Summary of ALX Oncology Holdings FY Conference Call Company Overview - **Company**: ALX Oncology Holdings (NasdaqGS:ALXO) - **Founded**: 2015 - **Lead Program**: Evorpacept, a CD47 blocker with a unique mechanism of action - **New Program**: ALX 2004, an EGFR-targeted antibody-drug conjugate (ADC) currently in clinical trials [2][4] Core Points and Arguments CD47 Mechanism and Evorpacept - Evorpacept is designed to block the "don't eat me" signal from CD47, which is crucial for immune evasion by cancer cells [2][3] - The company claims to be the only CD47 blocker in development with a dead Fc, allowing for full blockade of the "eat me" signal [3] - The approach has been validated through four clinical studies, demonstrating its potential effectiveness [3] Clinical Trials and Results - **Gastric Cancer Trial**: - Phase 2 trial showed a 41% overall response rate (ORR) for evorpacept plus TRP compared to 26% in the control arm [9] - In patients retaining HER2 positivity, the response rate was 49% versus 25% in the control arm, with a median duration of response of 15.7 months [11] - The FDA did not grant accelerated approval due to the availability of Enhertu, leading the company to refocus on breast cancer [9][11] - **Breast Cancer Studies**: - The company is advancing a study combining evorpacept with Herceptin and chemotherapy, with interim data expected in Q3 2026 [16][17] - The study aims to evaluate efficacy based on CD47 expression levels [16] Biomarker Development - The company is developing a companion diagnostic to identify patients with high CD47 expression, which is crucial for treatment selection [15][16] - CD47 is recognized as a poor prognostic marker across various cancers, but its predictive use for treatment decision-making is still under development [15] ALX 2004 Development - ALX 2004 is an EGFR-targeting ADC developed in-house, with a focus on optimizing linker payloads and epitope selection to address past challenges in EGFR-targeted therapies [22][23] - The phase 1 trial is being conducted in multiple solid tumors, with initial safety data expected in the first half of 2026 [24][25] Competitive Landscape - The company believes it has a unique asset in ALX 2004, with a distinct epitope and linker payload compared to existing EGFR-targeted ADCs [25][26] - There is competition from various ADCs, particularly from China, but ALX Oncology claims to be first in treating U.S. patients with this specific approach [26] Financial Position and Future Outlook - The company has sufficient cash to support operations through Q1 2027, with several important milestones expected in the next 12 months [27] - Key upcoming events include safety data for ALX 2004 and interim data for the breast cancer study involving evorpacept [27] Additional Important Points - The company is exploring partnerships, particularly in Asia, to expand its market reach for gastric cancer treatments [14] - The strategic shift towards focusing on anti-cancer antibodies for evorpacept combinations reflects a response to clinical learnings over the past decade [5][6]

ALX2004 Program Overview - ALX2004 is an EGFR-targeted ADC with a DAR of 8, utilizing a topoisomerase I inhibitor (Top1i) payload, with IND cleared in April 2025[13, 98] - ALX2004 is designed to maximize the therapeutic window and overcome toxicity challenges, with a focus on EGFR-expressing solid tumors[14, 99] - ALX2004's Phase 1a dose escalation trial is planned to start in mid-2025, targeting NSCLC, CRC, HNSCC, and ESCC[14, 99] ALX2004 Design and Preclinical Data - ALX2004's EGFR antibody binding epitope is selected to minimize off-tumor skin toxicities, and its affinity is tuned to maximize the therapeutic window[20] - The linker-payload is designed for lysosomal cleavage, similar to deruxtecan ADCs, with improved linker-antibody stability to minimize off-tumor payload release[20] - Preclinical data demonstrates dose-dependent activity across a range of tumors and EGFR expression levels, with a differentiated safety profile in NHP toxicity studies, showing no EGFR-related skin toxicity at clinically relevant doses[24] - In preclinical studies, ALX2004 demonstrated superior anti-tumor activity compared to DXd ADCs in CDX mouse models, showing improved bystander effect[47, 49] Clinical Development Plan - The Phase 1 trial is rationally designed around tumor types with established sensitivity to EGFR-directed therapies, including HNSCC, CRC, NSCLC, and ESCC, representing over 250,000 patient prevalence in the US[87] - The Phase 1 clinical development plan includes dose escalation (Phase 1a, up to 40 patients), dose exploration (up to 50 patients), and dose expansion (Phase 1b, up to 80 patients)[89, 90, 91] - ALX Oncology anticipates initial safety data for ALX2004 in EGFR-expressing solid tumors in the first half of 2026[101]