1954. In vivo Efficacy of Delayed Therapy with the Novel Inositol Acyltransferase Inhibitor Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

Abstract

Background Candida auris is an emerging pathogen associated with antifungal resistance and high mortality. The novel antifungal manogepix (APX001A) prevents glycosylphosphatidylinositol-anchored protein maturation through inhibition of the inositol acyltransferase Gwt1 enzyme, and has demonstrated in vitro and in vivo activity against numerous pathogenic fungi, including C. auris. We evaluated the efficacy of the prodrug fosmanogepix (APX001) following delayed initiation of therapy in a murine model of C. auris invasive candidiasis.MethodsNeutropenic outbred mice (10 per cohort) were inoculated intravenously with C. auris (minimum inhibitory concentrations [MICs]: manogepix 0.03 mg/mL, fluconazole >64 mg/mL, caspofungin 0.25 mg/mL).Treatment with placebo, fosmanogepix (104 or 130 mg/kg by intraperitoneal injection [IP] three times daily, or 260 mg/kg IP twice daily), fluconazole (20 mg/kg/day orally), or caspofungin (10 mg/kg/day IP) began 1 day later and continued for 7 days. Mice were followed post therapy until day 21 to assess survival. Kidneys and brains were collected on day 8, on the days that mice succumbed to infection, or on day 21. Fungal burden was assessed by colony-forming units (CFU).ResultsSurvival was significantly improved at each dose level of fosmanogepix (median >21 days; 90–100%) and high dose caspofungin (>21 days; 90%) compared with placebo (5 days; 10%; P < 0.0001). On day 8 post-inoculation, kidney and brain fungal burdens were significantly reduced in mice treated with fosmanogepix 260 mg/kg BID compared with placebo and in kidneys of mice treated with caspofungin (Table 1). In the survival arm, fungal burden in kidneys and brains was significantly lower at each dose level of fosmanogepix and with high dose caspofungin compared with placebo. In contrast, no improvements in survival or reductions in fungal burden were observed with fluconazole.ConclusionFosmanogepix demonstrated potent in vivo activity against invasive candidiasis caused by C. auris even with delayed initiation of treatment. Improvements in both survival and reductions in fungal burden within the kidneys and brains were observed. These data demonstrate the potential utility of fosmanogepix against C. auris infections. Disclosures All Authors: No reported Disclosures.