Evorpacept (ALX148), a CD47-Blocking Myeloid Checkpoint Inhibitor, in Combination with Azacitidine: A Phase 1 / 2 Study in Patients with Myelodysplastic Syndrome (ASPEN-02)

▪ Background: Evorpacept is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies, such as azacitidine (AZA), with minimal additional toxicity. Here, we present results from the phase 1 part of the ASPEN-02 study evaluating the safety and tolerability of evorpacept administered in combination with AZA in subjects with myelodysplastic syndrome (MDS). Methods: ASPEN-02 is a phase 1/2 open-label, multicenter study designed to evaluate the safety and tolerability and establish the recommended phase 2 dose (RP2D) of intravenous evorpacept in combination with AZA in phase 1 and to evaluate the efficacy of the combination of evorpacept + AZA compared to AZA alone in subjects with previously untreated higher risk MDS in phase 2. Adult subjects with newly diagnosed (ND) higher risk (IPSS-R>3.5) or relapsed/refractory (R/R) MDS were enrolled into phase 1 cohorts receiving escalating doses of evorpacept (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m 2 IV/SC x 7d) in a 28-day treatment cycle. The primary phase 1 endpoint is the frequency of first cycle dose-limiting toxicities (DLTs). The study is open for enrollment (NCT: NCT0441751). Results: As of July 15, 2021, 13 subjects were treated in phase 1 at evorpacept doses of 20 mg/kg Q2W (N=3), 30 mg/kg Q2W (N=3), and 60 mg/kg Q4W (N=7). Of the 7 ND subjects, 4 had therapy-related MDS, and 5 had TP53 mutation with complex cytogenetics. Of the 6 R/R subjects, all had received at least 1 prior hypomethylating agent (HMA)-based regimen. Median age of the phase 1 population was 74 years (range 56-82), and baseline ECOG scores were 0 (n=4) or 1 (n=9). No DLTs were observed in any cohort and a maximum tolerated dose (MTD) was not reached. All subjects experienced an adverse event. Treatment-related AEs (TRAEs) observed in >1 subject included constipation and infusion related reaction (n=3 each, 23%), and nausea and vomiting (n=2 each, 15%). Grade 3 or higher AEs of any causality occurring in >1 subject included febrile neutropenia (n=4; 31%), pneumonia (n=3, 23%), and anemia and thrombocytopenia (n=2 each, 15%). There was one Grade 3 or higher TRAE of transient neutropenia reported. There were no evorpacept-related serious adverse events (SAEs), no deaths on study, and no patients discontinued treatment due to an AE. Preliminary PK and PD data indicated dose-proportional pharmacokinetics consis