678. Galactomannan Is a Biomarker of APX001 (Fosmanogepix) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis

Abstract

BackgroundInvasive pulmonary aspergillosis (IPA) is a serious fungal infection afflicting immunocompromised patients. Galactomannan (GM) detection in biological samples using the Platelia ELISA has been shown to predict therapy response by azoles, and polyenes. We previously reported on the activity of APX001 (fosmanogepix) in treating murine IPA. Here, we investigated the potential use of GM as a biomarker of APX001 efficacy in an immunosuppressed murine model of IPA.MethodsICR mice (n = 8/group) were immunosuppressed with cyclophosphamide and cortisone acetate on days −2, and +3, relative to infection with Aspergillus fumigatus via inhalation. Treatment with placebo (diluent control), APX001 (104 mg/kg, PO, a human equivalent dose), or posaconazole (POSA, 30 mg/kg, BID [equivalent to 6× the humanized dose]) began 16-hour post-infection and continued daily. To extend the half-life of APX001, mice were administered 50 mg/kg of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) 2 hours prior to APX001 administration. Mice were sacrificed 48-, 72-, or 96-hour post-infection and their lungs, bronchoalveolar lavage (BAL) and sera were collected. Lung fungal burden was determined by conidial equivalent (CE) using qPCR, while GM was determined using the Platelia ELISA.ResultsCompared with placebo, APX001 or POSA treatment resulted in a gradual decrease in tissue fungal burden over time with APX001 or POSA showing significant reduction as early as 96 and 72 hours, respectively (P < 0.005). Although the super-therapeutic dose of POSA resulted in faster reduction in lung fungal burden after 72 hours, both drugs resulted in similar reduction (~6–7 log) in lung CE vs. placebo after 96 hours. Changes in GM levels in BAL or serum samples mirrored reductions in lung CFU with significant decrease seen after 96 hours or 72 hours for APX001 or POSA, respectively, vs. placebo (P < 0.02) (figure).ConclusionA human equivalent dose of APX001 and a super humanized dose of POSA resulted in a time-dependent reduction of lung fungal burden and GM levels when compared with placebo. These results show that GM can be used as a biomarker of APX001 efficacy in immunosuppressed mice. Disclosures All authors: No reported disclosures.