerated approval based on, ASPEN o nine, or are you keeping optionality here? Thank you.

48:55 Yeah. Maybe I'll have Those are great questions. Thanks. Go ahead. I'm sorry. I should stop doing that. And and, doctor Hurwitz, I'll have you make some comments after I'll address the regulatory one first, give you a chance, but I'll have you talk a little bit to the HER two data that was in the poster. So the regulatory strategy, Jason said it a few minutes ago that we do not have an expectation that we could replicate a 100% response rate. That's that would be fabulous if we could. And if we do, I think, absolutely, we would talk to the health authorities, the US FDA, about an accelerated approval strategy. I just think that that is, such a high bar, and we're also very, very aware that an advantage for patients would be anything north of, say, 30%.

49:55 So we'll just have to wait and see what those response rate what the response rate is in aspen o nine. I think regulatory approvals for single arm trials when you have a combination of two agents, very difficult to get an accelerated approval. It's also true that it's very difficult to get an accelerated approval with retrospective application of a companion diagnostic. We would need at least some additional prospectively selected patients. So there are a lot of regulatory considerations. But I think, you know, at this case, that is not our base case. Our base case is that a phase three trial will be required because the bar is high for accelerated approval, but we'll just have to wait and see what the response rate is. If it's extraordinary, we'll talk about it. If it's somewhere north of thirty percent but less than a 100%, you know, it's gonna be an uphill battle.

50:56 But, obviously, that would benefit patients if we could bring it to market sooner, but we'll wait and see. So maybe I'll flip it back to doctor Hurwitz to talk a little bit about some of this HER two data in the poster. Yeah. Thank you, Barb. The HER two data is actually kind of interesting. There are two aspects. First, there was the difference in the central confirmation of HER two positive disease that was shown in the poster where ten of the patients out of the twenty four were noted to have essentially confirmed HER two positive disease and fourteen were not. And I would just call out that, you know, this is not uncommon. It's been reported in other studies that there's discordance.

51:42 And it may not necessarily mean that there's been HER2 loss that's occurred over time. It may actually be related to artifacts from testing older tissue. It's it's important to keep in mind that in order for patients to enroll in the study, HER two status was based on archival tissue that was read locally. But once they got on the study, the assays that were done were done on fresh biopsy samples obtained at the start of the study from from most patients, and they those were tested centrally. And so the testing changed from local to central and also from archival tissue to fresh tissue after in HER two for the vast majority of subjects.

52:31 So either of those factors, could have contributed to the difference between local HER2 positive results and central positive results. Another point was in the poster in table two, there was some data presented looking at concordance between HER2 amplification status by the central tissue based FISH as well as plasma ctDNA next generation sequencing. And it's it's important to call out that of the, six patients with HER two amplification by FISH, or, excuse me, the seven patients, six of them were also noted to have amplification by ctDNA.

53:21 Just one of the patients there did not, and that may have just been due to the fact that there wasn't enough circulating. There was a low tumor fraction that was below the threshold of expression. But those that were negative centrally by FISH were also negative by ctDNA. And so that's reassuring and provides sort of validation that the central HER2 amplification is correlating well with circulating tumor DNA. We'll go to our next question from Roger Song with Jefferies. Team, congrats on the positive data and excited about the momentum going into ASPEN nine.

54:14 Maybe two from us. So you previously mentioned we're seeing roughly half of HER two positive patients being CD forty seven high. As we're into the early ASPEN o nine screening, is the observation you're seeing consistent with that half of HER two positive patients being CD forty forty seven high? And then, you know, is tissue adequacy and turnaround time any potential gating factor here for enrollment? Thank you. Yeah. Sure. Good good question. So I think on the ASPEN nine front, of course, we're gonna, you know, monitor that closely. And then in terms of a disclosure, you know, we'll we'll weigh it and disclose that, when we get to, the data readout on on 80 patients.

55:04 Obviously, I think it's something that's important, and and, you know, we're able to monitor really quite quickly. So the lag has has not been a concern, and and, of course, I think our team is is is focused on that. But, Barb, do you wanna add anything there? Only that, the aspen o nine study enrolls patients irrespective of c d forty seven. So there is no urgency in terms of the turnaround. You're absolutely right that it would be something that we need to ensure that we work through those processes for a future phase three, assuming that that future phase three requires c d forty seven overexpression for entry. But this study does not, so the urgency is not there.

56:00 But as Jason says, we're not going to disclose prevalence rates or any of the biomarker data until we come out with data in the middle twenty twenty seven. All right. Thank you. I'll go back to the queue. Thanks. Moving next to Sam Slutsky with LifeSci Capital. Hi. This is Oliver McKammon on for Sam Slutsky. Thanks for taking our questions. So in the Phase 1btwo breast cancer study, you defined CD47 high as total membrane staining of 20% or greater. And in the past, you talked about 10% or greater IHC three plus as being a cutoff for CD47 high.

56:49 Can you just discuss the nuances of the two cutoffs used and the selection process? Sure. Thanks, Oliver. Again, I think, Barb hit on this, but we fully anticipated even ahead of this data that the expression profiles would be would be different. There's, of course, a lot of similarities between her two positive tumor types, and so far as typically a drug that works in one will work in the other. That said, I think there will be a difference in in expression, and we're we're seeing that here. And, again, I would just highlight that, you know, if you think about defining a cutoff when you see ORR as high as we're seeing across both of those studies, you know, it suggests there's probably many different right answers, if you will, in terms of the cutoff we could use.

57:46 But, Barb, do you wanna expand on that? Just in terms of total membrane staining and how that's calculated. So the proportion of cells that are one plus or multiplied by one, the proportion of cells that are two plus IHC stain staining intensity would be multiplied by two and so forth. So IHC three, multiply the proportion of cells that are IHC three plus by and then you add those. So it's a cumulative total. So if I were to look at the the threshold for gastric 10% or more of cells being three plus, that would potentially be about a score of 30.

58:35 It may be that different labs and slightly different methods. But to put it in context, it's it's similar, but it's a cut point was a little bit lower in the zanidatinib trial. It was zanidatinib, vorpocept was a very small trial, so we will look again once we have data from aspirin o nine and and optimize that. So it may change. In fact, would and that likely change to much, much for a sample size. But, technically, they're doing it. And we modified the tech bed once we start to work towards development of hanging and diagnose with our partners at Ventana.

59:23 Very helpful. Thank you. Thanks, Oliver. And this now concludes our question and answer session. I would like to turn the floor back over to Jason Letman for closing comments. Great. Thanks, everybody. It's a strong quarter for us. Appreciate all the engagement here today. Both programs, as we mentioned, are on track and and super excited about what we're seeing in both. So, again, appreciate the questions and support. Looking forward to future updates. Enjoy your Friday and your weekend. Thanks so much. Ladies and gentlemen, thank you for your participation. This does conclude today's teleconference. You may disconnect your lines, and have a wonderful day.