726. APX001 (Fosmanogepix) Is Effective in an Immunosuppressed Mouse Model of Rhizopus oryzae Infection

BACKGROUND: Mucormycosis is a life-threatening infection that predominantly occurs in immunocompromised hosts. The antifungal APX001A (manogepix) inhibits Gwt1, an enzyme required for the conserved glycosylphosphatidyl inositol (GPI) post-translational modification in eukaryotes. We previously reported the activity of APX001 (fosmanogepix, the prodrug of APX001A) against Rhizopus delemar (minimum effective concentration [MEC] = 0.25 µg/mL). Here we assessed the activity against R. oryzae, which has an elevated MEC value. METHODS: R. oryzae 99–892 MIC and MEC values were 0.125 µg/mL and 4.0 µg/mL for isavuconazole (ISAV) and APX001A, respectively. ICR mice were immunosuppressed with cyclophosphamide (200 mg/kg) and cortisone acetate (500 mg/kg) on Days -2, +3, and +8 relative to intratracheal infection with 2.5 × 10(5) cells of R. oryzae 99–892. For survival studies, treatment with 104 mg/kg APX001 was compared with ISAV (110 mg/kg TID). Oral treatment started on Day +1 through Day +7, relative to infection for survival studies, and through Day +4 for tissue fungal burden studies (assessed by conidial equivalent [CE] using qPCR). Placebo mice received vehicle control. To extend the half-life of APX001, mice were administered 50 mg/kg of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) 2 h prior to APX001 administration. RESULTS: APX001 and ISAV equally prolonged median survival time of mice (n = 20) vs. placebo (12 and 14 days for APX001 and ISAV, respectively, vs. 8 days for placebo). Furthermore, APX001 and ISAV treatment both resulted in 30% 21-day survival vs. 0% survival of placebo mice (P < 0.05 by log-rank test). Both drug treatments resulted in ~1.5 log(10) reduction in lung and brain CE vs. placebo-treated mice (n = 10, P < 0.005 by Wilcoxon rank-sum test). CONCLUSION: Despite a higher MEC value, APX001 showed significant efficacy against R. oryzae that was as protective as ISAV in immunosuppressed mice. Given the previously reported activity of APX001 against a strain of R. delemar with a lower MEC value,APX001 has now been shown to be efficacious against both species of Rhizopus, which together are responsible for ~60–70% of isolates causing lethal mucormycosis. Thus, continued investigation of APX001 against mucormycosis is warranted. DISCLOSURES: All authors: No reported disclosures.