1614. Gwt1 Inhibitor, APX2104, Protects Against Invasive Aspergillosis in Neutropenic Mouse Model

Abstract

Background Aspergillus fumigatus is the leading cause of invasive aspergillosis (IA), a lethal infection among immunocompromised patients. Guideline-recommended antifungal therapy against IA is a triazole antifungal, with other secondary options including an echinocandin and amphotericin B. Concerns about drug-host toxicity and antifungal resistance have been globally reported, so new, safe, and effective therapeutics are imperative.Methods In vitro, CLSI standards were upheld as we tested APX2041, voriconazole, caspofungin, and amphotericin B against various A. fumigatus strains. In vivo we assessed toxicity and efficacy of APX2104 in immunocompromised mice respectively. Neutropenia was induced with 150 mg/kg of cyclophosphamide on days -2/+3 and 250 mg/kg of cortisone acetate on days -1/+6. Immunocompromised mice were infected in an inhalation chamber via 12 mL of aerosolized spores of A. fumigatus CEA10 at a concentration of 1x109 spores/mL (Day 0). Treatment started day +1 and ended day +7.Results In vitro, APX2041, the active-form of APX2104, has over a 16-fold lower minimum effective concentration (MEC) when compared to voriconazole, caspofungin, and amphotericin B against various A. fumigatus strains, including echinocandin- and azole-resistant strains. In vivo, given preliminary pharmacokinetic data, APX2104 was tested in non-infected immunocompromised mice at 60 mg/kg and 78 mg/kg once per day (QD). Deaths due to toxicity were seen only at a dose of 78 mg/kg, so 60 mg/kg was set as a safe dose for our in vivo efficacy studies. In IA-challenged neutropenic mice, treatment with either posaconazole (20 mg/kg BID) or APX2104 (60 mg/kg QD) equally prolonged survival in 14 of 15 (93%) mice 14 days post-infection (p= 0.985). Untreatment control yielded a survival of 3 of 15 (20%) 14 days post-infection (p= < 0.001). Consistent with our survival studies, H&E and GMS histological samples also demonstrated that APX2104 treatment decreased fungal burden within the lungs of neutropenic mice when compared to the untreated group.ConclusionFuture studies will test the efficacy of APX2104 and posaconazole against azole antifungal resistant strains in vivo, as our preliminary findings suggest that APX2104 is a plausible solution to cure IA disease and combat antifungal resistance.Disclosures All Authors: No reported disclosures