ALX Oncology Holdings Inc.

Welcome to the ALX Oncology Third Quarter 2025 Financial Results Conference Call-In Webcast. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. Please note this conference is being recorded. I would now like to turn the conference over to your host, Jason Letman. Please go ahead, sir.

Thanks everyone, and welcome to our Q3 2025 results. I appreciate everybody spending some time with us this morning, and I'm looking forward to this update. On slide two here, before we start our presentation of housekeeping, here are our forward-looking statements for your review. So on the next slide, slide three here, here is the agenda and our plan for today. We're going to be providing an update on our key accomplishments in the third quarter of 2025. Most notably, we are very excited to share with you the data set that will be presented at CITSE this weekend from a pre-planned analysis of our Aspen 06 trial that showed CD47 expression as a key predictive biomarker for increasing durable clinical response with avorpacept and HER2-positive gastric cancer patients. So our goals for today are most importantly to share these detailed results with you as we believe this data set now clearly validates the role of CD47 in HER2-positive cancers. We will then give you a sense of how this data now impacts our development strategy for Avorpicep going forward. We will also be providing an update on our novel ALEKS 2004 EGFR-targeted ADC, which is now in the clinic. Today, we are also excited to be joined by Dr. Peter Schmid from Barts Cancer Institute in the UK, who is a key opinion leader in breast cancer and investigator in our Avorpacept Phase 2 breast cancer study. He will be presenting his views on Avorpacept data and its potential within the current treatment paradigm for HER2-positive metastatic breast cancer. Then our CMO, Barb Quinkey, will provide an update on our novel EGFR-targeted ADC, ALX2004, which is currently dosing patients in our Phase I trial. Now on slide four, in the third quarter, we made significant advances in both the Vorbicept and ALX2004 clinical programs. We again are excited to present the full data at CITSE that is demonstrating the potential of CD47 expression as a predictive biomarker, and highlight a clear opportunity to now identify patients who are most likely to achieve the greatest benefit from EVO. As Barb will present in detail in her clinical section in this analysis, we saw that patients with high CD47 expression derived the greatest benefit across all key efficacy markers, response rates, duration of response, median PFS, and overall survival from the Borpacept versus those with low expression. The data is very clear, as the magnitude of benefit across many of these metrics was double or even triple those observed in the control arm, and also clearly compare very favorably with the large benchmark studies in second-line gastric cancer. Most importantly, these results support the potential to pursue a targeted oncology approach to additional tumor types with EVO. And given the broad overexpression of CD47 in both solid tumors and heme malignancies, it gives us a real opportunity to really focus EVO now as a targeted IO therapy. Our phase two clinical trial of breast cancer, which is designed to pursue a CD47 and HER2 biomarker-driven strategy based on this strong data, is on track to dose its first patient this quarter. And as we've discussed, EVO has the potential to represent the first and only option for metastatic breast cancer patients who overexpress CD47 which we know can lead to worse outcomes and a poor prognosis for these patients. And with our second pipeline product, our novel EGFR-targeted antibody, ALX2004, which is a highly differentiated ADC, we presented preclinical data and design of our Phase I trial at the TRIPLE Conference a few weeks ago. We're excited to announce today that we are currently enrolling patients in the second dose cohort, They're rapidly clearing the first dose cohort in this phase one trial. Turning to our financials quickly, we reported a total cash balance of $67 million, and that cash is expected to provide us runway into the first quarter of 2027, which positions us to achieve the value-enhancing data milestones for both ALX 2004 and Avorpacept that we have coming next year. Now, turning to slide five, it has been very well established that CD47 is widely overexpressed across almost every type of cancer. And it is also clear that CD47 overexpression matters, as it is clearly a negative biomarker for patients. So when you look at research in CD47 over the last decade plus, it is a very strong foundation that CD47 is clearly a negative prognostic biomarker. And what you can see here is a meta-analysis of 38 cohorts across 17 publications, which includes over 7,000 patients. And there really is no question that CD47 is clearly associated with shorter survival and worse outcomes. And you can see on the right the wide range of tumor types where this has been established. Now, turning to slide six, and as a reminder that during our Q2 call just a few months ago in August, we presented the top-line data which support that CD47 overexpression is a clear predictive biomarker for response with avorbicept in HER2-positive gastric patients. In this analysis, patients with both confirmed HER2 positivity and CD47 high expression had a dramatic response to avorbicept as compared to those in the control group who did not have EVO. And as you can see here on the IPT population, we saw a strong response of a 41% ORR in the EVO arm versus 27% ORR in the control arm. And if you look at the data now in patients that clearly have CD47 high expression, there's a magnitude of benefit for those patients where we had an ORR of 65% in the treatment arm versus 26% in control with a nominal p-value of less than 0.05. Now, as you can see on slide seven, and what we're very excited to share with you now and at CITSE later today, this strong ORR benefit with Avorpacept in combination with TRP and CD47 high patients was also reflected and translated well to DOR, EFS, as well as survival, as it's clear that patients who overexpress CD47 and retain HER2 expression is driving the effect here. This is very important as this clearly validates EVO's dual mechanism of action. And again, this is a second-line plus gastric population, which has historically been a very tough cancer to treat. So in addition to the ORR benefit, which had a delta of almost 40% versus control, the median duration of response here for those patients is over two years, which is more than triple the control. The median PFS was over 18 months in the EVO percept arm versus just seven months in control with an impressive hazard ratio of 0.39. And then we were also pleased to see these gains further translate to a benefit to overall survival where we saw a median OS of 17 months with Evo versus about 10 months in Control, and also a strong hazard ratio of 0.63. Barb will walk through this data in more detail, and the full data set will be shared at CITSE here soon. What is clear is that this data shows the potential for Ivorpacept to drive really substantial benefit for these patients with high CD47 expression. On the next slide, this just shows the focus set of milestones that we're driving to now. In summary, we're laser focused on these two programs. First, driving Ivorpacept into Aspen Breast, which is our study investigating patients posted HER2 And again, focused on CD47 high and understanding the impact of that biomarker. We continue to execute well against the milestones that we've communicated in the past and are anticipating first patient end Q4 of 2025 with interim data expected Q3 2026. ALX 2004 also remains on track and continues to proceed very well. We dosed our first patient in August of 2025, and we continue to expect initial safety data first half of 2026. Turning to the next slide, and in summary, before I hand the call over to Barb, we had a strong quarter, both in terms of execution, continued tight discipline around our capital, and are excited about the key value catalyst for ALX in 2026. And as you can see here on slide nine, this is a snapshot of our current clinical pipeline. As we have communicated previously, we are pursuing a focused development strategy for EVO in combination with anti-cancer antibodies, given the consistent proof of concept that we have seen in various clinical studies with different monoclonal antibodies. And this data here today further builds on that. In addition to our HER2-positive breast cancer program with a CD47 biomarker-driven approach, ALEKS 2004, again, our EGFR-targeted ADC, continues to progress well, and we are also very excited about our partner program with Sanofi, Sarqueza, and multiple myeloma, which is now in dose optimization phase. So next, we'll turn this over to Barb, who will take over and provide more details on the Avorpiceps CD47 biomarker data presentation coming here at CITSE. Barb?

Thank you, Jason. I will start by describing Avorpiceps mechanism of action. CD47 is broadly overexpressed on cancer cells as a means of evading the immune detection, and it does so by sending a don't eat me signal. Avorpicep is a fusion protein, and it's designed to block that signal. Avorpicep's FC region is engineered to be inactive, and since it's particularly effective when given in combination with an anti-cancer antibody, such as Herceptin, The active FC domain on the anti-cancer antibody can then trigger very effective phagocytosis, which otherwise would have been suppressed by the CD47 signal. Slide 12 shows that the Ahorciceps approach to blocking CD47 is different from the conventional approach pursued by other CD47-targeted agents. While CD47 is overexpressed in cancer cells, It is also expressed in healthy cells, such as red blood cells. The conventional approach to block CD47 with an antibody that then also binds to macrophages through an active FC has caused significant toxicities in some patients, and thus, this approach has largely failed. In contrast, the Avorbicep approach using an inactive FC spares normal cells, and our safety database in more than 750 avorpicep-treated patients confirms the safety of this approach. Slide 13 shows the design of the Aspen-06 gastric study that Jason has introduced earlier. We enrolled 127 second-line or third-line HER2-positive gastric cancer patients, all of whom had received prior HER2-directed therapy. Patients were randomized to avorpicep trastuzumab, ramicerumab, and paclitaxel, or the TRP alone. The primary endpoint was objective response. Importantly, because there can be loss of HER2 expression following prior HER2-directed therapy, we wanted to look beyond the HER2 status as diagnosed on archival tissue. Based on the known mechanism of action for avorbicep, our drug is not going to work as effectively if HER2 is not overexpressed on the cancer cell surface. To this end, cpDNA was obtained at baseline in all patients, and in addition, 48 patients underwent a biopsy, either at study entry or at some point following their prior HER2-directed therapy. In total, 95 patients, or 75% of the enrolled population, were confirmed as having retained HER2 positivity by either the ctDNA or on fresh biopsy. 90 of these 95 patients were valuable for CD47 expression in tumor cells using either archival tissue or where available fresh biopsy samples. High CD47 expression based on a cut point of IHC3 plus staining in at least 10% of the tumor cells was present in 48% of these 90 patients. The expanded results of this pre-planned exploratory analysis of efficacy by CD47 expression level in patients who retained HER2 positivity is the focus of the data that I will review with you today. Slide 14 shows the objective response rates in key subsets. As we've previously reported, In the 95 patients who retained HER2 positivity, we see a robust response rate of 48.9% for the avorpacept CRP arm versus 25% in the control arm. And in the subgroup by CD47 expression level, avorpacept produced a response rate of 65% compared to 26% in the control arm. amongst patients with the high CD47 expression levels. The response rate in the control arm was consistent across CD47 expression levels, and lower than that in the avorpicep arm in both the CD47 high and CD47 low groups. Moving to slide 15, I'm now displaying the duration of response in these same subgroups. Again, we see the potential of CD47 expression as a powerful predictive biomarker for avaricep benefit. The duration of response in all HER2 positive patients, irrespective of CD47 expression, was 15.7 months for avaricep plus TRP compared to 9.1 months for responders in the control arm. In the CD47 high group, the duration of response was three times longer for patients in the avorpacept trastuzumab RP arm compared to the control, with a median duration of response of 25.5 months versus 8.4 months. In the CD47 low group, avorpacept TRP had a median duration of response of 11.2 months compared to 12 months for TRP. In slide 16, we're now showing the progression-free survival in patients with confirmed HER2-positivity and high CD47 expression. The hazard ratio is 0.39, with a median TFS of 18.4 months for the Avorapaceptra's Tudumab RP arm, which is more than double the seven-month scheme in the TRP alone arm, again suggesting the potential for CD47 expression. as a powerful predictive biomarker for avorpicep benefits. Slide 17 shows a similar pattern of longer survival observed in the HER2-positive CD47-high avorpicep arm. Median overall survival was 17 months compared to 9.9 months for the control arm with a hazard ratio of 0.63. All of these data being presented at the CITSECON conference this week are based on mature follow-up. The median follow-up for survival, for example, was 25 months. Slide 18 shows some of the various cut points that we examined for CD47 expression based on the range and strength of IHC testing. As shown here, we looked at the median. We looked at medium or high-intensity staining defined as IHC 2-plus and 3-plus in at least 10% and in at least 25% of tumor cells. And we also looked at high intensity staining, or IHC3+, in tumor samples with 5% or more, or 10% or more of cancer cells expressing that high intensity staining. The prevalence of CD47 high across these ranges from 40% to nearly 60% of HER2 positive patients, depending on the cut point. The key takeaway from this slide is that we see consistent improvements in response rates, PFS, and OS in the Avorpacept treatment arm irrespective of the cut point for CD47 expression. On slide 19, I'm showing a cross-trial comparison of our Avorpacept efficacy data in patients with retained HER2 positivity and high CD47 expression relative to benchmark trial data in HER2-positive gastric cancer. With the usual cross-trial comparison caveats in mind, Evorpa's data directionally compares very favorably to recent in HER2 data from the DESTINY gastric O4 study in the second-line setting. In that trial of nearly 500 patients published earlier this year in the New England Journal of Medicine, Those patients required confirmation of HER2 status by fresh biopsy following a trastuzumab-containing regimen, and they randomized these patients to in HER2 or to RP as a control arm. As effective as the HER2 was in the second-line setting in that trial, our second- and third-line avorpacept data generated in patients with high CD47 expression, a known negative prognostic biomarker, appear much better. Turning our attention now from gastric cancer to HER2-positive breast cancer, slide 20 introduces a phase 1B2 trial in HER2-positive breast cancer patients conducted by Jazz that evaluated the safety and efficacy of avorpacept plus the antidatinib in patients who progressed on prior HER2-directed therapy. These patients were heavily pretreated, with a median of six higher lines of therapy. In nine patients confirmed to retain HER2 status by central assessment, the response rate was 56%. The median duration of response for that group ranged from 5.5 months to nearly 26 months, with the median not reached, and the median PFS being 7.4 months. These data compare favorably to benchmark data including, for example, the SOFIA trial, a predominantly second- and third-line HER2-positive breast cancer trial, which produced a response rate of 22% per margin to Tuximab. Moving to slide 21, we've now demonstrated in these two studies the potential of Avorkasap to engage the innate immune response. Validating the mechanism of action of the Vorapacept given in combination with anti-cancer directed antibodies in both HER2-positive breast cancer and in HER2-positive gastric cancer. This gives us strong conviction that Vorapacept's potential and its path forward in the HER2-positive breast cancer setting, which we'll talk about next. Slide 22 describes briefly the opportunity that we see for a Vorapacept in breast cancer, which now has a high probability of success, having been de-risked by the two positive data sets in two different HER2-positive settings. A CD47 HER2-positive biomarker-driven approach with Vorpacept enables a highly targeted strategy, potentially addressing the high unmet medical need in the evolving breast cancer landscape, which includes patients who have now progressed on in HER2. It is now my distinct pleasure to introduce Dr. Peter Schmidt, a professor of cancer medicine and center lead at the Center of Experimental Cancer Medicine at Cards Cancer Institute. He's a well-known global lead investigator on multiple ongoing phase three trials in metastatic and localized breast cancer. Just as two examples of trials with immunotherapy agents, he's a global lead investigator on the Pembrolizumab Keynote 522 study and the atezolizumab and PASSION 130 study. With that, I turn this over to you, Peter.